Conditions: Wilson Disease
Keywords: Wilson Disease ALXN1840 Copper
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 214
Healthy volunteers: no

Brief summary:
The study will evaluate the efficacy and safety of ALXN1840 (formerly called WTX101) administered for 48 weeks compared to standard of care (SoC) in Wilson Disease (WD) participants aged 12 and older in the Primary Evaluation Period. In addition, efficacy and safety will be evaluated during an optional 60-month Extension Period.

Detailed description:
The study consists of 2 cohorts. Cohort 1: Participants who have received SoC therapy for \> 28 days and Cohort 2: Participants who are treatment-naïve or who have received SoC therapy for ≤ 28 days.

All enrolled participants were randomized by cohort in a 2:1 ratio to treatment with ALXN1840 or SoC (either as continued therapy in Cohort 1 or as continued or initial therapy in Cohort 2).

Arms:
arm 1: ALXN1840 was administered orally for 48 weeks at doses ranging from 15 milligrams (mg) every other day (QOD) up to a titrated dose of 60 mg daily.

Participants who completed the Primary Evaluation Period had the option to participate in the up to 60-month Extension Period. arm 2: SoC medication was administered for 48 weeks. Participants who completed the Primary Evaluation Period had the option to participate in the up to 60-month Extension Period.

Interventions: intervention 1: ALXN1840 intervention 2: SoC Therapy
Intervention descriptions: intervention 1: ALXN1840 administered orally in 15 mg tablets intervention 2: Depending on the site/region, participants randomized to receive SoC treatment will receive trientine, penicillamine, Zinc, or a combination of these medicines, administered according to standard regimens.

Protocol document:
Prot_000.pdf: 
Protocol Amendment 3 (Global) 
WTX101-301 
27 Apr 2022 
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Alexion Confidential 
TITLE PAGE 
Protocol Title: 
A PHASE 3, RANDOMIZED, RATER-BLINDED, MULTI-CENTER STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF ALXN1840 ADMINISTERED FOR 
48 WEEKS VERSUS STANDARD OF CARE IN PATIENTS WITH WILSON DISEASE 
AGED 12 YEARS AND OLDER WITH AN EXTENSION PERIOD OF UP TO 
60 MONTHS 
Protocol Number: WTX101-301 
Amendment Number: 3 (Global) 
Compound Number: ALXN1840 (formerly WTX101) 
Short Title: 
Multicenter Study of Efficacy and Safety of ALXN1840 versus Standard of Care in Patients with 
Wilson Disease Aged 12 Years and Older  
Sponsor Name: 
Alexion Pharmaceuticals, Inc. 
Sponsor Address:  
121 Seaport Blvd 
Boston, MA 02210 
USA 
Regulatory Agency Identifying Number(s): 
EudraCT Number: 2017‐004135‐36 
IND Number: 119006 
Approval Date:  
Original Protocol 
07 Nov 2017 
Amendment 1 
17 Jan 2019 
Amendment 1.1 (Japan) 
25 Mar 2019 
Amendment 1.2 (Netherlands) 
22 May 2019 
Amendment 1.3 (Germany) 
17 May 2019 
Amendment 1.4 (Sweden) 
21 May 2019 
Amendment 1.5 (Germany) 
10 Jul 2019 
Amendment 1.6 (Austria) 
30 Apr 2020 
Amendment 2 (Global) 
25 Mar 2021 
Amendment 2.1 (UK) 
16 Apr 2021 
Amendment 3 (Global) 
27 Apr 2022 
NCT #:  NCT03403205


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Sponsor Signatory:
Date
Medical Monitor Name and Contact Information can be found in the Study Contact List
		



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INVESTIGATOR’S AGREEMENT 
 
I have read the Study WTX101-301 protocol amendment 3 and agree to conduct the study in 
accordance with this protocol, all applicable government regulations, the principles of the ICH 
E6 Guidelines for GCP, and the principles of the World Medical Association Declaration of 
Helsinki. I also agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.  
 
 
 
 
____________________________________ 
Printed Name of Investigator 
 
_____________________________________ 
Signature of Investigator 
 
_______________ 
Date 
 
 
 


Protocol Amendment 3 (Global) 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Amendment 3 (Global), 27 Apr 2022 
This amendment is considered to substantially impact the conduct of the study 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: 
The main reason for this amendment is to add the requirement for Alexion approval prior to 
increasing the dose of ALXN1840. Administrative Letters since approval of the previous 
amendment have also been incorporated. Changes from protocol amendment 2 are summarized 
in the table below. 
Section # and Name 
Description of Change 
Brief Rationale and/or clarifications 
Section 1.2, Schedule of 
Activities, Table 1 
• Collection of Wilson disease 
medication history deleted on Day 1. 
 
• Wilson disease medication history 
collected at Screening so not 
needed at Day 1 as well. 
• 
Administer/dispense ALXN1840 
added at Week 48 only for patients 
continuing in the extension period. 
• To align with current operating 
procedures of this study. 
Section 1.2, Schedule of 
Activities, Table 2 
• Plasma/serum PK/PD, Biomarkers, and 
Biobank samples added at Extension 
Period Week 264 and Early 
Termination 
• To align with current operating 
procedures of this study.  
• Non-verbal Stroop test added 
(Administrative Letter 10.1). 
• The non-verbal Stroop test was 
included in the original protocol 
and inadvertently deleted in 
Amendment 2. 
Section 1.2, Schedule of 
Activities, Table 3 
• Footnote added to Day 1 24-hour urine, 
transient elastography, and BPRS: 
assessments will be done only for 
patients from Study WTX101-201. 
• CGI, EQ-5D, and TSQM-9 added to 
Extension Period Weeks 168 and 192. 
To align with current operating 
procedures of this study. 
Section 4.3.1, 
ALXN1840; Section 
6.2.3.2 Dose Modification 
ALXN1840 
Addition of text to clarify that Alexion 
approval is needed to increase the dose of 
ALXN1840.  
To enhance Alexion oversight of dose 
escalations. 
Section 5.1 Inclusion 
criteria 
Inclusion criterion 1 for diagnosis of 
Wilson disease was expanded to include 
historical diagnosis (Administrative Letter 
9) 
To further clarify the process for 
confirming the score for patients who 
were diagnosed prior to the 
establishment of the 2012 European 
Association for the Study of Liver 
Wilson Disease Clinical Practice 
Guidelines. 
Section 6.2.3.2, Dose 
Modifications, Table 4 
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. 


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Section # and Name 
Description of Change 
Brief Rationale and/or clarifications 
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. 
Section 10.2.1, Clinical 
Laboratory Tests; 
Chemistry, Table 12 
HDL cholesterol added 
To align with current operating 
procedures of this study. 
All sections 
Minor editorial updates and corrections 
For clarification, and to ensure 
accuracy and consistency throughout 
the protocol. 
Abbreviations: BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression; EQ-5D = European 
Quality of Life Five Dimension; HDL = high density lipoprotein; PK = pharmacokinetics; PD = 
pharmacodynamics; TSQM-9 = Treatment Satisfaction Questionnaire for Medication. 


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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
1. 
PROTOCOL SUMMARY ..........................................................................................12 
1.1. 
Synopsis ......................................................................................................................12 
1.2. 
Schedule of Activities .................................................................................................16 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Study Rationale ...........................................................................................................26 
2.2. 
Background .................................................................................................................26 
2.2.1. 
Wilson Disease ...........................................................................................................26 
2.2.2. 
ALXN1840 .................................................................................................................28 
2.3. 
Benefit/Risk Assessment ............................................................................................29 
2.3.1. 
Potential Benefits ........................................................................................................29 
2.3.2. 
Potential and Identified risks ......................................................................................30 
2.3.3. 
Benefit/Risk Conclusions ...........................................................................................31 
2.3.3.1. 
Pregnancy Exposure ...................................................................................................31 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................32 
4. 
STUDY DESIGN .......................................................................................................35 
4.1. 
Overall Design ............................................................................................................35 
4.1.1. 
Primary Evaluation Period ..........................................................................................35 
4.1.2. 
Extension Period .........................................................................................................36 
4.2. 
Scientific Rationale for Study Design ........................................................................36 
4.3. 
Justification for Dose ..................................................................................................38 
4.3.1. 
ALXN1840 .................................................................................................................38 
4.3.2. 
Standard of Care .........................................................................................................38 
4.4. 
End of Study Definition ..............................................................................................38 
5. 
STUDY POPULATION .............................................................................................39 
5.1. 
Inclusion Criteria ........................................................................................................39 
5.1.1. 
Patients who have completed Study WTX101-201 ....................................................40 


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5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Screen Failures ............................................................................................................41 
6. 
STUDY TREATMENTS............................................................................................42 
6.1. 
Treatment Groups .......................................................................................................42 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................42 
6.2.1. 
Formulation and Packaging ........................................................................................42 
6.2.1.1. 
ALXN1840 .................................................................................................................42 
6.2.1.2. 
Standard of Care .........................................................................................................42 
6.2.2. 
Study Drug Preparation and Dispensing .....................................................................43 
6.2.3. 
Study Drug Administration.........................................................................................43 
6.2.3.1. 
ALXN1840 .................................................................................................................43 
6.2.3.2. 
Dose Modification for ALXN1840 ............................................................................43 
6.2.3.3. 
Standard of Care .........................................................................................................48 
6.2.3.4. 
Dose Modification for Standard of Care ....................................................................48 
6.2.3.5. 
ALXN1840 Administration During the Extension Period .........................................49 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................50 
6.4. 
Treatment Compliance ................................................................................................50 
6.5. 
Prior and Concomitant Medications and/or Procedures .............................................50 
6.5.1.1. 
Prohibited Medications ...............................................................................................51 
6.6. 
Contraception Guidance .............................................................................................51 
6.6.1. 
Guidance for Female Patients .....................................................................................51 
6.6.2. 
Guidance for Male Patients With a Partner Who is a Woman of Childbearing 
Potential ......................................................................................................................53 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................55 
7.1. 
Discontinuation of Study Intervention........................................................................55 
7.2. 
Patient Discontinuation/Withdrawal from the Study ..................................................55 
7.3. 
Lost to Follow Up .......................................................................................................56 
8. 
STUDY PROCEDURES AND ASSESSMENTS......................................................57 
8.1. 
Efficacy Assessments .................................................................................................57 
8.1.1. 
Assessment of Copper ................................................................................................57 
8.1.2. 
Model for End-Stage Liver Disease ...........................................................................57 
8.1.3. 
Unified Wilson Disease Rating Scale (Parts I, II, and III) .........................................57 


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8.1.4. 
Clinical Global Impression-Improvement Severity Scale and the Clinical 
Global Impression-Severity Improvement Scale ........................................................58 
8.1.5. 
Three Most Troublesome Symptoms ..........................................................................58 
8.1.6. 
Fibrosis-4 Index/Transient Elastography ....................................................................58 
8.1.7. 
Modified Nazer Score .................................................................................................58 
8.1.8. 
Brief Psychiatric Rating Scale-24 ...............................................................................59 
8.1.9. 
EuroQoL 5 Dimensions ..............................................................................................59 
8.1.10. 
Treatment Satisfaction Questionnaire for Medication ................................................59 
8.1.11. 
Timed 25F Walk Test .................................................................................................59 
8.1.12. 
Nine-Hole Peg Test .....................................................................................................59 
8.1.13. 
Non-Verbal Stroop Interference Test .........................................................................60 
8.1.14. 
Digit Span Test ...........................................................................................................60 
8.2. 
Safety Assessments .....................................................................................................60 
8.2.1. 
Physical Examination .................................................................................................60 
8.2.2. 
Vital Signs ..................................................................................................................60 
8.2.3. 
Electrocardiograms .....................................................................................................60 
8.2.4. 
Clinical Laboratory Evaluations .................................................................................61 
8.2.5. 
Pregnancy Test ............................................................................................................61 
8.3. 
Adverse Events and Serious Adverse Events .............................................................61 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................61 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................62 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................62 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................62 
8.3.5. 
Pregnancy ...................................................................................................................63 
8.3.6. 
Adverse Events of Special Interest .............................................................................63 
8.4. 
Overdose .....................................................................................................................64 
8.5. 
Pharmacokinetics, Pharmacodynamics, and Biomarkers ...........................................64 
8.5.1. 
Pharmacokinetics ........................................................................................................64 
8.5.2. 
Pharmacodynamics .....................................................................................................64 
8.5.3. 
Biomarkers and Biobank Samples ..............................................................................64 
8.6. 
Genetics ......................................................................................................................64 
8.7. 
Unscheduled Study Visits ...........................................................................................65 
9. 
STATISTICAL CONSIDERATIONS .......................................................................66 


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9.1. 
Analysis Populations ..................................................................................................66 
9.1.1. 
Full Analysis Set .........................................................................................................66 
9.1.2. 
Safety Analysis Set .....................................................................................................66 
9.1.3. 
Per-Protocol Set ..........................................................................................................66 
9.1.4. 
Extension Analysis Set ...............................................................................................66 
9.2. 
Statistical Methods ......................................................................................................67 
9.2.1. 
Analysis of Efficacy ...................................................................................................67 
9.2.1.1. 
Primary Efficacy Analysis ..........................................................................................67 
9.2.1.2. 
Secondary Efficacy Analysis ......................................................................................67 
9.2.2. 
Type I Error Control ...................................................................................................68 
9.2.3. 
Efficacy Analyses Relating to Exploratory Objectives ..............................................69 
9.2.4. 
Efficacy Subgroup Analysis .......................................................................................69 
9.2.5. 
Handling of Missing Data ...........................................................................................69 
9.2.6. 
Evaluation of Safety ...................................................................................................72 
9.2.6.1. 
Adverse Events ...........................................................................................................72 
9.2.6.2. 
Laboratory Assessments .............................................................................................72 
9.2.6.3. 
Electrocardiogram .......................................................................................................72 
9.2.6.4. 
Vital Signs ..................................................................................................................72 
9.2.6.5. 
Physical Examination .................................................................................................73 
9.2.7. 
Sample Size Determination ........................................................................................73 
9.2.8. 
Sample Size Re-estimation .........................................................................................74 
9.2.9. 
Extension Period Analyses .........................................................................................75 
9.2.10. 
Other Analyses ............................................................................................................75 
9.3. 
Data Monitoring Committee .......................................................................................75 
9.4. 
Neurological Adverse Event Panel .............................................................................76 
9.5. 
Hepatic Adjudication Panel ........................................................................................76 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................77 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................77 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................77 
10.1.2. 
Financial Disclosure ...................................................................................................77 
10.1.3. 
Informed Consent Process ..........................................................................................78 
10.1.4. 
Data Protection ...........................................................................................................78 


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10.1.5. 
Dissemination of Clinical Study Data ........................................................................78 
10.1.6. 
Data Quality Assurance ..............................................................................................79 
10.1.7. 
Source Documents ......................................................................................................79 
10.1.8. 
Publication Policy .......................................................................................................79 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................80 
10.2.1. 
Chemistry ....................................................................................................................80 
10.2.2. 
Coagulation .................................................................................................................80 
10.2.3. 
Endocrinology .............................................................................................................80 
10.2.4. 
Hematology .................................................................................................................80 
10.2.5. 
Urinalysis ....................................................................................................................81 
10.2.6. 
Other Tests ..................................................................................................................81 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................82 
Definition of Adverse Event ..........................................................................................................82 
Definition of Serious Adverse Event .............................................................................................83 
Suspected Unexpected Serious Adverse Reactions .......................................................................83 
Recording and Follow-up of AE and/or SAE ................................................................................84 
Reporting of SAEs .........................................................................................................................85 
10.4. 
Appendix 4: Collection of Pregnancy Information ....................................................86 
10.5. 
Appendix 5: Genetics .................................................................................................87 
Use/Analysis of DNA ....................................................................................................................87 
10.6. 
Appendix 6: Abbreviations .........................................................................................88 
10.7. 
Appendix 7: Protocol Amendment History ................................................................90 
10.7.1. 
Amendment 1, 17 Jan 2019 ........................................................................................90 
10.7.2. 
Amendment 1.1 (Japan) 25 Mar 2019 ........................................................................92 
10.7.3. 
Amendment 1.2 (Netherlands) 22 May 2019 .............................................................92 
10.7.4. 
Amendment 1.3 (Germany) 17 May 2019 ..................................................................93 
10.7.5. 
Amendment 1.4 (Sweden) 21 May 2019 ....................................................................93 
10.7.6. 
Amendment 1.5 (Germany) 10 Jul 2019 ....................................................................94 
10.7.7. 
Amendment 1.6 (Austria), 30 Apr 2020 .....................................................................95 
10.7.8. 
Amendment 2 (Global), 25 Mar 2021 ........................................................................96 
10.7.9. 
Amendment 2.1 (UK), 16 Apr 2021 .........................................................................101 
10.8. 
Appendix 8: Biobank Samples in the Netherlands ...................................................102 


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10.8.1. 
Purpose of the Biobank Samples ..............................................................................102 
10.8.2. 
Processing, Analyzing and Storage of the Samples ..................................................102 
10.8.3. 
Release of the samples ..............................................................................................102 
10.8.4. 
Procedures for coding and storage of personal data and biomaterial .......................103 
10.8.5. 
Consent procedure ....................................................................................................103 
10.9. 
Appendix 9: COVID-19 Urgent Safety Measures ....................................................105 
11. 
REFERENCES .........................................................................................................110 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities in the Primary Evaluation Period ...........................................18 
Table 2: 
Schedule of Activities in the Extension Period for Patients Who Received 
Standard of Care in the Primary Evaluation Period ....................................................21 
Table 3: 
Schedule of Activities in the Extension Period for Patients Who Received 
ALXN1840 in Study WTX101-301 Primary Evaluation Period or Completed 
the Main Period of Study WTX101-201 ....................................................................24 
Table 4: 
ALXN1840 Dose Modifications for Individual Patients ............................................45 
Table 5: 
Standard of Care Dose Modifications for Individual Patients ....................................49 
Table 6: 
Analysis of Key Secondary Endpoints Customized for Specific Regional 
Health Authorities .......................................................................................................67 
Table 7: 
Analysis Outline for Primary Endpoint ......................................................................69 
Table 8: 
Criteria for Sample size Re-estimation .......................................................................75 
Table 9: 
Chemistry ....................................................................................................................80 
Table 10: Hematology .................................................................................................................80 
Table 11: Urinalysis ....................................................................................................................81 
Table 12: Other Tests ..................................................................................................................81 
Table 13: COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) 
for Study WTX101-301 ............................................................................................106 
 
 
LIST OF FIGURES 
Figure 1: 
Schema for Study WTX101-301 ................................................................................35 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 3, Randomized, Rater-Blinded, Multi-Center Study to Evaluate the 
Efficacy and Safety of ALXN1840 Administered for 48 Weeks versus Standard of Care in 
Patients with Wilson Disease Aged 12 Years and Older, with an Extension Period of up to 
60 Months 
Short Title: Multicenter Study of Efficacy and Safety of ALXN1840 versus Standard of Care in 
Patients with Wilson Disease Aged 12 Years and Older 
Rationale: 
This study is being conducted to assess the efficacy and safety of ALXN1840 (formerly 
WTX101), a novel, first-in-class, copper-protein binding agent versus standard of care (SoC) in 
patients with Wilson Disease (WD) who are 12 years of age or older (18 years and older in 
Germany). Unlike current treatments for WD, ALXN1840 is designed to provide an alternative 
copper-protein transport mechanism, and rapidly form copper-protein complexes with very high 
specificity for copper to quickly treat the underlying disease by mobilizing excess tissue copper 
and promoting biliary excretion of copper (the body’s natural route of elimination) to reduce 
copper overload. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of ALXN1840 
administered for 48 weeks, compared to 
standard of care (SoC), on copper control in 
WD patients aged 12 years and older 
• 
Daily mean area under the effect-time curve 
(AUEC) of directly measured non-
ceruloplasmin-bound copper (dNCC) from 0 
to 48 weeks  
Secondary 
• 
Establish the safety and tolerability of 
individualized dosing of ALXN1840 
Incidence of  
• 
Adverse events/serious adverse events 
(AE/SAEs) 
• 
Clinical laboratory test data 
• 
Neurological and physical examination 
findings 
• 
12-lead electrocardiogram (ECG) data 
• 
Vital signs 
• 
Evaluate the effects of ALXN1840 on 
disability status  
• 
Change from baseline in the Unified Wilson 
Disease Rating Scale (UWDRS) Part II total 
score 
• 
Evaluate the effects of ALXN1840 on 
neurological status 
• 
Change from baseline in UWDRS Part III 
total score and individual item/subscales 
(arising from a chair, gait, handwriting, and 
speech) 
• 
Evaluate the global effects of ALXN1840 on 
global clinical symptoms 
• 
Clinical Global Impression-Improvement 
Scale (CGI-I) 
• 
Change from baseline in Clinical Global 
Impression-Severity Scale (CGI-S) 


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• 
Evaluate the effects of ALXN1840 on hepatic 
status  
• 
Change from baseline in Model for End-Stage 
Liver Disease (MELD) score 
• 
Evaluate the efficacy of ALXN1840 
administered for 48 weeks, compared to SoC, 
on copper control in WD patients aged 
12 years and older 
• 
Absolute change from baseline (Day 1) to 
48 weeks in calculated NCC (cNCC) in 
plasma.  
• 
Percentage change from baseline in cNCC in 
plasma. 
For ALXN1840-treated patients, the cNCC in plasma 
will be corrected for the amount of copper bound to the 
ALXN1840 tripartite complex (TPC) (cNCCcorrected) 
• 
Evaluate the effects of ALXN1840 on the 
cNCC responder rate 
• 
cNCC responder rate at 48 weeks 
Exploratory 
• 
Explore the effects of ALXN1840 on the 
individual patient's 3 most troublesome 
symptoms related to WD 
• 
Individualized assessment of each patient’s 
3 most troublesome symptoms 
• 
Explore the effects of ALXN1840 on hepatic 
fibrosis  
• 
Change from baseline in the Fibrosis-4 
(FIB 4) Index and by transient elastography 
• 
Explore the effects of ALXN1840 on hepatic 
status  
• 
Change from baseline in Modified Nazer 
Score 
• 
Explore the effects of ALXN1840 on 
psychiatric symptoms  
• 
Change from baseline in Brief Psychiatric 
Rating Scale-24 (BPRS-24) 
• 
Explore the effects of ALXN1840 on the 
following Quality of Life (QoL)/Patient 
Reported Outcomes (PRO) 
Change from baseline in QoL/PRO endpoint measures: 
• 
EuroQoL 5 Dimensions (EQ-5D) 
• 
Treatment Satisfaction Questionnaire for 
Medication-9 (TSQM-9) 
• 
Explore the change in the timed 25F Walk 
Test 
• 
Change from baseline in timed 25F Walk Test 
• 
Explore the change in the 9-hole Peg Test 
(9-HPT) 
• 
Change from baseline in 9-HPT 
• 
Explore the change in the non-verbal Stroop 
Interference Test 
• 
Change from baseline in non-verbal Stroop 
Interference Test 
• 
Explore the change in the Digit Span Test. 
• 
Change from baseline in Digit Span Test 
• 
Explore other directly measured 
pharmacodynamics (PD) and biomarkers of 
ALXN1840 
• 
Plasma total copper, plasma ultrafiltrate 
(PUF)-copper, dNCC, labile bound copper 
(LBC), ceruloplasmin (Cp), and 
ceruloplasmin-bound copper (CpC) 
concentration-time profiles in plasma 
• 
Daily mean AUEC of plasma dNCC (from 0 
to 24 and 24 to 48 weeks) 
• 
Daily mean AUEC of LBC from 0 to 
48 weeks 
• 
Daily mean AUEC of plasma total copper 
from 0 to 48 weeks 
• 
Absolute and percentage change from 
baseline (Day 1) to 48 weeks in dNCC 
• 
Absolute and percentage change from 
baseline (Day 1) to 48 weeks in LBC 
• 
Explore ALXN1840 effect on initial 
decoppering phase compared to SoC based on 
• 
Time to first confirmed increase in plasma 
dNCC and total copper concentration 


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directly measured pharmacokinetic (PK)/PD 
and biomarkers 
• 
Time to minimum and maximum concentration 
of: 
− Plasma total copper 
− Plasma dNCC 
− Plasma LBC 
− Ratio plasma dNCC:total copper 
− Ratio plasma LBC:total copper 
− Urinary molybdenum 
− Ratio urinary molybdenum:copper 
− Ratio urinary molybdenum:dosed 
molybdenum 
− Plasma Cp 
− Plasma CpC 
− Ratio plasma Cp:total copper 
− Ratio plasma CpC:total copper 
− Ratio plasma CpC:Cp 
• 
Explore ALXN1840 effect on subsequent 
maintenance phase compared to SoC based on 
directly measured PK/PD and biomarkers 
• 
Time for return to pre-dose baseline for the 
following measures: 
− Plasma total copper 
− Plasma dNCC 
− Plasma LBC 
− Ratio plasma dNCC: total copper 
− Ratio plasma LBC:total copper 
− Urinary molybdenum 
− Ratio urinary molybdenum:copper 
− Ratio urinary molybdenum:dosed 
molybdenum  
− Plasma Cp concentration 
− Plasma CpC concentration 
− Ratio plasma Cp:total copper 
− Ratio plasma CpC:total copper 
− Ratio plasma CpC:Cp 
• 
Explore PK of ALXN1840 
• 
Total molybdenum and PUF-molybdenum 
concentration-time profiles in plasma 
• 
Evaluate the effects of ALXN1840 on the 
LBC responder rate 
• 
LBC responder rate at 48 weeks 
• 
Explore the change in 24-hour urinary copper 
and urinary molybdenum 
• 
Change from baseline to 48 weeks in 24-hour 
urinary copper and urinary molybdenum 
Extension Period 
• 
Long term safety and efficacy 
• 
AEs, AESI, SAEs, laboratory tests 
(chemistry, hematology, coagulation, and 
urinalysis with microscopy), pregnancy 
testing in females of childbearing potential, 
physical examinations, vital signs, and ECGs. 
• 
CGI-I and the change from baseline in CGI-S 
• 
Change from baseline in MELD score 
• 
Change from baseline in UWDRS Part II total 
score 
• 
Change from baseline in UWDRS Part III 
total score and individual item/subscales 


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(arising from a chair, gait, handwriting, and 
speech) 
• 
NCC/NCCcorrected responder rate 
• 
LBC responder rate 
• 
Concentration-time profiles of the directly 
measured PK/PD and biomarkers 
Abbreviations: 25F = 25-foot; 9-HPT = 9-hole peg test; AE = adverse event; AESI = adverse event of special 
interest; AUEC = area under the effect-time curve; BPRS-24 = Brief Psychiatric Rating Scale-24; CGI-I = Clinical 
Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-Severity Scale; Cp = ceruloplasmin; 
CpC = ceruloplasmin-bound copper; ECG = electrocardiogram; EQ-5D(Y) = EuroQoL 5 Dimensions (Youth); 
FIB-4 = Fibrosis-4; LBC = labile bound copper; MELD = Model for End-stage Liver Disease; (d)(c)NCC = (directly 
measured) (calculated) non-ceruloplasmin-bound copper; cNCCcorrected = calculated corrected NCC; 
PD = pharmacodynamics; PK = pharmacokinetics; PRO = Patient Reported Outcomes; PUF = plasma ultrafiltrate; 
QoL = quality of life; SAE = serious adverse event; SoC = standard of care; TPC = tripartite complex; TSQM-9 = 
Treatment Satisfaction Questionnaire for Medication-9; UWDRS = Unified Wilson Disease Rating Scale 
 
Overall Design: 
This is a randomized, rater-blinded, multi-center study assessing the efficacy and safety of 
ALXN1840 versus SoC. In the Primary Evaluation Period, efficacy and safety will be assessed 
for an individualized ALXN1840 dosing regimen compared with SoC administered for 48 weeks 
in patients with WD who are aged 12 years and older (18 years and older in Germany). 
Approximately 180 patients will be enrolled globally. 
Patients meeting all inclusion and no exclusion criteria will be enrolled into the study and studied 
as outpatients. Eligible patients with WD will be enrolled into 1 of 2 cohorts. 
• Cohort 1: Patients who have received SoC therapy (ie, chelation therapy with 
penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc 
therapy) for > 28 days  
• Cohort 2: Patients who are treatment naïve or who have received SoC therapy for 
≤ 28 days  
All enrolled patients will be randomized by cohort in a 2:1 ratio to treatment with ALXN1840 or 
SoC (either as continued therapy in Cohort 1 or as continued or initial therapy in Cohort 2). 
Treatments will be assigned randomly, stratified by cohort. 
Patients who are randomized to receive ALXN1840 will be required to withhold treatment with 
SoC for ≥ 48 hours immediately prior to first study assessment on Day 1. Patients who are 
randomized to ALXN1840 will receive ALXN1840 as delayed-release tablets for oral 
administration at doses ranging from 15 mg every other day (QOD) to 60 mg once daily (QD). 
Efficacy and safety assessments will be performed at scheduled visits, while adverse events 
(AEs) and concomitant medications will be monitored continuously throughout the study. 
Patients randomized to SoC will initiate treatment or continue treatment on their current regimen 
where possible, without compromising the safety of individual patients. 
The Primary Evaluation Period will consist of an up to 28-day Screening Period, a 1-day 
Enrollment Visit, a 48-week Treatment Period, and a Follow-up Visit 4 weeks after the last dose 
for patients who do not elect to continue in the Extension Period. 


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Patients in Study WTX101-301 who have completed the 48-week Treatment Period and patients 
who completed participation in Study WTX101-201 will be offered the opportunity to participate 
in an up to 60-month Extension Period to evaluate the long-term safety and efficacy of 
ALXN1840.  
An independent Data Monitoring Committee (DMC), a Hepatic Adjudication Panel, and a 
Neurological Adverse Event (Neuro AE) Panel comprising experts in relevant fields with no 
direct relationship to the study, will be appointed by the sponsor. As detailed in their respective 
Charters (maintained separately from the study protocol), these committees 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.  
Number of Patients: 
Approximately 180 patients will be enrolled and randomized by cohort in a 2:1 ratio to treatment 
with ALXN1840 or SoC to obtain data from approximately 150 evaluable patients 
(100 ALXN1840, 50 SoC) for the primary analysis (Section 9.2.7). 
Statistical Analysis: 
The primary endpoint is the daily mean AUEC of directly measured plasma non-ceruloplasmin 
copper (dNCC) from 0 to 48 weeks. The AUEC for plasma dNCC concentration will be 
calculated using the trapezoidal rule, and then divided by number of days to yield a mean AUEC 
of plasma dNCC from baseline to Week 48.  
The primary efficacy analysis will be conducted on the available Week 48 data from the Primary 
Evaluation Period for all patients. A clinical study report (CSR) will be produced based on 
efficacy, safety, pharmacokinetic (PK), and pharmacodynamic (PD) data collected through the 
end of the 48-week Primary Evaluation Period. A final CSR to summarize long-term efficacy, 
safety, PK, and PD parameters will be produced at the end of the Extension Period. 
Mean AUEC of plasma dNCC concentration from baseline to 48 weeks will be compared 
between ALXN1840 and SoC using an analysis of covariance (ANCOVA) statistical model; 
treatment arm, baseline plasma dNCC concentration, and cohort, will be included in the model. 
Tests will be performed at a significance level of 0.05 (2-sided). 
Model-based estimates of the difference between randomized treatments (ALXN1840 – SoC) in 
AUEC0-48W, along with a 2-sided 95% confidence interval (CI) and p-value, will be provided. If 
the lower 2-sided 95% CI exceeds 0 µM, superiority will be concluded. 
The secondary efficacy endpoints and the methods for analyzing them will be defined in the 
Statistical Analysis Plan (SAP). 
1.2. 
Schedule of Activities 
The Schedule of Activities (SoA) for Screening and the Primary Evaluation Period is provided in 
Table 1. The Week 48 visit is the end of the Primary Evaluation Period and the beginning of the 
Extension Period (ie, the Week 48 visit and the Extension Day 1 visit occur on the same day). 
All assessments for the Week 48 visit will be performed prior to dosing of ALXN1840. Dosing 
of ALXN1840 on Extension Day 1 marks the beginning of the Extension Period. Patients who do 
not enter the Extension Period will discontinue dosing at Week 48 and will have a final study 


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visit for safety follow up at Week 52. The SoA for the Extension Period for patients who 
received SoC during the Primary Evaluation Period is provided in Table 2. The SoA for the 
Extension Period for patients who received ALXN1840 during the Primary Evaluation Period 
and for patients who completed Study WTX101-201 is provided in Table 3. 
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.  
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 (Section 8.7). 


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Table 1: 
Schedule of Activities in the Primary Evaluation Period 
Day 
Screeninga 
Treatment Period 
UNSb 
Follow-upc 
-28 
1d 
8 
15 
29d 
43d 
57d 
85d 
127d 
169
d 
211 
253d 
295 
337d 
 
365 
Week 
 
 
1
e 
2
e 
4 
6 
8 
12 
18 
24 
30e 
36 
42e 
48/ETf 
 
52 
Window (days) 
 
 
±3 
±7  
±3  
±7  
 
±7  
Obtain informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility 
criteria 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WD medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated physical 
examinationi 
 
X 
 
 
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 
 
 
X 
 
X 
 
 
 
X 
 
X 
FSHk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis B & C 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA sample 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testm 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Urinalysis  
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Chemistry, 
coagulation, 
hematology panel  
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
MELD and modified 
Nazern 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Fibrosis-4n 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Transient elastography 
 
Xo 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


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Day 
Screeninga 
Treatment Period 
UNSb 
Follow-upc 
-28 
1d 
8 
15 
29d 
43d 
57d 
85d 
127d 
169
d 
211 
253d 
295 
337d 
 
365 
Week 
 
 
1
e 
2
e 
4 
6 
8 
12 
18 
24 
30e 
36 
42e 
48/ETf 
 
52 
Window (days) 
 
 
±3 
±7  
±3  
±7  
 
±7  
Plasma/serum 
PK/PD/Biomarkers 
and Biobank samplesp 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
24-hour urineq 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
UWDRS Parts I, II, and 
IIIr,s 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
BPRS-24s,t 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
CGIu 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
EQ-5D 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
TSQM-9 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
3 most troublesome 
symptomss, v 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Timed 25F Walk Tests 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
9-hole Peg Tests 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Non-verbal Stroop 
Interference Tests 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Digit Span Tests 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Adverse event and 
concomitant medication 
 
Administer/dispense 
ALXN1840 or SoCw 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Xx 
 
 
Note: Patients who complete the 48-week period of randomized treatment in Study WTX101-301 will be offered the opportunity to participate in an up to 
60-month open-label Extension Period in which they will receive ALXN1840. 
a. 
Patients randomized to receive ALXN1840 will withhold treatment with SoC for ≥ 48 hours prior to first study assessment on Day 1.  
b. Unscheduled study visits may occur at any time during the study and may include any study procedures (including dispensing of ALXN1840/SoC) as 
deemed necessary by the Investigator. These visits may or may not be completed by a home healthcare nurse depending on the purpose of the 
unscheduled visit. Refer to Section 8.7. 
c. 
Follow-up visit procedures (Week 52) will be performed only for patients who do not enter the Extension Period. The Week 52 visit will be the End of 
Study visit for these patients. 
d. Assessments on Day 1 and other study visit days where laboratory sampling is planned should be performed pre-dose.  


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e. 
Week 1, Week 2, Week 30, and Week 42 (Day 8, Day 15, Day 211, and Day 295) will be performed via a safety phone call. If a neurological adverse 
event is reported, the following assessments must be performed as soon as possible: UWDRS Parts II and III, CGI-I and CGI-S. Investigators can 
perform additional assessments or laboratory testing at their discretion. 
f. 
Assessments at the Week 48 visit in the Primary Evaluation Period may be used as the Extension Period Day 1 assessments. 
g. 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 Medical Monitor. 
h. Patients will be randomized after meeting all inclusion and none of the exclusion criteria. Randomization may be required on or before Day-2 to allow 
for SoC to be withheld for ≥ 48-hours for patients randomized to receive ALXN1840 as noted in footnote a. All procedures required at Screening must 
be completed prior to the Day 1 visit.  
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 exam. 
j. 
Vital signs include height (Day 1 only; without shoes), heart rate, blood pressure, respiration rate, temperature, 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 separate 
informed consent. 
m. Serum and urine pregnancy tests will only be performed for females of childbearing potential. Female patients of childbearing potential must not be 
pregnant nor breastfeeding and must have a negative serum pregnancy test at Screening. Positive urine pregnancy results will be confirmed by a serum 
pregnancy test. In addition to pregnancy tests detailed at the visits in the Schedule of Activities, females of childbearing potential in Austria only will be 
required to perform urine pregnancy tests at least every 4 weeks at their home or the study site throughout their time in the study. 
n. To be calculated by the Central Laboratory. 
o. If transient elastography results are available from within 28 days prior to Day 1, this procedure does not have to be repeated at the Day 1 Visit. 
p. Plasma or serum samples will be obtained from the blood samples collected pre-dose on the day of visit. See Section 8.5. 
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, molybdenum, and copper. The container for 24-hour urine collection 
during should be dispensed at the study visit immediately prior to the next expected collection. Urine containers should be dispensed at the Screening 
Period, Day 1, and Weeks 8, 18, 24, and 36. 
r. 
The UWDRS Part I and III must be performed by a blinded neurologist. 
s. 
With the exception of Day 1, assessment can be completed within 2 days of the study visit day.  
t. 
The BPRS-24 can be performed by a qualified person who has completed the required training. 
u. CGI-I is not performed at Day 1. 
v. In addition to collection via a paper questionnaire, the patient’s 3 most troublesome symptoms may also be recorded by the site staff via video for 
patients who provide separate informed consent. 
w. Appropriately trained study staff will administer the ALXN1840 on Day 1 and will instruct patients on how to correctly dose themselves on the days 
when they take drug at home. ALXN1840 will not be dispensed or administered at the Early Termination Visit. 
x. ALXN1840 dispensed/administered only for patients continuing into the Extension Period. 
 
Abbreviations: BPRS-24 = Brief Psychiatric Rating Scale-24; CGI = Clinical Global Impression; CGI-I = Clinical Global Impression-Improvement Scale; CGI-S 
= Clinical Global Impression-Severity Scale; EOS = End of Study; EQ-5D = EuroQoL 5 Dimensions; ET = Early Termination; FSH = follicle-stimulating 
hormone; MELD = Model for End-Stage Liver Disease; PD = pharmacodynamic; PK = pharmacokinetic; 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 in the Extension Period for Patients Who Received Standard of Care in the Primary 
Evaluation Period 
Extension Study 
Day 
Extension Treatment Period 
UNSa ET EOS 
1b,c 
8 
15 
29 
43 
57 
85 
127 
169 
211 
253 
295 337 
421 
505 589 673 
841 1009 1177 1345 1513 1681 1849 
 
 
1877 
Extension Study 
Week 
 
1c 
2c 
4 
6 
8 
12 
18 
24 
30c 
36 
42c 
48e 
60 
72 
84 
96 
120 
144 168 
192 
216 
240 
264 
 
 
268 
Window (days) 
 
 
 
±3 
±7 
±3  
 
±7 
 
 
 
Physical 
examination 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
Vital signsd 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Pregnancy testf 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Chemistry, 
coagulation, 
hematology panel, 
and urinalysis 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
24-hour urineg 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
MELD and 
modified Nazerh 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Fibrosis-4h 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Transient 
elastography 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Plasma/serum 
PK/PD/ 
Biomarkers and 
Biobank samplesi 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
UWDRS Parts I, 
II, and IIIj,k 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
BPRS-24k,l 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CGI 
X  
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
EQ-5D 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
TSQM-9 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
3 most troublesome 
symptomsk,m 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Timed 25F Walk 
Testk 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Extension Study 
Day 
Extension Treatment Period 
UNSa ET EOS 
1b,c 
8 
15 
29 
43 
57 
85 
127 
169 
211 
253 
295 337 
421 
505 589 673 
841 1009 1177 1345 1513 1681 1849 
 
 
1877 
Extension Study 
Week 
 
1c 
2c 
4 
6 
8 
12 
18 
24 
30c 
36 
42c 
48e 
60 
72 
84 
96 
120 
144 168 
192 
216 
240 
264 
 
 
268 
Window (days) 
 
 
 
±3 
±7 
±3  
 
±7 
 
 
 
9-hole Peg Testk 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-verbal Stroop 
Testk 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Digit Span Testk 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event and 
concomitant 
medicationn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer/ 
dispense 
ALXN1840o 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Note: All patients who complete the 48-week period of randomized treatment in Study WTX101-301 will be offered the opportunity to participate in an up to 60-month open-label Extension Period in 
which they will receive ALXN1840.  
a. 
Unscheduled study visits may occur at any time during the protocol 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 depending on the purpose of the unscheduled visit. Refer to Section 8.7. 
b. 
Assessments on Day 1 and other study visit days where laboratory sampling is planned should be performed pre-dose. 
c. 
The Week 1, Week 2, Week 30, and Week 42 Visits will be performed via safety phone calls. During these phone visits, adverse events and concomitant medications will be assessed and 
recorded. If a neurological adverse event is reported, the following assessments must be performed as soon as possible: UWDRS Parts II and III, the CGI-I and CGI-S. Investigators can 
perform additional assessments or laboratory testing at their discretion. 
d. 
Vital signs include height (Day 1 only; without shoes), heart rate, blood pressure, respiration rate, temperature, and weight. 
e. 
Assessments at the Week 48 Visit will also be used as the Extension Period Day 1 assessments. 
f. 
Serum and urine pregnancy tests will only be performed for females of childbearing potential. Female patients of childbearing potential must not be pregnant nor breastfeeding and must 
have a negative serum pregnancy test at Screening. Positive urine pregnancy results will be confirmed by a serum pregnancy test. In addition to pregnancy tests detailed at the visits in the 
Schedule of Activities, females of childbearing potential in Austria only will be required to perform urine pregnancy tests at least every 4 weeks at their home or the study site throughout 
their time in the study. 
g. 
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 Study 
Day 1 and Weeks 8, 18, 24, 36, 60, 84, 96, 120, 144, 168, 192, 216, and 240. 
h. 
To be calculated by the Central Laboratory. 
i. 
Plasma or serum samples will be obtained from the blood samples collected pre-dose on the day of visit. See Section 8.5. 
j. 
The UWDRS Part I and III must be performed by a blinded neurologist. 
k. 
With the exception of Day 1, assessment can be completed within 2 days of the study visit day.  
l. 
The BPRS-24 can be performed by a qualified person who has completed the required training. 
m. 
In addition to collection via a paper questionnaire, the patient’s 3 most troublesome symptoms may also be recorded by the site staff via video for patients who provide separate informed 
consent. Note: this information is not required to be collected via video in the Extension Period of the study and also for patients who switch from SoC to ALXN1840 during the first year of 
the Extension Period. 
n. 
Adverse events and concomitant medications will be assessed and recorded via phone calls at Extension Study Safety Phone Visits (Weeks 1, 2, 30, and 42). 
o. 
Appropriately trained employees of the study site will administer the ALXN1840 on Day 1 and will instruct patients on how to correctly dose themselves on the days when they take drug at 
home. ALXN1840 will not be dispensed or administered at the Early Termination Visit. 


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Abbreviations: CGI = Clinical Global Impression; CGI-I = Clinical Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-Severity Scale; ECG = electrocardiogram; EOS = End 
of Study; EQ-5D = EuroQoL 5 Dimensions; ET = Early Termination; MELD = Model for End-Stage Liver Disease; PD = pharmacodynamic; PK = pharmacokinetic; 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 3: 
Schedule of Activities in the Extension Period for Patients Who Received ALXN1840 in Study WTX101-301 
Primary Evaluation Period or Completed the Main Period of Study WTX101-201 
Extension Treatment Period 
UNSa 
ET 
EOS 
Extension Study Day 
1b,d 
85 
169 
253 
337 
505 
673 
841 
1009 
1177 
1345 1513 1681 1849 
 
 
1877 
Extension Study Week 
 
12 
24 
36 
48 
72 
96 
120 
144 
168 
192 
216 
240 
264 
 
 
268 
Extension Study Day 
(including Primary Evaluation 
Period) 
 
421 
505 
589 
673 
841 
1009 
1177 
1345 
1513 
1681 1849 2017 2185 
 
 
2213 
Extension Study Week 
(including Primary Evaluation 
Period) 
 
60 
72 
84 
96 
120 
144 
168 
192 
216 
240 
264 
288 
312 
 
 
316 
Window (days) 
 
±7  
Informed consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
Vital signse 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
12-lead ECG 
X
d 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Pregnancy testf 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Chemistry, coagulation, and 
hematology panel and 
urinalysis 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
24-hour urineg,h 
X
d,i 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
MELD and modified Nazerj 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Fibrosis-4j 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Transient elastography 
X
d,i 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Plasma/serum PK/PD/ 
Biomarkers and Biobank 
samplesk 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
UWDRS Parts I, II, and IIIl,m 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
BPRSn 
X
d,i 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CGI 
X
d 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 


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EQ-5D 
X
d 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
TSQM-9 
X
d 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
Adverse event and 
concomitant medication 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
Administer/dispense 
ALXN1840o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Note: Patients who complete either the main study period of Study WTX101-201 or the 48-week period of randomized treatment in Study WTX101-301 will be 
offered the opportunity to participate in an up to 60-month open-label Extension Period in which they will receive ALXN1840. If a patient from 
Study WTX101-201 qualifies for the Extension Period and chooses to participate, they must sign an additional ICF for the Extension Period. Note that visits at 
Weeks 12 (Week 60 overall) and 36 (Week 84 overall) of the Extension Period are not required for patients who previously completed the main period of 
Study WTX101-201. 
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 depending on the purpose of the unscheduled visit. 
Refer to Section 8.7. 
b. Assessments on Day 1 and other study visit days where laboratory sampling is planned should be performed pre-dose. 
c. 
Only patients who rollover from Study WTX101-201 will consent to participate in Study WTX101-301 at the start of the Extension Period.  
d. Assessments at the Week 48 Visit will also be used as the Extension Period Day 1 assessments.  
e. 
Vital signs include height (Day 1 only; without shoes), heart rate, blood pressure, respiration rate, temperature, 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 nor breastfeeding and must have a negative serum pregnancy test at Screening. Positive urine pregnancy results will be confirmed by a serum 
pregnancy test. In addition to pregnancy tests detailed at the visits in the Schedule of Activities, females of childbearing potential in Austria only will be 
required to perform urine pregnancy tests at least every 4 weeks at their home or the study site throughout their time in the study. 
g. 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. 
h. 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 Weeks 60, 84, 96, 120, 144, 168, 192, 216, 240, 264, and 288. 
i. 
Only for patients from Study WTX101-201. 
j. 
To be calculated by the Central Laboratory. 
k. Plasma or serum samples will be obtained from the blood samples collected pre-dose on the day of visit. See Section 8.5. 
l. 
The UWDRS Part I and III must be performed by a blinded neurologist. 
m. With the exception of Day 1, assessment can be completed within 2 days of the study visit day.  
n. The BPRS-24 can be performed by a qualified person who has completed the required training. 
o. ALXN1840 will not be dispensed or administered at the Early Termination Visit. 
Abbreviations: BPRS-24 = Brief Psychiatric Rating Scale-24; CGI-I = Clinical Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-
Severity Scale; EOS = End of Study; EQ-5D = EuroQoL 5 Dimensions; ET = Early Termination; ICF = informed consent form; MELD = Model for End-Stage 
Liver Disease; PD = pharmacodynamic; PK = pharmacokinetic; TSQM-9 = Treatment Satisfaction Questionnaire for Medication-9; UNS = unscheduled; 
UWDRS = Unified Wilson Disease Rating Scale; WD = Wilson disease 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
This study is being conducted to assess the efficacy and safety of ALXN1840, a novel, 
first-in-class, copper -protein binding agent versus standard of care (SoC) in patients with Wilson 
Disease (WD) who are 12 years of age or older (18 years and older in Germany). Currently 
available drugs have high rates of treatment discontinuation due to tolerability and efficacy 
issues. They also need to be dosed 2 to 4 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 WD, which is a disease that requires life-long 
treatment (Maselbas, 2010; Dziezyc, 2014). 
Unlike currently available treatments for WD, ALXN1840 is designed to provide an alternative 
copper-protein transport mechanism, and rapidly form copper-protein complexes with very high 
specificity for copper to quickly treat the underlying disease by mobilizing excess tissue copper 
and promoting biliary excretion of copper (the body’s natural route of elimination) to reduce 
copper overload. 
2.2. 
Background 
2.2.1. 
Wilson Disease 
Wilson disease is an autosomal recessive disorder of impaired copper transport. Mutations in the 
ATP7B gene result in deficient production of the copper-transporter ATPase2, leading to 
impaired incorporation of copper into ceruloplasmin (Cp), impaired biliary excretion of copper, 
increased exchangeable copper, and copper 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 copper 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 hepatic 
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). 


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The liver represents one of the main copper storage organs in humans. In healthy people, 
intracellular copper homeostasis is tightly regulated. Copper is transported into cells by copper 
transporter 1 (CTR1), and then transferred to copper chaperones such as the copper chaperones 
for antioxidant 1, cytochrome c oxidase, and superoxide dismutase. Copper accompanying the 
chaperone is delivered to a specific copper-requiring enzyme. If excess amounts of copper 
appear, the excess copper is bound to metallothionein (MT) as monovalent copper (Cu+) via 
copper thiolate bridges by abundant cysteine residues in MT, thus leading to a detoxification of 
copper through a reduction of its redox potential. 
In patients with WD, copper is not removed from the tissue compartments due to the deficient 
activity of ATPase2 due to its absence or reduced function. This results in an accumulation of 
copper, 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 
copper exists because MT tightly binds copper. However, beyond the copper buffering capacity 
of MT, free copper ions appear and this excessive amount of free intracellular copper triggers 
pro-oxidant properties, leading to an increased risk of tissue/organ damages with clinical 
manifestations as a result. Historically, it has been assumed that the hepatic toxicity of copper in 
WD is mediated by copper that is not bound to ceruloplasmin or MT (Ogra, 1996). Increased 
non-ceruloplasmin-bound copper (NCC) from the liver then enters the circulation in a form that 
is mostly bound to albumin and is available for uptake into other organs where it may cause 
damage. Therefore, the plasma calculated NCC (cNCC) concentration may serve as an important 
biomarker for tissue copper overload. However, achieving a normalized plasma cNCC 
concentration does not necessarily reflect normalized tissue copper levels, particularly in organs 
with relatively slow copper exchange, such as the brain (Pfeiffenberger, 2019). 
The optimal treatment goal of an effective therapy for WD should be to remove excessive copper 
from the tissues. The current treatments for WD are general chelator therapies D-penicillamine 
(Cuprimine, Depen) and trientine (Syprine), which non-specifically chelate copper and promote 
urinary copper excretion. In addition, zinc, which blocks dietary uptake of copper, is used mainly 
for maintenance treatment. Zinc impairs the absorption of copper by the induction of MT in the 
enterocytes of the gastrointestinal (GI) tract. As tissue copper concentrations are not readily 
sampled, the adequacy of therapeutic copper control is currently monitored through periodic 
assessment of the 24-hour urinary copper excretion (Roberts, 2008; EASL 2012). The daily 
urinary copper excretion rate and plasma NCC concentration are both highly variable and neither 
is ideal for monitoring therapeutic copper control (Pfeiffenberger 2019). 
Disease control in patients with neurological symptoms at WD diagnosis is an area of particular 
concern. More than one-third of patients presenting with neurological symptoms show no 
improvement after 4 years of treatment with chelators. This failure to respond to chelation 
therapy with neurological presentation may reflect irreversible damage to the nervous system 
(Weiss, 2013). Also, in a recent study, approximately 50% of patients had residual neurological 
symptoms despite years of therapy on a copper-modulating agent (Holscher, 2010). 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 copper from the liver 
leading to elevations in brain copper associated with neurological progression (Brewer, 2009). 
This theory is supported by non-clinical data (Zhang, 2015; Chen, 2012). Copper accumulation 


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in the central nervous system is an evolutionary and long-term process. Excessive copper in the 
body as a whole (not just from the liver) may gradually accumulate in the central nervous system 
over time, which is also reflected in the time it typically takes to show efficacy after WD 
treatment such as ALXN1840 (approximately 2 years). 
Currently available drugs have high rates of treatment discontinuation due to 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) is a novel, first-in-class, copper-protein binding 
agent in development for treatment of WD. ALXN1840 targets the following medical needs: 
• Rapid and sustained control of copper and clinical symptoms, with a low risk of 
neurological worsening – through the rapid formation of irreversible copper 
tetrathiomolybdate-protein complexes leading to a rapid copper mobilization and 
elimination that could protect patients with WD from tissue toxicity including 
neurological deterioration. Results from Studies WTX101-HV-106 and WTX101-201 
support a proposed mechanism of action of ALXN1840 whereby copper is mobilized 
to the bloodstream and sequestered through the formation of stable tripartite 
complexes (TPCs). 
• A therapeutic option that is efficacious and well tolerated, and suitable for all naïve 
and pre-treated patients, including those with neurological symptoms who are at 
greatest risk of neurological deterioration during the initial phases of chelation 
therapy. 
• Improved compliance over long-term treatment through an improved tolerability and 
the convenience of a simplified dosing regimen (once daily [QD]) compared to 
current therapeutic options (multiple daily dosing in the fasted state). 
ALXN1840 (bis-choline tetrathiomolybdate) has been chosen for clinical development in WD 
due to its improved stability properties compared with ammonium tetrathiomolybdate, which has 
been studied in WD and other indications. Good Laboratory Practice studies conducted in 
Sprague-Dawley rats and Beagle dogs have shown that the salt cation (ammonium or 
bis-choline) does not impact the pharmacokinetic (PK) or pharmacodynamic (PD) effects of 
tetrathiomolybdate, and ammonium tetrathiomolybdate as well as bis-choline tetrathiomolybdate 
non-clinical and clinical data to date support the efficacy and safety of ALXN1840.  
ALXN1840 has been evaluated in patients with WD in the Phase 2 Study WTX101-201, which 
enrolled 28 patients with WD. Final results from the main 24-week study showed that 
ALXN1840 monotherapy reduced mean serum cNCCcorrected by 72% at Week 24 compared with 
baseline. The reduction in cNCCcorrected was sustained through Week 72 or longer. Initial 
increases in total plasma copper, exchangeable copper, and labile bound copper (LBC, mostly 
bound to albumin) were observed, followed by a gradual decline to baseline or even lower. 
These results suggest that ALXN1840 mobilizes copper from tissues to blood, forming 
copper-albumin-tetrathiomolybdate complexes that are ultimately eliminated from the body, 


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thereby meeting the treatment goal of a therapy for WD that removes excessive copper from 
tissues such as the liver.  
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, was 
stabilized or improved in the majority of 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 generally 
mild to moderate, asymptomatic, and normalized with dose adjustments. No paradoxical 
neurological worsening was observed upon treatment initiation with ALXN1840 (Weiss, 2017). 
All patients who completed the 24-week Study Period were enrolled in a 36-month Extension 
Period. Preliminary available follow-up data at 48 weeks from the ongoing 36-month Extension 
Period of the study were consistent with the 24-week Study Period results. 
The clinical study experience with tetrathiomolybdate in WD also consists of 120 patients with 
WD treated with ammonium tetrathiomolybdate. The information presented is based on 
peer-reviewed literature (eg, non-Wilson Therapeutics AB sponsored studies) (Brewer, 2003; 
Brewer, 2006; Brewer, 2009). Additionally, ALXN1840 (bis-choline tetrathiomolybdate) has 
been administered to 5 patients with WD in a named patient program in Canada and Sweden. 
In addition to the WD studies performed, there has been extensive clinical study experience with 
both ammonium tetrathiomolybdate and ALXN1840 in patients with other conditions, which 
contributes to the knowledge of the safety of tetrathiomolybdate in humans. 
In total, tetrathiomolybdate has been evaluated in more than 800 patients in studies of WD, 
oncology, macular degeneration, and primary biliary cirrhosis indications using either the 
ammonium or the bis-choline tetrathiomolybdate salt forms, in 36 healthy volunteers in Phase 1 
studies, where bis-choline salt of tetrathiomolybdate was tested in uncoated capsules or 
enteric-coated tablets. ALXN1840 has been generally well-tolerated, and the most frequently 
reported drug-related AEs in WD were increases in hepatic transaminases. Aminotransferase 
elevations were much less common in patients without WD compared with patients with WD; 
however, it should be noted that in the oncology program, which constitutes the majority of 
patients without WD, causality of tetrathiomolybdate for these elevations was difficult to 
establish due to underlying disease. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ALXN1840 are 
provided in the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
More information about the known and expected benefits and risks and reasonably expected AEs 
with ALXN1840 may be found in the current edition of the Investigator’s Brochure. Detailed 
information about the known and expected benefits and risks and reasonably expected AEs of 
treatments administered as SoC may be found in the relevant product labels. 
2.3.1. 
Potential Benefits 
The main objective of effective WD treatment is to provide rapid copper control, ie, mobilization 
and elimination of copper. The current goal of treatment for WD is to establish and maintain 


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negative or neutral whole-body copper balance (Roberts, 2008; EASL, 2012). As such, current 
clinical recommendations suggest that copper control is essential for stabilization or 
improvement of hepatic, neurologic or psychiatric manifestations of WD. The concentration of 
circulating plasma total copper is expected to be low in WD due to decreased levels of Cp. In 
line with the efficacy assessments relied upon for approval of the copper chelators penicillamine 
and trientine, the measures of the primary endpoint for Studies WTX101-201 and WTX101-203 
were based on assessing the control of plasma exchangeable copper via cNCC/NCCcorrected 
calculations. 
As copper concentrations are consistently low at baseline in treatment naïve patients with WD, it 
is difficult to justify using serial copper blood measures as an adequate monitoring tool for 
therapeutic efficacy. As plasma total copper concentrations are consistently low in WD, serial 
measurement of total copper has not previously been considered to be informative for monitoring 
treatment. However, the temporal patterns for both plasma total copper and molybdenum seen in 
Study WTX101-201 support the decoppering mechanism of action of ALXN1840. After the 
initial decoppering phase of approximately 24 weeks, participants with WD apparently entered a 
maintenance phase where tissue copper became less available and, thus, less TPC was formed, 
even though the ALXN1840 dose was generally maintained. Overall, ALXN1840 PK (plasma 
total molybdenum) and PD (plasma total copper) profiles changed coordinately and were highly 
correlated, with both PK and PD apparently dependent on formation of copper-albumin-TPC 
complexes. These observations support the ability of ALXN1840 to reduce copper overload in 
patients with WD. Results from the Phase 2 Study WTX101-201 demonstrate a rapid and 
significant (p<0.0001) reduction of mean serum cNCCcorrected levels after initiation of treatment, 
with significant improvements in neurological status, as measured by UWDRS Part III 
(p<0.0001) and patient-reported disability, measured by UWDRS Part II (p<0.001), as well as a 
stabilization or improvement of hepatic status in most patients following 24 weeks of 
ALXN1840 treatment (Weiss, 2017). In the Extension Period of Study WTX101-201, 48-week 
follow up data indicate maintained overall improvement in disability as shown by mean 
reduction in the UWDRS Part II score and maintained overall improvement in neurologic status 
as shown by mean reduction in UWDRS Part III. Treatment with ALXN1840 was generally well 
tolerated with most reported AEs being mild (Grade 1) to moderate (Grade 2).  
Approximately half of newly diagnosed patients with WD are younger than 18 years old 
(Ferenci, 2019). Standard treatments for WD are approved for use in children or adolescents, but 
significant unmet needs still exist with respect to efficacy, safety, and simplicity of dosing 
regimens. All currently available WD treatments are associated with adverse effects (such as 
neurological worsening) in a subset of patients, which can require adjustment, substitution, or 
even discontinuation of treatment. These adverse effects also reduce the patient’s compliance 
with treatment, which by itself can lead to clinical deterioration and even death. All require 
multiple daily doses to achieve adequate copper control. The burden of multiple daily doses for 
standard treatments may negatively impact medical adherence and clinical outcomes, particularly 
among patients who discontinue treatment entirely. Once-daily dosing and the small tablet 
diameter of the 15 mg dose of ALXN1840 (5 mm) may increase therapeutic adherence. 
2.3.2. 
Potential and Identified risks 
In patients with WD, the most commonly reported AEs associated with multiple ALXN1840 
dosing are reversible, dose-dependent, liver test elevations (transaminases) observed after 


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treatment initiation with doses of 30 mg per day or higher. In the Phase 2 Study WTX101-201, 
reversible liver test elevations were observed in 39% of patients. These elevations were generally 
mild to moderate, asymptomatic and normalized with dose adjustments. No initial drug-induced 
neurological worsening was observed upon treatment initiation with ALXN1840. As 
tetrathiomolybdate is a copper modulating agent, there is the risk of producing copper deficiency 
with prolonged dosing with ALXN1840. Changes in hematological parameters 
(thrombocytopenia and leukopenia), attributed by the Investigators to overtreatment and resultant 
copper deficiency, have been observed. Multiple-dose WD studies, like Study WTX101-301, 
therefore, involve frequent monitoring for these potential adverse hematological and hepatic 
effects of ALXN1840.  
Details of potential safety risks related to the COVID-19 pandemic and mitigation measures are 
provided in Section 10.9. 
2.3.3. 
Benefit/Risk Conclusions 
Based on the efficacy results from Study WTX101-201 (lowering of free copper, stabilization or 
improvement of liver status and improvement in neurological symptoms) and the risk mitigation 
measures included in the protocol to account for the most common AEs reported in the study, 
Alexion considers that ALXN1840 has an acceptable benefit/risk in adult patients. The 
pathophysiology of copper overload does not differ substantially between adolescents and adults 
with WD, and the approved treatment options and therapeutic goal of copper control are also the 
same for adolescents and adults. Therefore, Alexion considers the acceptable benefit/risk extends 
to adolescent patients.  
2.3.3.1. 
Pregnancy Exposure 
No studies of ALXN1840 have been conducted in pregnant women. Pregnant or nursing female 
patients will be excluded from the clinical study. Patients enrolled in the study, and their 
spouses/partners, must use a highly effective method of contraception as required in Section 5.1. 
In the event of a pregnancy, the patient will be discontinued from study drug (ie, ALXN1840 or 
SoC; Section 7.1).  


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of ALXN1840 
administered for 48 weeks, compared to 
standard of care (SoC), on copper control in 
WD patients aged 12 years and older 
• 
Daily mean area under the effect-time curve 
(AUEC) of directly measured non-
ceruloplasmin-bound copper (dNCC) from 0 
to 48 weeks  
Secondary 
• 
Establish the safety and tolerability of 
individualized dosing of ALXN1840 
Incidence of  
• 
Adverse events/serious adverse events 
(AE/SAEs) 
• 
Clinical laboratory test data 
• 
Neurological and physical examination 
findings 
• 
12-lead electrocardiogram (ECG) data 
• 
Vital signs 
• 
Evaluate the effects of ALXN1840 on 
disability status  
• 
Change from baseline in the Unified Wilson 
Disease Rating Scale (UWDRS) Part II total 
score 
• 
Evaluate the effects of ALXN1840 on 
neurological status 
• 
Change from baseline in UWDRS Part III 
total score and individual item/subscales 
(arising from a chair, gait, handwriting, and 
speech) 
• 
Evaluate the global effects of ALXN1840 on 
global clinical symptoms 
• 
Clinical Global Impression-Improvement 
Scale (CGI-I) 
• 
Change from baseline in Clinical Global 
Impression-Severity Scale (CGI-S) 
• 
Evaluate the effects of ALXN1840 on hepatic 
status  
• 
Change from baseline in Model for End-Stage 
Liver Disease (MELD) score 
• 
Evaluate the efficacy of ALXN1840 
administered for 48 weeks, compared to SoC, 
on copper control in WD patients aged 
12 years and older 
• 
Absolute change from baseline (Day 1) to 
48 weeks in calculated NCC (cNCC) in 
plasma.  
• 
Percentage change from baseline in cNCC in 
plasma. 
For ALXN1840-treated patients, the cNCC in plasma 
will be corrected for the amount of copper bound to the 
ALXN1840 tripartite complex (TPC) (cNCCcorrected) 
• 
Evaluate the effects of ALXN1840 on the 
cNCC responder rate 
• 
cNCC responder rate at 48 weeks 
Exploratory 
• 
Explore the effects of ALXN1840 on the 
individual patient's 3 most troublesome 
symptoms related to WD 
• 
Individualized assessment of each patient’s 
3 most troublesome symptoms 
• 
Explore the effects of ALXN1840 on hepatic 
fibrosis  
• 
Change from baseline in the Fibrosis-4 
(FIB 4) Index and by transient elastography 
• 
Explore the effects of ALXN1840 on hepatic 
status  
• 
Change from baseline in Modified Nazer 
Score 
• 
Explore the effects of ALXN1840 on 
psychiatric symptoms  
• 
Change from baseline in Brief Psychiatric 
Rating Scale-24 (BPRS-24) 


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• 
Explore the effects of ALXN1840 on the 
following Quality of Life (QoL)/Patient 
Reported Outcomes (PRO) 
Change from baseline in QoL/PRO endpoint measures: 
• 
EuroQoL 5 Dimensions (EQ-5D) 
• 
Treatment Satisfaction Questionnaire for 
Medication-9 (TSQM-9) 
• 
Explore the change in the timed 25F Walk 
Test 
• 
Change from baseline in timed 25F Walk Test 
• 
Explore the change in the 9-hole Peg Test 
(9-HPT) 
• 
Change from baseline in 9-HPT 
• 
Explore the change in the non-verbal Stroop 
Interference Test 
• 
Change from baseline in non-verbal Stroop 
Interference Test 
• 
Explore the change in the Digit Span Test. 
• 
Change from baseline in Digit Span Test 
• 
Explore other directly measured 
pharmacodynamics (PD) and biomarkers of 
ALXN1840 
• 
Plasma total copper, plasma ultrafiltrate 
(PUF)-copper, dNCC, labile bound copper 
(LBC), ceruloplasmin (Cp), and 
ceruloplasmin-bound copper (CpC) 
concentration-time profiles in plasma 
• 
Daily mean AUEC of plasma dNCC (from 0 
to 24 and 24 to 48 weeks) 
• 
Daily mean AUEC of LBC from 0 to 
48 weeks 
• 
Daily mean AUEC of plasma total copper 
from 0 to 48 weeks 
• 
Absolute and percentage change from 
baseline (Day 1) to 48 weeks in dNCC 
• 
Absolute and percentage change from 
baseline (Day 1) to 48 weeks in LBC 
• 
Explore ALXN1840 effect on initial 
decoppering phase compared to SoC based on 
directly measured pharmacokinetic (PK)/PD 
and biomarkers 
• 
Time to first confirmed increase in plasma 
dNCC and total copper concentration 
• 
Time to minimum and maximum concentration 
of: 
− Plasma total copper 
− Plasma dNCC 
− Plasma LBC 
− Ratio plasma dNCC:total copper 
− Ratio plasma LBC:total copper 
− Urinary molybdenum 
− Ratio urinary molybdenum:copper 
− Ratio urinary molybdenum:dosed 
molybdenum 
− Plasma Cp 
− Plasma CpC 
− Ratio plasma Cp:total copper 
− Ratio plasma CpC:total copper 
− Ratio plasma CpC:Cp 
• 
Explore ALXN1840 effect on subsequent 
maintenance phase compared to SoC based on 
directly measured PK/PD and biomarkers 
• 
Time for return to pre-dose baseline for the 
following measures: 
− Plasma total copper 
− Plasma dNCC 
− Plasma LBC 
− Ratio plasma dNCC: total copper 


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− Ratio plasma LBC:total copper 
− Urinary molybdenum 
− Ratio urinary molybdenum:copper 
− Ratio urinary molybdenum:dosed 
molybdenum  
− Plasma Cp concentration 
− Plasma CpC concentration 
− Ratio plasma Cp:total copper 
− Ratio plasma CpC:total copper 
− Ratio plasma CpC:Cp 
• 
Explore PK of ALXN1840 
• 
Total molybdenum and PUF-molybdenum 
concentration-time profiles in plasma 
• 
Evaluate the effects of ALXN1840 on the 
LBC responder rate 
• 
LBC responder rate at 48 weeks 
• 
Explore the change in 24-hour urinary copper 
and urinary molybdenum 
• 
Change from baseline to 48 weeks in 24-hour 
urinary copper and urinary molybdenum 
Extension Period 
• 
Long term safety and efficacy 
• 
AEs, AESI, SAEs, laboratory tests 
(chemistry, hematology, coagulation, and 
urinalysis with microscopy), pregnancy 
testing in females of childbearing potential, 
physical examinations, vital signs, and ECGs. 
• 
CGI-I and the change from baseline in CGI-S 
• 
Change from baseline in MELD score 
• 
Change from baseline in UWDRS Part II total 
score 
• 
Change from baseline in UWDRS Part III 
total score and individual item/subscales 
(arising from a chair, gait, handwriting, and 
speech) 
• 
NCC/NCCcorrected responder rate 
• 
LBC responder rate 
• 
Concentration-time profiles of the directly 
measured PK/PD and biomarkers 
Abbreviations: 25F = 25-foot; 9-HPT = 9-hole peg test; AE = adverse event; AESI = adverse event of special 
interest; AUEC = area under the effect-time curve; BPRS-24 = Brief Psychiatric Rating Scale-24; CGI-I = Clinical 
Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-Severity Scale; Cp = ceruloplasmin; 
CpC = ceruloplasmin-bound copper; ECG = electrocardiogram; EQ-5D(Y) = EuroQoL 5 Dimensions (Youth); 
FIB-4 = Fibrosis-4; LBC = labile bound copper; MELD = Model for End-stage Liver Disease; (d)(c)NCC = (directly 
measured) (calculated) non-ceruloplasmin-bound copper; cNCCcorrected = calculated corrected NCC; 
PD = pharmacodynamics; PK = pharmacokinetics; PRO = Patient Reported Outcomes; PUF = plasma ultrafiltrate; 
QoL = quality of life; SAE = serious adverse event; SoC = standard of care; TPC = tripartite complex; TSQM-9 = 
Treatment Satisfaction Questionnaire for Medication-9; UWDRS = Unified Wilson Disease Rating Scale 
 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
Figure 1 provides a schematic view of the study design. 
Figure 1: 
Schema for Study WTX101-301 
 
Abbreviation: SoC = standard of care. 
 
4.1.1. 
Primary Evaluation Period 
This is a randomized, rater-blinded, multi-center study assessing the efficacy and safety of 
ALXN1840 versus SoC. In the Primary Evaluation Period, efficacy and safety will be assessed 
for an individualized ALXN1840 dosing regimen compared with SoC administered for 48 weeks 
in patients with WD who are aged 12 years and older (18 years and older in Germany). 
Approximately 180 patients will be enrolled globally. 
Patients meeting all inclusion and no exclusion criteria will be enrolled into the study and studied 
as outpatients. Eligible patients with WD will be enrolled into 1 of 2 cohorts. 
• Cohort 1: Patients who have received SoC therapy (ie, chelation therapy with 
penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc 
therapy) for > 28 days 
• Cohort 2: Patients who are treatment naïve or who have received SoC therapy for 
≤ 28 days  
All enrolled patients will be randomized by cohort in a 2:1 ratio to treatment with ALXN1840 or 
SoC (either as continued therapy in Cohort 1 or as continued or initial therapy in Cohort 2). 
Treatments will be assigned randomly, stratified by cohort, utilizing an interactive voice/web 
response system. 
Screening
28 Days
Primary Evaluation Period
48 Weeks
Cohort 1 and Cohort 2
Extension 
Period
Up to 60 months
ALXN1840
SOC
ALXN1840
Informed 
consent
Baseline
*Week 48
48 hr washout 
of prior SoC  
prior to 
treatment if 
randomized to 
ALXN1840
Week 4
Week 6
Week 8
Week 12
Week 24
Week 18
Week 36
Week 268
*If patient continues to extension
**If patient does not continue to extension
**Week 52
Week 24, then every 24 
weeks for patients from 
Study WTX101-201 and 
patients who received SoC in 
the Primary Evaluation 
Period
Cohort 1 or Cohort 2
Randomization
Extension population:
•
Completed WTX101-301 
Primary Evaluation Phase 
•
Completed WTX101-201
Extension Day 1 then every 
12 weeks from Week 60 for 
patients who received 
ALXN1840 in the Primary 
Evaluation Period


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Patients who are randomized to receive ALXN1840 will be required to withhold treatment with 
SoC for ≥ 48 hours immediately prior to first study assessment on Day 1. Patients who are 
randomized to ALXN1840 will receive ALXN1840 as delayed-release tablets for oral 
administration at doses ranging from 15 mg every other day (QOD) to 60 mg QD. Efficacy and 
safety assessments will be performed at scheduled visits, while AEs and concomitant 
medications will be monitored continuously throughout the study. Patients randomized to SoC 
will initiate treatment or continue treatment on their current regimen where possible, without 
compromising the safety of individual patients. 
The Primary Evaluation Period will consist of an up to 28-day Screening Period, a 1-day 
Enrollment Visit, a 48-week Treatment Period, and a Follow-up Visit 4 weeks after the last dose 
for patients who do not elect to continue in the Extension Period.  
4.1.2. 
Extension Period 
Patients in Study WTX101-301 who have completed the 48-week Treatment Period and patients 
who completed participation in Study WTX101-201 will be offered the opportunity to participate 
in an up to 60-month Extension Period to evaluate the long-term safety and efficacy of 
ALXN1840.   
If a patient from Study WTX101-201 qualifies for the Extension Period and chooses to 
participate, they must sign an additional informed consent form (ICF) for the Extension Period. 
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. 
4.2. 
Scientific Rationale for Study Design 
Control of exchangeable copper is essential for management of hepatic and neuropsychiatric 
manifestations in patients with WD. Results from Studies WTX101-HV-106 and WTX101-201 
support a proposed mechanism of action of ALXN1840 whereby copper is mobilized to the 
bloodstream and sequestered through the formation of stable TPCs, with a low risk for 
neurologic worsening due to copper exchange from chelators with a lower affinity for copper. 
Study WTX101-301 is the first prospective, randomized study to compare tetrathiomolybdate 
with penicillamine, trientine or zinc in WD.  
The primary endpoint will integrate copper mobilization and elimination (ie, copper control) 
throughout the 48-week Primary Treatment Period by assessment of AUEC for plasma dNCC 
concentration. AUEC characterizes and measures the cumulative effect of ALXN1840. 
Measurement of dNCC in plasma is highly sensitive and accurate, requiring no special formulas 
or assumptions. As proposed, dNCC AUEC0 – 48W is an indirect measure of copper mobilization 
and elimination. Results from the Phase 2 Study WTX101-201 are strongly suggestive of rapid 
onset of TPC formation within hours following ALXN1840 administration, potent mobilization 
of copper from tissue into plasma persisting through Week 12, and nearly complete decoppering 
by Week 24. Over the course of 24-48 weeks of treatment with ALXN1840 in Study WTX101-
201, the plasma dNCC concentration continued to gradually decrease to baseline. The gradual, 


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sustained reduction of plasma dNCC concentrations over time indicates that copper mobilized by 
ALXN1840 is not simply redeposited back into the tissue, as both plasma concentrations of 
tetrathiomolybdate (from a daily weighted average dose of 30 mg ALXN1840 administration) 
and circulating bodily albumin (the other 2 components of TPC) remained essentially constant 
and sufficiently available for TPC formation throughout the study. Thus, daily mean dNCC 
AUEC0 – 48w is suitable as a quantitative measure of ALXN1840 treatment effect (tissue 
decoppering) in WD based on its mechanism of action. 
Measurement of the AUEC for dNCC as the primary outcome measure overcomes many of the 
limitations of the estimated cNCC approach. Calculated estimates of NCC rely on separate 
measurements of plasma total copper and ceruloplasmin protein. The amount of copper within 
Cp is further estimated based on an assumed ratio of 6 copper atoms per molecule of Cp, which 
may be an overestimate in WD. Overestimation of ceruloplasmin-bound copper (CpC) results in 
approximately 20% of samples yielding physiologically impossible negative values for cNCC. In 
patients treated with ALXN1840, estimation of cNCC requires additional correction for the 
presence of copper in the TPC. TPC copper cannot be measured directly but must instead be 
estimated based on the plasma concentration of molybdenum.  
For the primary evaluation of efficacy and safety, a treatment period of 1 year was chosen to 
allow sufficient time for evaluation of changes in biochemical measures of copper, as well as 
changes in liver function and neurologic disability and an adequate evaluation of safety and 
tolerability. 
Following the Primary Evaluation Period, patients randomized to SoC during the Primary 
Evaluation Period will switch to treatment with ALXN1840 in the Extension Period, providing 
further evaluation of changes in copper, liver function and neurologic dysfunction. The 
Extension Period of up to 5 additional years will allow further evaluation of the long-term 
efficacy, safety, tolerability, and clinical outcomes in patients treated with ALXN1840.  
The phenotypic spectrum of WD was taken into account when selecting hepatic and neurologic 
secondary endpoints. The Model for End-Stage Liver Disease (MELD) score is a widely 
accepted composite score which reflects the severity of liver disease and is used to estimate 
expected survival in patients with acute or chronic liver failure (UNOS, 2015). The MELD score 
ranges from 6 (normal) to 40 (very severe liver failure). MELD scores for patients in Study 
WTX101-301 are expected to be nearly normal, as patients with decompensated liver disease are 
excluded. The MELD score is expected to remain stable or improve to a modest extent. The 
Nazer score is similar to the MELD score, but was developed specifically for liver disease 
associated with WD. 
The UWDRS scoring system was developed specifically for the motor and movement disorders 
associated with chronic copper neurotoxicity in WD. Based on advice from the FDA, Alexion 
decided to assess some individual items/subscales of the UWDRS Part III (arising from a chair, 
gait, handwriting, and speech) in addition to the UWDRS Parts I, II, and III overall, to further 
define the range of burdensome signs and symptoms of WD, so as to further understand the 
assessment of treatment effects on patients with WD. The UWDRS scores for consciousness 
(Part I) and abnormal neurologic examination findings (Part III) will be determined by a trained 
neurologist rater who is blinded to study treatment randomization. These scores will be used to 
provide a rigorous dataset for evaluating changes from baseline. 


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Inclusion of adolescents ≥12 years in this protocol (except in Germany, where only patients aged 
18 years and older are included) is justified by the natural history of WD. In a large European 
cohort of 1357 patients, the average age at diagnosis of WD was 19.8 years, and half of all 
patients were diagnosed before the age of 18 (Ferenci, 2019). Compared with adults, children 
and adolescents are more likely to present with hepatic symptoms rather than neuropsychiatric 
manifestations. The goal of treatment in adolescents is the same as in adults, namely prompt and 
effective removal of excess copper from tissues. 
4.3. 
Justification for Dose 
4.3.1. 
ALXN1840  
ALXN1840 daily dosing intended for use in this study is based on the doses established as safe 
and effective in the previous WD studies performed with ALXN1840. Daily doses of 30 to 
60 mg have been shown as effective in de-coppering newly diagnosed patients with WD or 
maintaining a normal copper level in patients with WD previously treated with SoC (Weiss, 
2017). In patients with WD treated with ALXN1840, asymptomatic elevation hepatic 
transaminases and/or gamma glutamyltransferase were seen in 39% of patients. Elevation of 
liver enzymes was dose-dependent and reversible with interruption or dose reduction of 
ALXN1840. Therefore, the dose of ALXN1840 in the current study will start at 15 mg daily and 
will be limited to a maximum of 60 mg daily, the highest dose studied and considered to have a 
good safety profile in healthy volunteers. The intent is to individually titrate the dose of 
ALXN1840, as is done with the currently available chelators, to an appropriate dose based on 
cNCC levels adjusted for molybdenum plasma concentration, hematology values, and liver 
function tests. The dosing regimen for ALXN1840, therefore, includes the following features: 
• Initial dosing QD as described in Section 6.2.3.1. 
• Up titration design and individualized dosing as indicated by neurological and liver 
function testing, after Sponsor approval. 
In line with currently available WD treatments, the dose of ALXN1840 will be adjusted in 
individual patients, depending on clinical response and safety, as appropriate, based on protocol 
specified guidelines. A detailed dosing guide for ALXN1840 dose modifications is outlined in 
Section 6.2.3.2 and Table 4.  
4.3.2. 
Standard of Care 
To the extent possible, without compromising the safety of individual patients, the type and dose 
of SoC medication should not be changed throughout the 48-week study period. Dose 
modification guidance is detailed in Section 6.2.3.4.  
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last patient last visit of the 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 apply: 
1. Established diagnosis of WD by Leipzig-Score ≥ 4 documented by testing as outlined in 
the 2012 European Association for the Study of Liver WD Clinical Practice Guidelines 
(Ferenci, 2003; EASL, 2012). Note: Historical test results for WD (including some or all 
of the following: presence of Kayser-Fleischer rings, neurologic symptoms, serum 
ceruloplasmin below the reference range, Coombs-negative hemolytic anemia, elevated 
liver or urinary copper, and presence of mutations in the ATP7B gene, or other, as 
considered appropriate) may be used to confirm the diagnosis of WD. 
2. 12 years of age or older at time of informed consent/assent (18 years and older in 
Germany). 
3. Willing and able to give written informed consent and comply with the study visit 
schedule. For patients < 18 years of age (or below the age of adulthood under Japanese 
local law for patients in Japan), patient's legal guardian must be willing and able to give 
written informed consent and the patient must be willing to give written informed assent 
(if applicable as determined by the central or local Institutional Review Board [IRB]/ 
Institutional (or Independent) Ethics Committee [IEC]). If allowable per local 
regulations, a patients’ Legally Acceptable Representative may provide informed consent 
if a patient is unable to do so. 
4. Able to understand and willing to comply with study procedures, restrictions, and 
requirements, as judged by the Investigator. 
5. Willing to withhold treatment with SoC for ≥ 48 hours immediately prior to first study 
assessment on Day 1. 
6. Adequate venous access to allow collection of required blood samples 
7. Willing to avoid use of vitamins and/or minerals containing copper, zinc, or molybdenum 
throughout the study duration 
8. Willing to avoid intake of foods and drinks with high contents of copper throughout the 
study duration 
9. Female patients of childbearing potential, if heterosexually active, must be willing to 
follow protocol-specified guidance for highly effective contraception starting at least 
6 weeks before the Day 1 visit and continuing through 28 days after the last dose of study 
drug (either ALXN1840 or SoC). Male patients, if heterosexually active, must be willing 
to follow protocol-specified guidance for highly effective contraception beginning at the 
Day 1 visit and continuing through 90 days after the last dose of study drug (either 
ALXN1840 or SoC). See Section 6.6 for additional details. 


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5.1.1. 
Patients who have completed Study WTX101-201 
Patients from Study WTX101-201 are eligible to roll over from that study to the Extension 
Period of Study WTX101-301 if they satisfy the below criteria. 
1. The patient is willing and able to give written informed consent and comply with the 
study visit schedule.  
2. Able to understand and willing to comply with study procedures, restrictions, and 
requirements, as judged by the Investigator. 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. Decompensated hepatic cirrhosis 
2. MELD score > 13 
3. Modified Nazer score > 7 (Dhawan, 2005) 
4. Clinically significant GI bleed within past 3 months 
5. Alanine aminotransferase > 2 × upper limit of normal (ULN) for patients treated for 
> 28 days with WD therapy (Cohort 1) 
6. Alanine aminotransferase > 5 × ULN for treatment naïve patients or patients who have 
been treated for ≤ 28 days (Cohort 2) 
7. Marked neurological disease requiring either nasogastric feeding or intensive inpatient 
medical care 
8. Hemoglobin < 9 g/dL  
9. Participation in a clinical study of an experimental or unapproved/unlicensed therapy 
during the screening period or within 4 weeks prior to informed consent 
10. History of seizure activity within 6 months prior to informed consent 
11. Pregnant (or women who are planning to become pregnant) or breastfeeding women 
12. Known sensitivity to ALXN1840, ALXN1840 excipients (anhydrous di-calcium 
phosphate, anhydrous sodium carbonate), or any of the ingredients contained in 
ALXN1840 or related compounds 
13. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus 
(patients with positive hepatitis C antibody result would require confirmation of active 
disease with a positive hepatitis C polymerase chain reaction test), or seropositivity for 
human immunodeficiency virus (HIV) 
14. Previous treatment with tetrathiomolybdate 
15. Any disease, disability, illness or abnormal laboratory values in the opinion of the 
Investigator, compromise patient safety or interfere with the collection or interpretation 
of study results 


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16. Patients with end-stage renal disease on dialysis (chronic kidney disease stage 5 
[CKD 5]) or creatinine clearance < 30 mL/min  
17. In the opinion of the Investigator, the patient and/or their legal guardian (in the case of 
adolescent patients or patients below the age of adulthood under Japanese local law for 
patients in Japan) is likely to be non-compliant or uncooperative during the study 
5.3. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently entered in the study due to failure to meet study entry criteria. 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 
(Schulz, 2010) and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, 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 Medical 
Monitor.  


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6. 
STUDY TREATMENTS 
6.1. 
Treatment Groups 
Patients in the Primary Evaluation Period will be randomized to either ALXN1840 or SoC 
treatment. Patients will be enrolled into 1 of 2 cohorts: 
• Cohort 1: Patients who have received SoC therapy (ie, chelation therapy with 
penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc 
therapy) for > 28 days  
• Cohort 2: Patients who are treatment naïve or who have received SoC therapy for 
≤ 28 days 
All patients in the Extension Period will receive treatment with ALXN1840.  
6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Formulation and Packaging 
6.2.1.1. 
ALXN1840  
ALXN1840 will be supplied as white, round, delayed-release tablets for oral administration. 
Each tablet contains 15 mg of the bis-choline salt of tetrathiomolybdate, bis[2-hydroxyethyl) 
trimethyl-ammonium] tetrathiomolybdate, and the following excipients: tribasic calcium 
phosphate, sodium carbonate, sodium starch glycolate, and magnesium stearate. The tablets are 
coated with an inner pre-coat (Opadry 03K19229 clear) and outer enteric coat (Acryl-EZE 
white). Tablets are debossed on 1 side with a hexagon. 
ALXN1840 will be supplied in treatment kits containing 28 tablets. The treatment kit consists of 
thermoform blister strips mounted into a cardboard wallet. Each treatment kit will 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. ALXN1840 must be stored, inventoried and the 
inventories carefully and accurately documented according to applicable state, federal and local 
regulations, ICH Guidelines, GCPs and study procedures. 
The ALXN1840 treatment kits should be stored at refrigerated conditions, 2°C to 8°C (36°F to 
46°F). 
6.2.1.2. 
Standard of Care 
Patients randomized to receive SoC treatment will continue their current therapy or initiate 
therapy with chelation with penicillamine or trientine, zinc, or a combination of both chelation 
and zinc therapy if they are not currently on SoC at the start of the study.  
Standard of care treatment should be stored according to the details in the package labeling. 


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6.2.2. 
Study Drug Preparation and Dispensing 
Appropriately trained employees of the study site will administer ALXN1840 on Day 1 and will 
instruct patients on how to correctly dose themselves on the days when they take ALXN1840 at 
home. Additional details will be provided in the Pharmacy manual.  
At each clinic visit, patients will be asked about their compliance with the agreed dosing regimen 
of ALXN1840 or SoC. Once compliance with ALXN1840 or SoC has been calculated, patients 
may be dispensed new ALXN1840 or SoC to cover dosing requirements until the next in-clinic 
visit if required. Drug accountability documentation for ALXN1840 and SoC will be kept at the 
individual clinical site including records of receipt and dispensing. 
6.2.3. 
Study Drug Administration 
6.2.3.1. 
ALXN1840  
ALXN1840 will be administered orally at doses ranging from 15 mg QOD to 60 mg QD. 
ALXN1840 will be administered QD or QOD in the fasted state (1 hour before or 2 hours after 
meals). 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. 
Individualized ALXN1840 dosing will be utilized throughout the study based on the following 
parameters: 
• Clinical criteria: dose-titration based on hepatic and neurological status 
• NCCcorrected: dose-titration instructed based on cNCC levels adjusted for the amount 
of copper bound to the ALXN1840 TPC 
• Safety monitoring: dose modification criteria are based on regularly scheduled 
assessments for recognized hematological effects of copper lowering, hepatic testing, 
and neurological test 
6.2.3.2. 
Dose Modification for ALXN1840 
In all patients, ALXN1840 will be administered at a 15 mg QD starting dose on Day 1 
continuing for the first 4 weeks. After 4 weeks, up-titration to 30 mg QD may be performed after 
Sponsor approval, if the disease is not adequately controlled, taking into account the patient’s 
clinical status and free blood copper levels, as measured by cNCC/cNCCcorrected, and none of the 
Dose Modification Criteria apply. Further dose increases are possible after Sponsor approval in 
15 mg increments at least 4 weeks apart following the same aforementioned criteria. The dose 
should be lowered or interrupted if any of the relevant Dose Modification Criteria are met. 
Deviation from the dose modification guidelines must be agreed with the Sponsor Medical 
Monitor. 
When cNCCcorrected levels have fallen to within the normal range (< 2.3 µmol/L), and/or the 
clinical status of the patient is stable or improved for 2 consecutive study visits, ALXN1840 
dosage may be maintained or reduced at the discretion of the Investigator. To avoid 
over-treatment, the dose may be reduced at any time, at the discretion of the Investigator, guided 
by the following: if the patient’s clinical status indicates possible over-treatment and/or 


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cNCC/cNCCcorrected values are below the normal range. Specific criteria for dose modification of 
ALXN1840 are detailed in Table 4.


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Table 4: 
ALXN1840 Dose Modifications for Individual Patients  
Test 
Result 
Conditions 
Action With ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Re-Challengeb,c, d 
ALT 
> 5 × ↑ from 
baseline 
ALT above normal 
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 normal 
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 normal 
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 normal 
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,c, d 
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 level. 
> 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 level. 
> 30% ↓ from 
baseline 
Platelets below 
normal 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 level. 
> 30% ↓ from 
baseline 
Neutrophils below 
normal 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. 
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 
Medical Monitor. 


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Test 
Result 
Conditions 
Action With ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Re-Challengeb,c, d 
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 Medical Monitor 
will evaluate the need for dose 
modification (interruption, 
increase or decrease) based on 
copper 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 exam part 
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 Medical 
Monitor. 
Psychiatric 
assessment 
Clinically significant signs of psychiatric 
worsening 
Investigator and Medical Monitor 
will evaluate the need for dose 
modification (interruption, 
increase or decrease) based on 
copper 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 Medical 
Monitor. 
a. For changes in safety monitoring, weekly repeat testing for laboratory parameters can be completed by a home healthcare nurse if a routine study visit is not 
scheduled during this time period. 
b. A maximum of 3 re-challenges will be allowed for ALXN1840. 
c. For re-challenges, patients who were on 15 mg QOD should be re-challenged at the 15 mg QOD dose. 
d. The Investigator, in consultation with the Medical Monitor, may change dose and dose frequency in patients who require re-challenge. 
Abbreviations: ALT = alanine aminotransferase; 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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6.2.3.3. 
Standard of Care 
To the extent possible, without compromising the safety of individual patients, the type of SoC 
medication should not be changed throughout the 48-week study period, unless required as part 
of the treatment (eg, if a patient initiates SoC at the start of the study).  
Similarly, to the extent possible, without compromising the safety of individual patients, the 
dosing of the SoC medication should remain consistent throughout the 48-week study period, 
unless required as part of the treatment (eg, titration of SoC initiated at the start of the study). 
6.2.3.4. 
Dose Modification for Standard of Care 
If the SoC dose, frequency or specific drug agent (ie, penicillamine, trientine or zinc) needs to be 
changed for efficacy or safety reasons, the specific change and rationale for it must be 
documented. The rationale for a change from one agent to another (eg, a change from 
penicillamine or trientine to zinc due to intolerance or AE) must also be documented. Deviation 
from the dose modification guidelines must be agreed with the Sponsor Medical Monitor. 
Specific criteria for dose modification of SoC if neurologic or psychologic worsening occurs are 
detailed in Table 5. 


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Table 5: 
Standard of Care Dose Modifications for Individual Patients 
Test 
Result and Conditions 
Action With SoC 
Dosing 
Changes in Safety 
Monitoringa 
Re-
Challengea,b,c 
UWDRS-
III and 
clinical 
neurologica
l 
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 Medical 
Monitor will evaluate 
the need for dose 
modification 
(interruption, increase or 
decrease) based on 
copper 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 complete 
UWDRS exam. Re-
evaluate neurologic 
status, including 
complete UWDRS 
examination, no later 
than next study visit, 
even if not planned per 
the SoA. 
Discuss with the 
Medical 
Monitor. 
Psychiatric 
assessment 
Clinically significant 
signs of psychiatric 
worsening 
Investigator and Medical 
Monitor will evaluate 
the need for dose 
modification 
(interruption, increase or 
decrease) based on 
copper 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 
Medical 
Monitor. 
a. A maximum of 3 re-challenges will be allowed. 
b. For re-challenges, patients who were on 15 mg QOD should be re-challenged at the 15 mg QOD dose. 
c. The Investigator, in consultation with the Medical Monitor, may change dose and dose frequency in patients who 
require re-challenge.  
Abbreviations: QOD = every other day; SoA = Schedule of Activities; SoC = standard of care; UWDRS = Unified 
Wilson Disease Rating Scale. 
6.2.3.5. 
ALXN1840 Administration During the Extension Period 
All patients will be treated with ALXN1840 in the Extension Period. Patients who received 
ALXN1840 in the Primary Evaluation Period of Study WTX101-301 will continue to receive the 
same dose they received at last study visit in the Primary Evaluation Period; individualized 
dosing will be subsequently managed described in Section 6.2.3.1. Patients who transition from 
SoC in the Extension Period will be administered ALXN1840 as described in Section 6.2.3.1. 
Dose modification, if required, will be made as described in Section 6.2.3.2. Patients who 
received ALXN1840 in Study WTX101-201 will continue to receive the same dose they 
received at the last study visit in the Extension Period. 
ALXN1840 treatment kits will be dispensed to patients as outlined in the Pharmacy manual. A 
sufficient number of kits should be dispensed to the patient to cover the need until the next visit, 
including the possible need for up titration.  


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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Patients will be randomized after meeting all inclusion and none of the exclusion criteria. 
Randomization may be required on or before Day -2 to allow for SoC to be withheld for ≥ 48 
hours for patients randomized to receive ALXN1840. 
Patients will be randomized, stratified by cohort, via an interactive voice/web response system in 
a 2:1 ratio to treatment with ALXN1840 or continued treatment with SoC in Cohort 1 or as 
continued or initial therapy in Cohort 2. 
This study is rater-blinded for the UWDRS assessment only. The rater will be blinded and will 
have no knowledge of the patient’s treatment assignment and no access to systems that could 
result in potential unblinding of treatment assignment. Both raters and patients will be instructed 
to avoid lines of inquiry, questions, and responses that could potentially lead to their unblinding. 
The rater assessments will be strictly limited to administration of the protocol specified 
instruments and assessments. 
6.4. 
Treatment Compliance 
Compliance with ALXN1840/SoC will be assessed by the study team at study visits. Changes in 
dose regimen (including any deviation from the prescribed dosing regimen), missed doses and 
drug interruptions will be recorded in the electronic data capture (EDC) system.  
Patients who take 80% or more of the scheduled doses of ALXN1840/SoC 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. 
6.5. 
Prior and Concomitant Medications and/or Procedures 
Any medications 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 electronic 
case report form (eCRF). Medications specific for WD taken at any time prior to the study will 
also be recorded.  
Patients should follow their study doctor's advice regarding adherence to a low copper diet. 
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 
Medical Monitor with questions. Refer to the current Investigator’s Brochure for potential 
inhibitory effect of ALXN1840 on the metabolism of certain drugs that are substrates of 
cytochrome P450 (CYP) enzymes (eg, CYP2C9 and CYP2B6). 
• Gadolinium- and iodine-containing contrast media are known to interfere with tests 
on molybdenum. Gadolinium- and iodine-containing contrast media are requested not 
to be used within the 96 hours prior to molybdenum testing. 


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• Barium-containing contrast media are known to interfere with tests on copper. 
Barium-containing contrast media are requested not to be used within the 96 hours 
prior to copper testing. 
6.5.1.1. 
Prohibited Medications 
The following medications are prohibited during the study: 
• Estrogens may interfere with biliary copper 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 6.6. 
• Vitamin E has been used as an adjunctive therapy in WD treatment regimens. Patients 
must not initiate use of vitamin E during the study. 
• Use of an experimental or unapproved/unlicensed therapy. 
• Patients must not use vitamins and/or minerals containing copper, zinc, or 
molybdenum. 
6.6. 
Contraception Guidance 
6.6.1. 
Guidance for Female Patients 
Female patients of non-childbearing potential are exempt from contraception requirements. 
Non-childbearing potential for female patients is defined as any of the following: 
• Prior to first menses 
• Postmenopausal, as documented by amenorrhea for at least 1 year prior to the Day 1 
visit and follicle stimulating hormone (FSH) serum levels consistent with 
postmenopausal status 
• Permanent sterilization at least 6 weeks prior to the Day 1 visit: 
− Hysteroscopic sterilization 
− Bilateral tubal ligation or bilateral salpingectomy 
− Hysterectomy 
− Bilateral oophorectomy 
The following text applies to all patients except those in Canada or Japan, for whom details are 
provided below. Female patients or female partners of male patients of childbearing potential 
(including breastfeeding females), if heterosexually active, must use a highly effective method of 
contraception starting at least 6 weeks before the Day 1 visit and continuing through 28 days 
after the last dose of study drug, including at least one of the below. Female patients must not 
donate eggs (ova, oocytes) for the purpose of reproduction during this period. 
a. Intrauterine device (without copper) in place for at least 6 weeks  
b. Progestogen-only hormonal contraception (either oral, injectable, or implantable) for 
at least 6 weeks  


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c. Intrauterine progestogen releasing system for at least 6 weeks  
d. Bilateral tubal occlusion for at least 6 weeks  
e. Combined (estrogen and progestogen containing) hormonal contraception (either oral, 
intravaginal, or transdermal) for at least 6 weeks. 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; see Section 6.5.1.1.  
f. Surgical sterilization of the male partner (medical assessment of azoospermia is 
required if vasectomy was performed within the prior 6 months) 
The following applies to patients in Japan only: 
A female patient of childbearing potential who is sexually active must use one of the highly 
effective contraceptive methods listed below, which are approved in Japan.   
a. Intrauterine device or intrauterine progestogen-releasing system (without copper) in 
place for at least 6 weeks  
b. Bilateral tubal occlusion for at least 6 weeks  
c. Combined (estrogen and progestogen containing) hormonal contraception for at least 
6 weeks. 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; see 
Section 6.5.1.1.  
d. Surgical sterilization of the male partner (medical assessment of azoospermia is 
required if vasectomy was performed within the prior 6 months) 
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. 
The following applies to patients in Canada only: 
Female patients of childbearing potential must use two highly effective methods of 
contraception, or one effective plus one highly effective method, including at least one of the 
following highly effective methods:  
g. Intrauterine device (without copper) in place for at least 6 weeks.  
h. Progestogen-only hormonal contraception (either oral, injectable, or implantable) for 
at least 6 weeks.  
i. Intrauterine progestogen releasing system for at least 6 weeks.  


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j. Bilateral tubal occlusion for at least 6 weeks.  
k. Combined (estrogen and progestogen containing) hormonal contraception (either oral, 
intravaginal, or transdermal) for at least 6 weeks. Estrogen-containing hormonal 
contraception is acceptable only if it has been used for at least 6 weeks immediately 
prior to the Day 1 visit.  
Other methods of contraception that are not considered highly effective for female patients in 
Canada 
• Barrier methods, such as male or female condoms, diaphragm, or cervical cap, used 
alone or in combination, are acceptable in combination with a highly effective 
method. 
• Spermicides must be used in combination with barrier methods, and such a 
combination is to be considered a single method. 
• Withdrawal (coitus interruptus) is not acceptable. 
• Lactational amenorrhea is not acceptable. 
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 6 weeks.  
• Periodic abstinence (eg, calendar, symptothermal, or post-ovulation methods) is not 
considered a highly effective method of contraception for female patients. 
6.6.2. 
Guidance for Male Patients With a Partner Who is a Woman of Childbearing 
Potential 
• Male patients who have had a vasectomy greater than 6 months prior must use a 
condom during heterosexual intercourse. Male patients who have had a vasectomy 
less than 6 months prior must use a condom and spermicide during heterosexual 
intercourse. 
• Male patients who have not had a vasectomy must use a condom and spermicide 
during heterosexual intercourse. 
• 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 must use a condom and 
spermicide during intercourse. 


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− Periodic abstinence (eg, calendar, symptothermal, or post-ovulation methods for a 
female partner) is not considered a highly effective method of contraception for 
male patients. 
• Male patients must not donate sperm from the Day 1 visit until 90 days after the last 
dose of study drug. 
• 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. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PATIENT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
Dose modification and reasons for interruption or discontinuation of dosing are detailed in 
Section 6.2.3.2 for ALXN1840 and Section 6.2.3.4 for SoC. 
7.2. 
Patient Discontinuation/Withdrawal from the Study 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
• The patient or legal guardian (for adolescent patients, or patients below the age of 
adulthood under Japanese local law for patients in Japan) 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 decompensation 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 
− Patients entering the Extension Period from Study WTX101-201 must follow the 
requirements for highly effective contraception as defined by the protocol for 
Study WTX101-301. 
• Requirement to take prohibited concomitant medication 
• Patient failure to comply with protocol requirements or study-related procedures 
A participant must be withdrawn from this study if they receive an experimental or 
unapproved/unlicensed therapy. 
See the SoA in Table 1, Table 2, and Table 3 for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
Early Termination (ET) Visit. Patient withdrawal (including any reason for withdrawal, if 
provided by the patient) must be documented in the eCRF. 


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In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records. 
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. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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8. 
STUDY PROCEDURES AND ASSESSMENTS  
Study procedures and their timing are summarized in the Schedules of Activities in Section 1.2. 
The procedures to be performed at Screening and during the Primary Evaluation Period are 
detailed in Table 1. The procedures to be performed for patients who enter the Extension Period 
and were randomized to SoC are detailed in Table 2. The procedures to be performed for patients 
who enter the Extension Period and were either randomized to ALXN1840 in 
Study WTX101-301 or completed Study WTX101-201 are detailed in Table 3. 
The end of study for each patient and for the overall study is detailed in Section 4.4. 
8.1. 
Efficacy Assessments  
The time points for all efficacy assessments are provided in the SoA (Section 1.2). 
8.1.1. 
Assessment of Copper 
Measurements of plasma dNCC concentration are the primary assessment for the efficacy of 
ALXN1840 treatment in WD. The AUEC for plasma dNCC concentration over time aims to 
quantify the dynamic tissue mobilization and decoppering effect of ALXN1840 based on 
preliminary analysis of Study WTX101-201 data. This assessment is also applicable to SoC 
treatments based on preliminary analysis of Study WTX101-203 data. In addition, plasma Cp, 
CpC, plasma total copper, and LBC will be measured with AUEC calculated for plasma total 
copper and LBC. 
The LBC method measures exchangeable plasma copper that is not bound to either Cp or TPC. 
8.1.2. 
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 above. 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 international normalized ratio for prothrombin time (INR) to predict survival. In patients 
with a MELD score > 11, the serum sodium is also taken into account (UNOS, 2015). 
The MELD score will be calculated by a Central Laboratory. 
8.1.3. 
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 neurologist who is blinded to the treatment 
randomization, while UWDRS Part II may be reported to a non-blinded member of the study 
team by the patient, family member, or caregiver (Czlonkowska, 2007; Leinweber, 2008). The 
UWDRS has not been formally evaluated in adolescents. However, the components of Part I 
(level of consciousness), Part II (patient or caregiver-reported disability) and Part III (neurologic 


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examination findings) are not fundamentally different between adults and adolescents. Patients 
aged 12 years and older are expected to be able to comply with UWDRS assessments. 
8.1.4. 
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 Clinical Global Impression-Severity scale (CGI-S) 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 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 Clinical Global Impression-Improvement scale (CGI-I) 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. 
8.1.5. 
Three Most Troublesome Symptoms 
Patients will be assessed for their 3 most troublesome symptoms of WD. Each patient, or the 
patient and caregiver, will identify their 3 most troublesome symptoms as well as the impact 
these symptoms have on their activities of daily living. In addition to collection via a paper 
questionnaire, the patient’s 3 most troublesome symptoms may also be recorded by the site staff 
via video for patients who provide separate informed consent. Note: this information is not 
required to be collected via video in the Extension Period of the study and also for patients who 
switch from SoC to ALXN1840 during the first year of the Extension Period. 
8.1.6. 
Fibrosis-4 Index/Transient Elastography 
The Fibrosis-4 (FIB-4) Index is a formula used to predict liver fibrosis based on standard 
biochemical values (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and 
platelet count) and age. The FIB-4 Index will be calculated by a Central Laboratory. 
Transient elastography is a non-invasive imaging method that evaluates the degree of liver 
fibrosis or fatty deposits in the liver, by determining the speed of sound waves through the liver 
utilizing a sonogram. 
8.1.7. 
Modified Nazer Score 
The modified Nazer Score is an assessment of liver status and consists of a composite of 
5 laboratory parameters: aspartate aminotransferase, international normalized ratio, 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. 


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8.1.8. 
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 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, etc) who has completed the training required to administer the 
instrument. 
8.1.9. 
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. 
Note that although the EQ-5D is designed for use in patients aged 16 years and older, the EQ-5D 
can also be used in patients aged 12 to 15 years and is appropriate given these patients will be 
followed for several years in the study (Van Reenen, 2014). 
8.1.10. 
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? 
8.1.11. 
Timed 25F Walk Test 
The Timed 25-foot (25F) Walk Test is a quantitative mobility and leg function performance test 
based on a timed 25-foot walk. Scoring for the Timed 25F Walk Test is the average of the 
2 trials. Patients may use assistive devices when doing this task.  
8.1.12. 
Nine-Hole Peg Test 
The 9-Hole Peg Test (9-HPT) is a brief, standardized, quantitative test of upper extremity 
function. Both the dominant and non-dominant hands are tested twice. The total time to complete 
the task is recorded. Two consecutive trials with the dominant hand are immediately followed by 
two consecutive trials with the non-dominant hand. 


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8.1.13. 
Non-Verbal Stroop Interference Test 
In psychology, the Stroop effect is a demonstration of interference in the reaction time of a task. 
There will not be any verbal communication during this test. The test will be taught with 
nonverbal directions, using gestures and demonstration.  
8.1.14. 
Digit Span Test 
The complete Digit Span Test is measured for forward and reverse-order recall of digit 
sequences and digit span sequencing. Digit sequences are presented beginning with a length of 
2 digits and 2 trials are presented at increasing list length. Testing ceases when the patient fails to 
accurately report either trial at 1 sequence length or when the maximal list length is reached 
(9 digits, 8  backwards).  
8.2. 
Safety Assessments 
The time points for all safety assessments are provided in the SoA (Section 1.2). 
8.2.1. 
Physical Examination 
A physical examination is required during screening and will include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose, and throat), lymph nodes, thyroid, and musculoskeletal (including 
spine and extremities) systems. Unified Wilson Disease Rating Scale Part III is the neurological 
examination used in this study.  
Note: A neurological examination will be conducted by a blinded neurologist for UWDRS 
Part III on Day 1 (see Section 8.1.3). 
An abbreviated physical examination consists of a body system relevant examination based upon 
Investigator (or designee) judgment and patient symptoms. At least 1 body system must be 
checked for an abbreviated exam. 
8.2.2. 
Vital Signs 
Vital sign measurements will be taken after the patient has been resting for at least 5 minutes and 
will include systolic and diastolic blood pressure (BP; mm Hg), heart rate (beats/minute), 
respiratory rate (breaths/minute), height, weight, and temperature (°C or °F). 
8.2.3. 
Electrocardiograms 
Single 12-lead electrocardiograms (ECGs) will be obtained in triplicate, as outlined in the SoA 
(Section 1.2) using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. 
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 eCRF. 


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8.2.4. 
Clinical Laboratory Evaluations 
Clinical laboratory measures include chemistry, hematology, coagulation, and urinalysis (with 
microscopy). All protocol-required laboratory assessments, as defined in Section 10.2 
(Appendix 2), must be conducted in accordance with the laboratory manual and the 
SoA (Section 1.2). 
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.  
Detailed procedures of sampling preparation, storage, and shipment will be described in a 
specific laboratory manual that will be provided to all sites. 
8.2.5. 
Pregnancy Test 
For females of childbearing potential, a serum or urine pregnancy test (ie, beta-human chorionic 
gonadotropin) will be performed according to the SoA (Section 1.2).  
In addition to pregnancy tests detailed at the visits in the SoA, females of childbearing potential 
in Austria only will be required to perform urine pregnancy tests at least every 4 weeks at their 
home or the study site throughout their time in the study. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
Serum and urine pregnancy tests will only be performed for females of childbearing potential. 
Female patients of childbearing potential must not be pregnant nor breastfeeding and must have a 
negative serum pregnancy test at Screening. Positive urine pregnancy results will be confirmed 
by a serum pregnancy test.  
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.3 (Appendix 3). 
Adverse events will be reported 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 intervention or study procedures, or that 
caused the patient to discontinue the study (see Section 7).  
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All events will be collected from the signing of the ICF until the follow-up contact specified in 
the SoA (Section 1.2). 
Medical occurrences that begin before the start of ALXN1840/SoC but after obtaining informed 
consent will be recorded as pre-treatment AEs. 


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All SAEs will be recorded and must be reported to the Sponsor or designee within 24 hours, as 
indicated in Section 10.3. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after the conclusion of 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs, and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3 
(Appendix 3). 
8.3.2. 
Method of Detecting AEs and SAEs 
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 and non-serious AEs of special interest (AESIs) (as defined 
in Section 8.3.6), 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 given in Section 10.3 (Appendix 3). 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of patients and the 
safety of a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 


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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, both in development or postapproval, 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 (ie, ALXN1840 or SoC) or withdraws from the study. 
If a female patient or a patient’s female partner becomes pregnant during the conduct of this 
study, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and Outcome 
Form” to Alexion Global Drug Safety (GDS) via fax or email (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 facsimile (Section 10.4). 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that the investigational 
product 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, spontaneous abortion, fetal death, stillbirth, congenital anomalies, and 
ectopic pregnancy). Elective abortions without complications should not be reported as AEs. 
8.3.6. 
Adverse Events of Special Interest  
Any new neurological symptom or clinically significant worsening of an ongoing neurological 
symptom after initiation of study drug (ALXN1840 or SoC) will be designated to be an AESI, 
whether serious or non-serious. 
If a patient has an AESI, in addition to assessments deemed clinically relevant by the 
Investigator, the following assessments should be performed to the extent possible to help assess 
the AE and patient status: UWDRS Part III, non-verbal Stroop Interference Test, Digit Span 
Test, and the CGI-I and CGI-S. The Investigator or Sub Investigator can perform additional 
assessments or laboratory testing at their discretion. 
Adverse events of special interest will be assessed by a panel of 3 independent neurologists not 
participating in the study. The panel will assess the probability that clinically significant 
worsening or a new clinically significant neurological symptom is related to disease progression 
or caused by the study drug (ALXN1840 or SoC). They will be blinded to the treatment given to 
the patient. All available relevant patient information will be provided to this panel to aid in their 
assessment. The assessment of AESIs by the panel will be independent of and in addition to the 
usual assessments of the AE, including assessments of severity (intensity) and causality, by both 
the Investigator and Alexion. 


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8.4. 
Overdose 
For patients receiving ALXN1840 an overdose is defined as any daily dose exceeding 60 mg. 
For patients receiving SoC, an overdose is defined as any daily dose exceeding the maximum 
daily dose listed on the local label in that country. 
Adverse events related to overdose of both ALXN1840 and SoC will be captured in the EDC 
system. 
8.5. 
Pharmacokinetics, Pharmacodynamics, and Biomarkers 
The PK/PD/Biomarker profiling visits are specified in the Schedules of Activities (Table 1, 
Table 2, and Table 3). The actual date and time (24-hour clock time) of each sample will be 
recorded. Pre-dose whole blood samples will be collected at each designated visit for the 
measurement of the following ALXN1840 PK, PD, and biomarker analysis: 
8.5.1. 
Pharmacokinetics 
Blood samples for PK analysis will be collected to measure plasma total molybdenum and 
plasma ultrafiltrate (PUF) molybdenum. 
8.5.2. 
Pharmacodynamics 
Blood samples will be collected to directly measure plasma total copper, PUF copper, dNCC, 
and LBC. Calculations may be performed for cNCC and cNCCcorrected, the latter of which is non-
ceruloplasmin-bound and non-molybdenum-albumin-bound copper.  
8.5.3. 
Biomarkers and Biobank Samples 
Blood samples will be collected to measure plasma Cp and CpC.  
Urine samples will be collected for analysis of urine copper and molybdenum.  
Additional biomarker or biobank samples will be collected for the analysis of molybdenum 
and/or copper species associated with treatment. 
Details of the use, analysis, and storage of biobank samples in the Netherlands are provided in 
Section 10.8. 
Details including further handling and processing instructions and sampling time windows will 
be provided in the study laboratory manual. 
8.6. 
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. Patients who 
do not wish to participate in the genetic research may still participate in the study. 
Details on processes for collection and shipment and destruction of these samples can be found 
in the laboratory manual. Details of the use, analysis, and storage of the DNA samples collected 
are provided in Section 10.5. 


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8.7. 
Unscheduled Study Visits 
Unscheduled Study Visits may occur at any time during the study and may include any study 
procedures (including dispensing of ALXN1840/SoC) as deemed necessary by the Investigator. 
These visits may or may not be completed by a home healthcare nurse depending on the purpose 
of the visit. If the Unscheduled Study Visit is for weekly repeat laboratory assessments as 
required in Table 1, these can be completed by a home healthcare nurse. 


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9. 
STATISTICAL CONSIDERATIONS 
All statistical analyses will be performed by Alexion Pharmaceuticals or under the authority of 
Alexion Pharmaceuticals. 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 database lock. Any deviations from the 
planned analysis as described in the SAP will be justified and recorded in the final study report. 
Statistical analyses will be carried out using SAS®, Version 9.3 or later, SAS Institute, Cary, 
North Carolina, USA. 
In general, continuous variables will be summarized by descriptive statistics (number of patients, 
mean, standard deviation [SD], minimum, median, and maximum). Categorical data will be 
summarized by absolute and relative frequencies. 
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 study drug 
(ALXN1840 or SoC). 
9.1. 
Analysis Populations 
9.1.1. 
Full Analysis Set 
The Full Analysis Set includes all randomized patients who received at least 1 dose of 
randomized treatment. Patients will be analyzed as randomized. 
9.1.2. 
Safety Analysis Set 
The safety analysis will be performed on the Safety Analysis Set. This dataset includes all 
patients who received at least 1 dose of randomized treatment. Patients will be summarized 
according to the treatment actually received. 
9.1.3. 
Per-Protocol Set 
The Per-Protocol Set includes all patients who are randomized and had at least baseline and 48-
week efficacy assessments for dNCC in the Primary Evaluation Period. Patients with major 
protocol deviations that are likely to impact the primary efficacy 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. 
9.1.4. 
Extension Analysis Set 
This dataset includes all patients who entered the Extension Period and received at least 1 dose 
of ALXN1840 in the Extension Period. 


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9.2. 
Statistical Methods 
9.2.1. 
Analysis of Efficacy 
9.2.1.1. 
Primary Efficacy Analysis 
The primary estimand is the difference in daily mean dNCC AUEC from 0 to 48 weeks between 
ALXN1840 and SoC in patients with WD, regardless of less-than-complete adherence or use of 
another medication that affects plasma dNCC, with no benefit derived from treatment after 
death.  
The AUEC for dNCC concentration will be calculated using the trapezoidal rule, and then 
divided by number of days to yield a mean daily AUEC plasma dNCC concentration from 
baseline to Week 48 (expressed as µmol/L and described as AUEC0-48W).  
The AUEC0-48W will be compared between ALXN1840 and SoC using an analysis of covariance 
(ANCOVA) statistical model; treatment arm, baseline plasma dNCC concentration, and cohort, 
will be included in the model. Tests will be performed at a significance level of 0.05 (2-sided). 
Model-based estimates of the difference between randomized treatments (ALXN1840 – SoC) in 
AUEC0-48W, along with a 2-sided 95% CI and p-value will be provided. If the lower 2-sided 95% 
CI exceeds 0 µM, superiority will be concluded. 
Cohort 1: Patients previously treated for > 28 days 
The supportive analysis of the primary endpoint within Cohort 1 will mirror that described for 
the overall population analysis except that the analysis will remove cohort from the model. 
Cohort 2: Patients who are treatment naïve or previously treated for ≤ 28 days 
The AUEC0-48W will be analyzed descriptively; there will be no formal statistical comparison 
made between the randomized treatment arms. The AUEC0-48W will be estimated using the same 
model terms as described for the analysis of Cohort 1 patients.  
9.2.1.2. 
Secondary Efficacy Analysis 
Key secondary endpoints and associated multiplicity testing will be adapted to regional 
expectations as agreed upon discussion with the US FDA and EMA CHMP (Table 6). 
The secondary efficacy endpoints and the methods for analyzing them will be defined in more 
detail in the SAP. 
Table 6: 
Analysis of Key Secondary Endpoints Customized for Specific Regional 
Health Authorities 
 
US FDA and Japan PMDA 
EMA CHMP 
Key secondary 
endpoints 
• 
UWDRS Part II 
• 
Individual items/subscores from UWDRS 
Part III (arising from a chair, gait, 
handwriting, and speech) 
• UWDRS Part II 
• UWDRS Part III 
• CGI-I and CGI-S 
• Percent change from baseline in 
cNCC/cNCCcorrected 
• cNCC/cNCCcorrected response rate 
Abbreviations: CGI-I = Clinical Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-
Severity Scale; CHMP = Committee for Medicinal Products for Human Use; cNCC = calculated non-ceruloplasmin-


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bound copper; cNCCcorrected = calculated corrected NCC; EMA = European Medicines Agency; FDA = Food and 
Drug Administration; PMDA = Pharmaceuticals and Medical Devices Agency; UWDRS = Unified Wilson Disease 
Rating Scale. 
9.2.2. 
Type I Error Control 
A multiplicity adjustment will be applied to address the following two sources of multiplicity in 
this trial: 
1. Analysis of the primary/key secondary endpoints. 
2. Data-driven decision rule (sample size re-estimation rule) at the interim analysis. 
The proposed multiplicity adjustment guarantees strong control of the overall Type I error rate 
control with respect to these sources of multiplicity at a two-sided alpha = 0.05. 
The multiplicity adjustment relies on a prospectively defined multiple testing procedure. This 
procedure will be applied in conjunction with the combination function approach (Wassmer, 
2016) at the interim and final analyses to ensure strong Type I error rate control. The 
combination function approach will be applied using the modification described in Sugitani et al. 
(Sugitani, 2016). 
To address multiplicity induced by the first source of multiplicity in this trial, namely, 
multiplicity induced by the analysis of the primary/key secondary endpoints, a multiple testing 
procedure will be applied. This procedure is defined using the graphical method (Bretz, 2009).   
To account for the second source of multiplicity (data-driven decision rule at the interim 
analysis), the multiple testing procedure will be applied separately to the two trial stages: 
• Stage 1 includes all patients who are included in the interim database. 
• Stage 2 includes all patients who are not included in the interim database. 
The multiple testing procedure will account for the interim decision rule to support inferences at 
the final analysis for primary/key secondary endpoints.  For example, if a decision is made to 
increase the sample size in the trial, the evidence of treatment effectiveness from the two trial 
stages will be pooled with pre-defined weights using the modified combination function 
principle.  The standard analysis will be performed at the final analysis if the sample size is not 
adjusted at the interim analysis. 
Let p denote the two-sided treatment effect p-values for the null hypotheses of interest computed 
from the Stage 1 data. Similarly, let q denote the two-sided treatment effect p-values for the null 
hypotheses computed from the Stage 2 data.   
The combined p-value for each hypothesis is derived using the weighted inverse-normal 
combination function, ie, 
𝑐𝑐(𝑥𝑥, 𝑦𝑦) = 1 −Ф ቀ√𝑤𝑤Ф−1(1 −𝑥𝑥) + √1 −𝑤𝑤Ф−1(1 −𝑦𝑦)ቁ, 
where Ф(𝑥𝑥) denotes the cumulative distribution function of the standard normal distribution, and 
𝑤𝑤 and 1 −𝑤𝑤 are the pre-defined weights assigned to Stages 1 and 2.   
The combined p-value for the hypothesis 𝐻𝐻𝑖𝑖 is computed as follows:  
𝑟𝑟𝑖𝑖= 𝑐𝑐(𝑝𝑝𝑖𝑖, 𝑞𝑞𝑖𝑖). 


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These combined p-values are equivalent to those derived from a weighted combination of test 
statistics from the two stages (Cui, 1999; Lehmacher, 1999).  
The resulting combined p-values will then be passed to the multiple testing procedure to perform 
inferences at the final analysis, ie, the adjusted p-values will be computed for the null hypotheses 
and each null hypothesis will be rejected at the final analysis if its adjusted p-value does not 
exceed a one-sided 𝛼𝛼= 0.025. 
The proposed multiplicity adjustment guarantees overall Type I error rate control in the strong 
sense with respect to both sources of multiplicity in the adaptive study. 
9.2.3. 
Efficacy Analyses Relating to Exploratory Objectives 
The analysis methods for efficacy endpoints relating to exploratory objectives will be described 
in full in the SAP. 
9.2.4. 
Efficacy Subgroup Analysis 
For exploratory purposes, the primary and secondary efficacy endpoints will also be evaluated in 
clinically relevant subgroups. These subgroups will be described in full in the SAP. 
9.2.5. 
Handling of Missing Data 
An outline of how the primary endpoint will be analyzed is provided in Table 7. 
Table 7: 
Analysis Outline for Primary Endpoint 
Endpoint 
Daily mean dNCC AUEC0-48W, expressed as µM 
Analysis Method 
Analysis of covariance (ANCOVA) 
Primary Analysis  
Population 
How to handle missing data 
Full Analysis Set 
1. Patients who die during study 
o 
Baseline plasma dNCC concentration will be carried forward  
2. Patients who drop out due to other reasons  
o 
Multiple imputation assuming missing not at random. 
ALXN1840 missing value will be imputed with multiple 
imputation based on the response for SoC participants (jump 
to reference method) 
3. All other intermediate missing (including missing due to COVID-
19 pandemic) 
o 
Use interpolation to fill out intermediate missing values 
Sensitivity 
Analysis 1 
Population 
How to handle missing data 
Per Protocol Set 
Per Protocol Set will only include patients who had at least baseline 
and 48-week assessments for plasma dNCC concentration, so only 
intermediate missing data.  
• 
Use available time points only to derive dNCC 
AUEC0-48W using trapezoidal rule. Equivalent to 
interpolation. 
Sensitivity 
Analysis 2  
Population 
How to handle missing data 
Full Analysis Set 
Tipping point analysis 
Use available time points only to derive dNCC AUEC0-48W 
using trapezoidal rule. 
Two-dimensional tipping point analysis will be applied to 
participants with missing data at Week 48 regardless of type 
of intercurrent events. 


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Abbreviations: AUEC0-48W = area under the effect-time curve from 0 to 48 weeks; dNCC= direct non-ceruloplasmin-
bound copper. 
Handling of Missing Data for Primary Analysis 
For intermediate missing data, interpolation will be used to fill out missing values. For 
participants who die during study, their baseline plasma dNCC concentration will be carried 
forward. For participants who drop out due to other reasons, multiple imputation will be used to 
impute missing dNCC concentration assuming data are missing not at random. In this case, 
responses for both treatment groups will be imputed with multiple imputation based on the 
response for SoC participants (jump to reference method). Cohort, baseline, and previous visit 
value will be included in the imputation model. The following steps will be repeated: 
Step 1: Missing values at each visit will be imputed 10 times via SAS PROC MI, and imputed 
values will be retained in the imputed datasets. 
Step 2: Mean daily AUEC0-48W dNCC concentration will be derived using the trapezoidal rule 
(Yeh, 1978) and scaled by the number of days. 
Step 3: ANCOVA analysis will performed for each of the 10 imputed datasets, with least square 
(LS) means (standard error [SE]) for each treatment arm and difference in LS means between 
studies (SE) saved from each of the 10 analyses. 
Step 4: 10 set of analysis results will be combined using Rubin's rules (Rubin, 1987) via SAS 
PROC MIANALYZE. The treatment differences, CIs, and p-values were estimated by 
MODELEFFECTS and STDERR statement. 
Tipping point analysis: 
A tipping point analysis will be conducted for the primary endpoint, by splitting the patients into 
two subgroups: “observed” and “missing”. “Observed” are those patients with baseline and 
Week 48 assessment in plasma dNCC concentration, while “missing” refers to all other patients. 
An efficient two-dimensional tipping point analysis will be accomplished by performing two 
one-dimensional analyses: (a) vary assumptions about the missing outcomes in the ALXN1840 
arm, while fixing those about the SoC arm, and (b) vary assumptions about the missing outcomes 
in the SoC arm, while fixing those in the ALXN1840 arm. The combination of assumed missing 
data values that maintain the statistically significant Superiority conclusion are bound by the two 
one-way tipping points (Gorst-Rasmussen, 2020). 
Step 1: Within the “observed” subgroup, ANCOVA analysis will be performed on the daily 
mean dNCC AUEC0-48W with cohort and baseline plasma dNCC as covariates. The LS means 
and SEs for ALXN1840 and SoC, respectively, and the residual error estimate, will be extracted. 
a. ALXN1840 varied, SoC fixed 
Step 2: 
i. 
For “missing” SoC patients, the daily mean dNCC AUEC0-48W is generated randomly as a 
deviate from a normal distribution with mean equal to the LS mean for “observed” SoC 
patients, and SD equal to the residual error estimate, as obtained in Step 1. 
ii. 
For “missing” ALXN1840 patients, the LS mean for daily mean dNCC AUEC0-48W in 
Step 1 will be decreased by a small increment (δ=10%), to reflect a marginally worse 
AUEC0-48W value. For these patients, the daily mean dNCC AUEC0-48W will be 


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generated randomly as a deviate from a normal distribution with mean equal to 
(100 − δ)% of the LS mean for “observed” ALXN1840 patients, and SD equal to the 
residual error estimate, as obtained in Step 1. 
iii. 
Combine “observed” and “missing” patients into a complete dataset. Analyze the 
complete dataset using ANCOVA with cohort and baseline plasma dNCC as covariates, 
to give LS means and SEs for ALXN1840 and SoC, with treatment effect estimate and 
associated SE. 
Step 3: 
i. 
Step 2 will be repeated 10 times for the same increment δ, giving rise to 10 sets of LS 
means, treatment effect estimates, and associated SEs. 
ii. 
The 10 treatment effect estimates will be combined via PROC MIANALYZE using 
Rubin’s method. 
Step 4: Steps 2 and 3 will be repeated with larger increments (δ =20%, 30%,…, 90%) to reflect 
an even-poorer outcome with ALXN1840 treatment. 
Step 5: The treatment effect estimates, associated SEs, and CIs generated for all increments (δ = 
10%, 20%,…, 90%)  will be summarized in a table, and the first point at which superiority fails 
(if it exists) will be highlighted. 
b. ALXN1840 fixed, SoC varied 
Step 2: 
i. 
For “missing” ALXN1840 patients, the daily mean dNCC AUEC0-48W is generated 
randomly as a deviate from a normal distribution with mean equal to the LS mean for 
“observed” ALXN1840 patients, and SD equal to the residual error estimate, as obtained 
in Step 1. 
ii. 
For “missing” SoC patients, the LS mean for daily mean dNCC AUEC0-48W in Step 1 will 
be increased by a small increment (δ=10%), to reflect a marginally better AUEC0-48W 
value. For these patients, the daily mean dNCC AUEC0-48W will be generated randomly 
as a deviate from a normal distribution with mean equal to (100 + δ)% of the LS mean for 
“observed” SoC patients, and SD equal to the residual error estimate, as obtained in Step 
1. 
iii. 
Combine “observed” and “missing” patients into a complete dataset. Analyze the 
complete dataset using ANCOVA with cohort and baseline total copper as covariates, to 
give LS means and SEs for ALXN1840 and SoC, with treatment effect estimate and 
associated SE. 
Step 3: 
i. 
Step 2 will be repeated 10 times for the same increment δ, giving rise to 10 sets of LS 
means, treatment effect estimates, and associated SEs. 
ii. 
The 10 treatment effect estimates will be combined via PROC MIANALYZE using 
Rubin’s method. 


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Step 4: Steps 2 and 3 will be repeated with larger increments (δ =20%, 30%,…, 200%) to reflect 
an even-better outcome with SoC treatment. 
Step 5: The treatment effect estimates, associated SEs, and CIs generated for all increments (δ = 
10%, 20%,…, 90%) will be summarized in a table, and the first point at which superiority fails 
(if it exists) will be highlighted. 
9.2.6. 
Evaluation of Safety 
Safety and tolerability over the course of the study period is a secondary endpoint and will not be 
subject to formal analysis. Rather, descriptive statistics will be used to summarize the safety data 
by treatment arm. The Safety Analysis Set dataset will be used for the evaluation of safety. 
9.2.6.1. 
Adverse Events 
The verbatim terms as reported in the eCRF by Investigators to identify AEs will be coded using 
the Medical Dictionary for Regulatory Activities, 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, AESIs, SAEs, AEs leading to treatment discontinuation or withdrawal, and AEs 
leading to death. No statistical comparison of the overall incidence of AEs will be done between 
arms. 
9.2.6.2. 
Laboratory Assessments 
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. 
9.2.6.3. 
Electrocardiogram 
QT intervals will be corrected for heart rate according to Bazett (QTcB = QT/(RR1/2) and 
Fridericia (QTcF = QT/(RR1/3). 
All corrected values will be tabulated according to the ICH E14 Guidelines as follows: QTc 
actual values: ≤450 ms, >450 to ≤480 ms, >480 to ≤500 ms, and >500 ms. ECG results will be 
tabulated. 
9.2.6.4. 
Vital Signs 
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. 


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9.2.6.5. 
Physical Examination 
Physical examination results will be tabulated; abnormalities will be listed. 
9.2.7. 
Sample Size Determination 
The original primary endpoint is copper control assessed as the percent change from baseline to 
48 weeks in cNCC levels; for ALXN1840-treated patients, the cNCC level will be corrected for 
the amount of copper bound to the ALXN1840 TPC. 
The hypothesis to be tested with regards to the primary endpoint is 
𝐻𝐻0: 𝜇𝜇𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴1840 −𝜇𝜇𝑆𝑆𝑆𝑆𝑆𝑆≥Δ vs 𝐻𝐻1: 𝜇𝜇𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴1840 −𝜇𝜇𝑆𝑆𝑆𝑆𝑆𝑆< Δ  
where Δ=15% is the non-inferiority margin, 𝜇𝜇ALXN1840 and 𝜇𝜇𝑆𝑆𝑆𝑆C represent 48-week mean percent 
change for ALXN1840 and SoC, respectively. 
For patients who have been previously treated with SoC for >28 days (ie, corresponding to 
Cohort 1 in the present study), the NCC data in Study WTX101-201 gives a mean percent 
change in cNCC level at 24 weeks of 80% with estimated projected SD of 20% to 30% at 
48 weeks. Based on this anticipated degree of variability, 90 Cohort 1 patients, randomized by 
cohort on a 2:1 basis, will provide between 60% and 91% power to rule out a difference of 
Δ = 15% in mean percent change in NCC values, ALXN1840 versus SoC, with a 1-sided Type I 
error of 2.5%. 
The number of patients in Cohort 2 is based on feasibility only, and there is no supporting power 
calculation. The intent of Cohort 2 is to provide at least some randomized data in patients who 
are treatment naïve or have been previously treated with SoC for ≤ 28 days to descriptively 
assess within arm changes from baseline. No formal statistical comparisons are planned within 
Cohort 2 patients alone. 
In relation to the overall analysis of cNCC percent change from baseline to 48 weeks, Study 
WTX101201 gives a mean percent change in cNCC level at 24 weeks of 78%. A total of 
120 patients (90 patients in Cohort 1 and 30 patients in Cohort 2) will provide between 73% and 
97% power to rule out a difference of Δ = 15%, in mean percent change in NCC values, 
ALXN1840 versus SoC, in the overall patient population, with a 1-sided Type I error of 2.5%. 
Study WTX101-201 had a minimum cNCC value of 0.8 for study entry while this study has no 
minimum requirement. This may result in the entry of patients with negative baseline cNCC 
values into this study who will be non-evaluable for the primary analysis and/or have a smaller 
effect size. For these reasons, and to achieve a pooled safety database of at least 100 patients 
treated with ALXN1840 for at least 1 year pooling Studies WTX101-201 and WTX101-301, 
these numbers have been inflated by 25% to achieve a total of 150 evaluable patients 
(approximately 113 patients in Cohort 1 and 37 patients in Cohort 2). 
To help ensure that at least 150 evaluable patients complete 48 weeks of treatment, 
approximately 180 patients (approximately 135 patients in Cohort 1 and approximately 
45 patients in Cohort 2) will be enrolled in total, this will also provide additional safety and 
tolerability data. 
The proposed 150 evaluable patients will provide adequate power (approximately 99%) for the 
new primary endpoint, namely, daily mean dNCC AUEC from 0 to 48 weeks. This power 


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calculation uses previously observed data on Cohort 1 patients. In Study WTX101-201, Cohort 1 
patients treated with ALXN1840 showed AUEC of dNCC with a mean (SD) of 3.96 (2.047), 
while in Study WTX101-203, Cohort 1 patients treated with SoC showed a mean (SD) of 0.85 
(0.425). With a significance level of 2.5% using a one-sided unequal variance t-test, 150 patients 
(100 to ALXN1840 and 50 to SoC) will provide >99% power to reject the null hypothesis of 
equal means. 
Because the study size and power are sensitive to the assumptions used for effect size, 
variability, and withdrawal rates, a sample size re-estimation will be performed. Details of the 
sample size re-estimation are provided in Section 9.2.8.  
9.2.8. 
Sample Size Re-estimation 
A sample size re-estimation (SSR) will be performed to reassess the required size of the study 
population based on estimation of the original primary endpoint. Enrollment of patients will 
proceed without interruption while the analysis is ongoing. There are no plans to stop the study 
early for demonstration of noninferiority or superiority at the SSR. The sample size will not be 
reduced from the planned enrollment of 180 designed to achieve 150 evaluable patients and the 
maximum total number of patients enrolled may be increased to achieve up to 225 evaluable 
patients. 
The SSR will be performed including approximately 31% of enrolled patients (eg, approximately 
the first 55 of the total 180 patients to be enrolled). It will be conducted after the last of these 
patients completes Week 48, or has withdrawn from the study, whichever comes first. 
Based on the results of this re-estimation procedure, the study may need to enroll an estimated 
additional 75 evaluable patients, bringing the total to approximately 225 evaluable patients. The 
cap is non-binding and the analysis may lead to a different total number that may be higher or 
lower than that currently estimated. 
The SSR will be based on a conditional power for noninferiority (CPni) using a promising zone 
with boundaries of ≥ 30% and < 80%. The CPni will be calculated using the results obtained at 
this interim analysis and will assume population mean percent change in cNCC equals the 
observed sample mean percent change in cNCC at the time of the SSR. 
If the CPni is below 30%, or equal to or above 80%, (ie, outside the promising zone) then no 
increase in sample size will be made. If the CPni is within the promising zone then the sample 
size will be increased by the amount estimated needed to achieve a CPni of 80%. This decision 
rule is illustrated in Table 8. 
The SSR will be repeated based on conditional power for superiority using the same boundaries 
and decision rules described for noninferiority. 
The adaptive re-estimation methodology and practicalities will be documented in a pre-defined 
charter. An independent statistical center (ISC) will be established for creating the SSR report 
and will work with the existing DMC to review the SSR report and implement the sample size 
re-assessment in accordance with the SSR charter. The recommendations of the ISC/DMC to the 
Sponsor will be non-binding as the statistical adaptive algorithm should be seen as a guideline to 
aid decision making rather than as a definitive rule. Other criteria, such as secondary endpoints, 


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safety issues, feasible recruitment rates, withdrawal rates, and budgetary limits, can impact both 
independent recommendations by the ISC/DMC and decisions by the Sponsor.  
Table 8: 
Criteria for Sample size Re-estimation 
Criterion 
Decision 
CPni < 30%  
Continue to N=150 evaluable 
Promising zone: 
30% ≤ CPni <80% 
Increase to N=225 evaluablea 
80% ≤ CPni 
Continue to N=150 evaluable 
a Decision is non-binding and N=225 may be exceeded to achieve CPni=80% 
Abbreviation: CPni = conditional power for noninferiority. 
9.2.9. 
Extension Period Analyses 
Given the single arm, open-label nature of the Extension Period, data evaluation will be 
predominantly descriptive. All data collected in the Extension Period will be fully listed, with 
patient data from the antecedent parent study included to provide a full longitudinal profile over 
time for each patient. For Extension Period patients who received ALXN1840 in the antecedent 
parent study, their main baseline will be the baseline from that study; and for Extension Period 
patients who received SoC in the antecedent parent study, their main baseline will be the baseline 
from the Extension Period. 
Full details of all planned analyses will be specified in an Extension SAP, which will be finalized 
prior to data lock of the Extension Period data. The Extension Period SAP will contain details of 
all the analyses including specifications for all tables, listings and figures. All statistical 
programming will be performed using SAS® software. 
9.2.10. 
Other Analyses 
Detailed population PK/PD analyses including the staged population PK/PD model development 
scheme during the treatment period will be described in the PK/PD Modeling and Simulation 
Analysis Plan, which will be finalized before database lock.  
9.3. 
Data Monitoring Committee 
An independent DMC, comprising experts in relevant fields with no direct relationship to the 
study, will be appointed by the Sponsor. 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 specific responsibilities of the 
DMC are described in the DMC Charter.  
Final decisions regarding the conduct of the study will be made by the Sponsor 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. 


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9.4. 
Neurological Adverse Event Panel 
A separate independent Neuro AE Panel, comprising independent experts in relevant fields will 
be appointed by the Sponsor. As detailed in the Neuro AE Panel Charter (maintained separately 
from the study protocol), the Neuro AE Panel will review and monitor study data for 
neurological AEs 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 Neuro AE 
Panel Charter. 
Each member of the Neuro AE Panel 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. 
9.5. 
Hepatic Adjudication Panel 
A separate independent Hepatic Adjudication Panel, comprising experts in hepatology and 
drug-induced liver injury, will be appointed by the Sponsor. 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 GCP Guidelines 
− Applicable laws and regulations 
• The protocol, substantial 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 substantial amendments to the protocol will require IRB/IEC and 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 the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 


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10.1.3. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the patient, their 
legal guardian (in the case of an adolescent patient, or a patient below the age of adulthood under 
Japanese local law for patients in Japan), or his/her legally authorized representative (if 
allowable per local regulations) and answer all questions regarding the study. If allowable by 
local regulations, a legally authorized representative may be able to provide informed consent on 
a patient's behalf if the patient is unable to provide informed consent. 
Patients must be informed that their participation is voluntary. Patients, legal guardians of 
adolescent patients (or patients below the age of adulthood under Japanese local law for patients 
in Japan) or a patient’s legally acceptable representative 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 written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study.  
The Investigator must retain the original version of the signed ICF(s). A copy of the signed 
ICF(s) must be provided to the patient or the patient’s legally authorized representative.  
A patient who is rescreened is not required to sign another ICF unless an updated ICF is 
available. 
10.1.4. 
Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Patient records or datasets that are 
transferred to the Sponsor will contain the identifier only; patient names or other information that 
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 the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, appropriate IRB/IEC 
members, and inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 


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10.1.6. 
Data Quality Assurance 
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the 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.  
The Sponsor 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 5 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor.  
10.1.7. 
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 (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 eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records. Also, current 
medical records must be available. Source documents are filed at the Investigator’s site. 
10.1.8. 
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 
10.2.1. 
Chemistry 
Table 9: 
Chemistry 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Bicarbonate 
Aspartate aminotransferase 
Total Calcium 
Blood urea nitrogen 
Glucose 
Chloride 
Lactate dehydrogenase 
Creatininea 
Potassium 
Gamma-glutamyl transferase 
Total bilirubin 
Creatine phosphokinase 
Conjugated bilirubin 
Magnesium 
Uric acid 
Sodium 
Phosphate 
Protein 
Total cholesterol 
Triglycerides 
HDL cholesterol  
a Including calculated creatinine clearance calculated by Cockcroft-Gault method for patients aged 18 years or older, 
and the Schwartz formula for patients < 18 years of age. 
10.2.2. 
Coagulation 
• Prothrombin time 
• Partial thromboplastin time 
• International normalized ratio 
10.2.3. 
Endocrinology 
• Follicle-stimulating hormone (For post-menopausal females only) 
10.2.4. 
Hematology 
Table 10: 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell counta 
White blood cell count 
Mean corpuscular volume 
Mean cell hemoglobin 
Mean cell hemoglobin concentration 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
 
a Including nucleated red blood cells. 
 


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10.2.5. 
Urinalysis 
Table 11: 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes 
Microscopy 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Red blood cells 
Bacteria 
Creatinine 
 
10.2.6. 
Other Tests 
Table 12: 
Other Tests 
HIV, hepatitis B, and hepatitis C screen 
Serum and urine pregnancy test  
Ceruloplasmin 
Total copper and total molybdenum 
24-hour urine 
PUF molybdenum and copper 
24-hour urine copper and molybdenum 
Labile bound copper 
Abbreviation: PUF = plasma ultrafiltrate 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of Adverse Event 
AE Definition 
• 
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered 
a pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment (ICH E2A). 
• 
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 the study 
intervention, whether or not considered related to the study intervention. 
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. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or 
SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE.   
Events NOT Meeting the AE Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is the 
AE. Situations in which an untoward medical occurrence did not occur (eg, hospitalization for elective 
surgery if planned before the signing the ICF, admissions for social reasons or for convenience). 
• 
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. 
• 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to establish 
drug effect. 
• 
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. 


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Definition of Serious Adverse Event 
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). 
A SAE is defined as any untoward medical occurrence 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 intervention 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. 
Suspected Unexpected Serious Adverse Reactions 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed in the 
Investigator’s Brochure version corresponding to the onset date of the event and that the Investigator identifies as 
related to investigational product or procedure. The United States Title 21 Code of Federal Regulations (CFR) 
312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated detailed guidance documents 
or national regulatory requirements in participating countries require the reporting of SUSARs. Alexion has 
procedures that will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidance documents. Suspected unexpected serious adverse 
reactions will be reported to the national competent authority and IRBs/IECs where applicable. 
 


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Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to Alexion or 
designee in lieu of completion of the AE/SAE report. If applicable, additional information such as relevant 
medical records should be submitted with a signed SAE cover page to Alexion GDS via email: 
 or facsimile: 
 In this case, all patient identifiers, with the 
exception of the patient number, will be redacted on the copies of the medical records before sending to 
GDS. 
• 
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 Severity 
The Investigator will make an assessment of severity for each AE and SAE reported during the study and assign 
it to 1 of the following categories from National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0, published 27 Nov 2017. Each CTCAE term is a Lowest Level Term (LLT) per the 
MedDRA. Each LLT will be coded to a MedDRA Preferred Term:  
• 
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 ADL) 
• 
Grade 3: Severe (severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL) 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
Any change in the severity of an AE should be documented based on specific guidelines in the eCRF Completion 
Guidelines. 
Severity and seriousness must be differentiated: severity describes the intensity of an AE, while the term 
seriousness refers to an AE that has met specific criteria for an SAE as described above. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study drug and occurrence of each 
AE/SAE. An Investigator causality assessment must be provided for all AEs (both nonserious and 
serious). This assessment must be recorded in the eCRF and on any additional forms, as appropriate. The 
definitions for the causality assessments are as follows: 
− 
Not related: This relationship suggests that there is no causal association between the study 
drug and the reported event. 
− 
Related: This relationship suggests that there is causal association between the study drug and 
the reported event. 
Adverse Event and Serious Adverse Event Recording  
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study drug administration will be considered and investigated. 
• 
This protocol will use the current Investigator’s Brochure as the Reference Safety Document. The 
expectedness and reporting criteria of an SAE will be determined by the Sponsor, based on the 
Reference Safety Document version that corresponds with the onset date of the event. The Investigator 
will also consult the Investigator’s Brochure in his/her assessment. 
• 
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 designee. However, it is very important that the Investigator 


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AE and SAE Recording 
always make an assessment of causality for every event before the initial transmission of the SAE 
data to Alexion GDS. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send an 
SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by Alexion or designee to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• 
If a patient dies during participation in the study or during a recognized follow-up period, the Investigator 
will provide Alexion or designee with a copy of any post-mortem findings including histopathology. 
• 
The site will enter new or updated SAE data into the electronic system as soon as it becomes available, but 
no later than 24 hours. The Investigator will submit any updated SAE data to the GDS within 24 hours of 
awareness of the information.  
Reporting of SAEs 
SAE Reporting to Alexion GDS via an Electronic Data Collection Tool 
• 
All SAEs will be recorded and reported to Alexion immediately and within 24 hours of awareness. 
• 
The primary mechanism for reporting an SAE to Alexion will be the EDC system. 
• 
If the electronic system is unavailable or site staff is unable to process the SAE via the EDC system 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 facsimile or email. Facsimile transmission or email may also be used in the 
event of electronic submission failure. 
• 
Email: 
 or Fax: 
 
• 
The site will enter the SAE data into the EDC system as soon as it becomes available. 
• 
When further information becomes available, the EDC should be updated immediately with the new 
information and an updated SAE report should be submitted to Alexion Global Drug Safety (GDS) 
within 24 hours of Investigator/site awareness.  
• 
After the participant has completed the study, no new data or changes to existing data are expected to be 
entered in the EDC system. 
o 
If a site receives a report of a new SAE from a study participant which the Investigator 
considers to be related to the study intervention, or the site receives updated data on a 
previously reported SAE after the EDC system has been taken offline, then the site can report 
this information on a paper Contingency Form for SAE Reporting via facsimile or email. 
SAE Reporting to Alexion or Designee via Paper CRF 
• 
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 the Sponsor 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: Collection of Pregnancy Information 
Pregnancy Testing 
Women of childbearing potential should only be included after a confirmed menstrual period and 
a negative highly sensitive serum pregnancy test (see the SoA Section 1.2).  
Additional pregnancy testing should be performed per the time points specified in the SoA 
(Section 1.2). 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected.  
Collection of Pregnancy Information  
Pregnancy data will be collected during this study for all female patients and female 
spouses/partners of male patients. Any female patient who becomes pregnant during the study 
should be considered for discontinuation from the study intervention and withdrawn from the 
study.  
Exposure during pregnancy (also referred to as exposure in utero) can be the result of either 
maternal exposure or transmission of study intervention via semen following paternal exposure. 
If a female patient or a male patient’s female spouse/partner becomes pregnant during the 
conduct of this study, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and 
Outcome Form” to Alexion GDS via facsimile or email. 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 study intervention 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 via email or facsimile. 
Pregnancy is not regarded as an AE unless there is a suspicion that the study intervention 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, spontaneous abortion, fetal death, stillbirth, congenital anomalies, and ectopic pregnancy). 
Elective abortions without complications should not be reported as AEs. 


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10.5. 
Appendix 5: Genetics 
Use/Analysis of DNA 
• Genetic variation in the ATP7B gene may impact a patient’s response to study 
intervention, susceptibility to, and severity and progression of disease. 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 WD and related diseases. They may 
also be used to develop tests/assays including diagnostic tests related to ALXN1840 
and WD.  
• DNA samples will be analyzed for variants in the coding and regulatory sequences of 
the ATP7B gene and other genes, if considered related to WD.  
• Additional analyses may be conducted if it is hypothesized that this may help resolve 
issues with the clinical data, such as identifying gene mutations that may affect the 
metabolism of ALXN1840.  
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to ALXN1840 or study interventions 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. 
• The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on ALXN1840 continues but no longer 
than 10 years or other period as per local requirements.  
 


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10.6. 
Appendix 6: Abbreviations 
 
Abbreviation 
Definition 
9-HPT 
9-hole Peg Test 
25F 
25-foot 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AUEC 
area under the effect-time curve 
BfArM 
Federal Institute for Drugs and Medical Devices in Germany 
BPRS-24 
Brief Psychiatric Rating Scale-24 
CGI-I 
Clinical Global Impression-Improvement Scale 
CGI-S 
Clinical Global Impression-Severity Scale 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cp 
Ceruloplasmin 
CpC 
Ceruloplasmin-bound copper 
CPni 
Conditional power for noninferiority 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTR1 
Copper transporter 1 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
EQ-5D (Y) 
EuroQoL 5 Dimensions (Y) 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FIB-4 
Fibrosis-4 
FSH 
Follicle-stimulating hormone 
GDS 
Global Drug Safety 
GI 
Gastrointestinal 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 


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Abbreviation 
Definition 
IEC 
Institutional Ethics Committee 
INR 
International normalized ratio for prothrombin time 
IRB 
Institutional Review Board 
ISC 
Independent statistical center 
LBC 
Labile bound copper 
LLT 
Lowest level term 
LS 
Least-squares 
MELD 
Model for End-Stage Liver Disease 
MT 
Metallothionein 
(d)(c)NCC 
(directly measured) (calculated) non-ceruloplasmin-bound copper 
NCCcorrected 
Non-ceruloplasmin-bound copper in plasma corrected for the amount of copper bound 
to the ALXN1840 tripartite complex 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
PUF 
Plasma ultrafiltrate 
QD 
Once daily 
QOD 
Every other day 
QoL 
Quality of life 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SoA 
Schedule of Activities 
SoC 
Standard of care 
SSR 
Sample size re-estimation 
SUSAR 
Suspected unexpected serious adverse reaction 
TPC 
Tripartite complex 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication-9 
ULN 
Upper limit of normal 
UMCU 
University Medical Center Utrecht 
UWDRS 
Unified Wilson Disease Rating Scale 
VAS 
Visual Analogue Scale 
WD 
Wilson disease 
WMO 
Medical Research Involving Human Subjects Act 


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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. 
DOCUMENT HISTORY 
Document 
Date 
Original Document 
07 Nov 2017 
Amendment 1 
17 Jan 2019 
Amendment 1.1 (Japan) 
25 Mar 2019 
Amendment 1.2 (Netherlands) 
22 May 2019 
Amendment 1.3 (Germany) 
17 May 2019 
Amendment 1.4 (Sweden) 
21 May 2019 
Amendment 1.5 (Germany) 
10 Jul 2019 
Amendment 1.6 (Austria) 
30 Apr 2020 
Amendment 2 (Global) 
25 Mar 2021 
Amendment 2.1 (UK) 
16 Apr 2021 
Amendment 3 (Global) 
27 Apr 2022 
10.7.1. 
Amendment 1, 17 Jan 2019 
This amendment was 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: 
Substantial changes and administrative changes to the protocol are detailed in the tables below. 
Substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Title Page, Sponsor 
Signatory 
Change of Sponsor (from Wilson 
Therapeutics AB to Alexion 
Pharmaceuticals Inc.), Medical Monitor 
(from 
 to 
), and 
product code (from WTX101 to 
ALXN1840) 
To reflect the legal and administrative 
integration of Wilson Therapeutics AB into 
Alexion Pharmaceuticals, Inc. 
Section 1 Synopsis, 
Section 2.1 Study 
Rationale, Section 4.2, 
Scientific Rationale 
for Study Design, 
Section 8.1 Inclusion 
Criteria 
To include adolescent patients (12 to 17 
years old) 
To expand the population who can receive 
ALXN1840 to include adolescents as well as 
adults, because approximately half of all 
patients are diagnosed before 18 years of age 
(Ferenci, 2019). 
Section 1 Synopsis, 
Section 9.2.7 Sample 
Size Determination 
To increase the sample size from 102 to 
180 patients (targeting approximately 
150 evaluable patients for up to 
48 weeks), for enhanced statistical 
power to test for superiority versus 
Standard of Care 
To enhance robustness for superiority testing 
of ALXN1840 versus Standard of Care and 
ensure that approximately 100 patients with 
1 year of treatment will be available for the 
safety database. 
Section 9.2.8 Sample 
Size Re-estimation 
To add the sample size re-estimation  
To confirm the appropriate sample size to 
test the hypothesis and allow for a possible 
increase in the sample size.  


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Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 1 Synopsis, 
Section 4.3 
Justification for Dose 
Maximum daily dose permitted 
decreased from 90 mg to 60 mg 
Results from Phase 1 and Phase 2 studies 
indicate that the ALXN1840 60 mg dose was 
well-tolerated in healthy volunteers, and it is 
anticipated to have an appropriate efficacy 
and safety profile in patients with Wilson 
Disease. Doses greater than 60 mg daily 
have not been tested in healthy volunteers. 
Section 6.2.3.2 Dose 
Modification and 
Table 6 
Changes in dose modification criteria 
and actions in individual patients for 
patients receiving ALXN1840 
Provide more guidance on criteria that may 
prompt an increase or decrease in dosing of 
ALXN1840. Requirement for documentation 
of the rationale and decision-making for 
dose modification. 
To lower the re-challenge dose of 
ALXN1840 to 15 mg QOD to enhance 
safety. 
Section 6.2.3.4 Dose 
Modification and 
Table 7 
Changes in dose modification criteria 
and actions in individual patients for 
patients receiving Standard of Care 
Provide more guidance on criteria that may 
prompt an increase or decrease in dosing of 
Standard of Care. Require documentation of 
the rationale and decision-making for dose 
modification. 
Section 5.1. Inclusion 
Criteria 
Criteria relating to contraception 
condensed into one criterion and new 
section, Section 6.6 Contraception 
Guidance, added  
To clarify contraception guidance  
Section 5.2 Exclusion 
Criteria 
Criteria updated to exclude patients 
with creatinine clearance < 30 mL/min 
The safety of ALXN1840 in patients with 
creatinine clearance < 30 mL/min has not yet 
been studied.  
Section 9.5 Hepatic 
Adjudication Panel 
Addition of an independent Hepatic 
Adjudication Panel to evaluate potential 
cases of drug-induced liver injury. 
Elevations of liver enzymes and bilirubin 
were seen in 39% of patients treated with 
ALXN1840 in the Phase 2 Study WTX101-
201. The Hepatic Adjudication Panel will 
provide additional review and 
recommendations to enhance patient safety. 
Administrative Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or clarifications 
Section 4.4 End of 
Study Definition 
Text added on the end of the study 
To define the end of the study 
Section 5 Study 
Population 
Addition of text on protocol waivers or 
exemptions 
To clarify that prospective approval of 
protocol deviations to recruitment and 
enrollment criteria, also known as protocol 
waivers or exemptions, is not permitted 
Section 5.3 Screen 
Failure 
Text added on screen failures 
Section added to confirm definition of screen 
failures 
Section 8.4 Overdose 
Addition of language on overdose 
To clarify what constitutes an overdose of 
study drug (ALXN1840 or Standard of Care) 
Section 10.1 
Appendix 1: 
Regulatory, Ethical, 
and Study Oversight 
Considerations 
Text added or updated 
Section added to comply with current 
Regulatory requirements and for compliance 


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Section # and Name 
Description of Change 
Brief Rationale and/or clarifications 
Section 10.3 
Appendix 3: Adverse 
Events: Definitions 
and Procedures for 
Recording, 
Evaluating, Follow-
up, and Reporting 
Revision of safety language, including 
update of adverse event reporting based 
on Reference Safety Information 
To align with Alexion’s current text on 
safety reporting 
Section 10.5 
Appendix 5: Genetics 
Text added on the use, analysis, and 
storage of DNA samples 
To add details of what analysis of genetic 
tests may be undertaken 
All sections 
Change of template 
To align the protocol with Alexion’s current 
protocol template 
All sections 
Minor editorial updates and corrections 
For clarification, and to ensure accuracy and 
consistency throughout the protocol 
10.7.2. 
Amendment 1.1 (Japan) 25 Mar 2019 
Overall Rationale for the Amendment: 
Substantial changes to the protocol were made based on feedback from the Japanese 
Pharmaceuticals and Medical Devices Agency. Substantial changes and administrative changes 
to the protocol are detailed in the tables below. 
Substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 5.1 Inclusion 
Criteria 
Section 5.2 Exclusion 
Criteria 
Section 7.2 Patient 
Discontinuation/Withdrawal 
from the Study 
Section 10.1.3 Informed 
Consent Process 
Change to reflect that the legal 
guardian of patients who are below 
the legal age for an adult in Japan 
must give consent to participate in or 
withdraw from the study 
To reflect that the age where a subject 
becomes an adult in Japan is 20 years old, 
not 18 years old, as defined in the Global 
Study Protocol 
Section 6.6.1 Guidance for 
Female Patients 
Addition of text noting which 
methods of female contraception are 
authorized in Japan 
To clarify which methods of female 
contraception are authorized in Japan 
Administrative Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or clarifications 
All sections 
Minor editorial updates and corrections 
For clarification, and to ensure accuracy and 
consistency throughout the protocol 
10.7.3. 
Amendment 1.2 (Netherlands) 22 May 2019 
This amendment was 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: 
Substantial changes to the protocol were made based on requirements from the University 
Medical Center Utrecht, the Netherlands, to add details regarding biobank samples. These 
changes, and administrative changes to the protocol are detailed in the tables below. 


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Substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 8.5.3 Biomarkers 
and Biobank Samples 
Section 10.5 Appendix 5: 
Biobank Samples 
Addition of an appendix detailing 
information on the management, 
storage, and analysis of biobank 
samples for the study site in the 
Netherlands 
To include the Biobank Regulations from 
the University Medical Center Utrecht 
Administrative Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or clarifications 
All sections 
Minor editorial updates and corrections 
For clarification, and to ensure accuracy and 
consistency throughout the protocol 
10.7.4. 
Amendment 1.3 (Germany) 17 May 2019  
This amendment was 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: 
A substantial change to the protocol was made in response to the requirement from the Federal 
Institute for Drugs and Medical Devices in Germany (BfArM) to include further justification as 
to why adolescent patients aged 12 to < 18 years should be included in this study, which 
currently only allows patients aged 18 years and above to enroll. In addition, details of the 
formula used to calculate creatinine clearance in patients < 18 years of age were added to the 
protocol. The changes to the protocol are detailed in the table below. 
Substantial Change to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 2.3.2, Potential 
and Identified Risks 
Text added relating to the maximum 
number of attempts to be made for blood 
samples and the failure escalation 
procedure 
To ensure any risk associated with 
venous vessel access for blood samples 
are appropriately mitigated 
Section 4.3.1, 
ALXN1840 
Brief details of the PK results that 
support the proposed starting and 
maximum dose selection in patients aged 
12 to <18 years is have been added. 
To include justification of the dose for 
patients aged 12 to < 18 years. 
Section 10.2.1, Chemistry 
Table 8 Chemistry 
Text added to the footnote noting that 
the Schwartz formula is used to calculate 
creatinine clearance in patients < 18 
years of age 
To reflect that different methods are used 
to calculate creatinine clearance in 
patients < 18 years of age and those 
18 years and older 
10.7.5. 
Amendment 1.4 (Sweden) 21 May 2019  
This amendment was 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 address requests by the Swedish Health Authority to provide 
clarification of when the primary efficacy analysis will be performed and to add details of the 
conclusions of the benefit/risk assessment. Some minor administrative changes were also made, 


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for clarity and consistency. Substantial changes and administrative changes to the protocol are 
detailed in the tables below. 
Substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 2.3 
Text added regarding the conclusions of 
the benefit/risk assessment. 
To clarify the benefit/risk. 
Synopsis 
Section 9.2.1.1, Primary 
Efficacy Analysis 
Details added of when the primary 
efficacy analysis will be performed. 
To ensure clarity regarding when the 
primary efficacy analysis will be 
performed. 
Section 10.1.1 
Added text on the competent authority 
To confirm that protocol amendments 
should be approved by the competent 
authority, in addition to the IEC/IRB 
Section 10.2.1, 
Chemistry Table 8 
Chemistry 
Text added to the footnote noting that 
the Schwartz formula is used to calculate 
creatinine clearance in patients < 
18 years of age 
To reflect that different methods are used 
to calculate creatinine clearance in 
patients < 18 years of age and those 
18 years and older. 
Administrative Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
All sections 
Minor editorial updates and corrections 
For clarification, and to ensure accuracy and 
consistency throughout the protocol 
10.7.6. 
Amendment 1.5 (Germany) 10 Jul 2019 
This amendment was 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: 
The purpose of this amendment was to remove adolescents from the study in Germany, ie, 
patients aged 12 to 17 years of age in response to comments from the Federal Institute for Drugs 
and Medical Devices in Germany (BfArM) on Protocol Amendment 1. Only patients aged 18 
years and older were to be enrolled in the study at sites in Germany, as per the original protocol 
dated 07 Nov 2017. This amendment only applied to Germany; other countries in the study were 
able to enroll patients aged 12 to 17 years under Protocol Amendment 1, if permitted by their 
respective regulatory authorities. Substantial changes to the protocol are detailed in the table 
below. 


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Substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
Title Page 
Section 1.1 Synopsis 
Section 2.1, Study Rationale 
Section 2.3.1, Potential Benefits 
Section 3, Objectives and Endpoints 
Section 4.1.1, Primary Evaluation 
Period 
Section 4.2, Scientific Rationale for 
Study Design 
Section 5.1, Inclusion Criteria 
Section 8.1.3, Unified Wilson Disease 
Rating Scale (Parts I, II, and III) 
Section 8.1.9, EuroQoL 5 Dimensions 
Removal of text relating to inclusion 
of patients aged 12 to 17 years in the 
study in Germany. 
It has been decided not to 
include patients aged 12-17 
years in Germany, in response 
to comments from BfArM. 
Note: this amendment only 
applies to Germany; other 
countries in the study will be 
able to enroll patients aged 12 
to 17 years under Protocol 
Amendment 1, if permitted by 
their respective regulatory 
authorities. 
10.7.7. 
Amendment 1.6 (Austria), 30 Apr 2020 
This amendment was 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: 
Substantial changes to the protocol and administrative changes are detailed in the tables below. 
Substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 1.2 Schedule of 
Activities, Tables 3, 4, and 
5 
Section 8.2.5 Pregnancy 
Test 
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 
Section 1.2 Schedule of 
Activities, Table 5 only 
Addition of text that patients who 
transferred from Study WTX101-201 
do not need to attend visits at Weeks 60 
and 84 
These visits were not required for 
patients who had previously been in 
Study WTX101-201. 
Section 1.2 Schedule of 
Activities, Table 4 only 
and Section 8.1.5 Three 
Most Troublesome 
Symptoms 
Text added to clarify that videos of 
patients reporting their 3 most 
troublesome symptoms are not 
collected in the Extension Period of the 
study 
Videos are not required for patients in 
the Extension Period 
Section 8.3.1 Time Period 
and Frequency for 
Collecting AE and SAE 
Information 
Text corrected to confirm that medical 
occurrences that occur after consent but 
before study drug are reported as pre-
treatment adverse events 
To clarify that medical occurrences that 
occur after consent is given but before 
administration of study drug should be 
reported as pre-treatment adverse events, 
not medical history 
Section 9.2.7 Sample Size 
Determination 
Numbers of patients revised to 
approximately 113 evaluable patients 
Cohort 1 and 37 evaluable patients in 
Cohort 2 
To reflect the correct ratio of patients in 
Cohorts 1 and 2, ie, 3:1. 


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Administrative Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or clarifications 
Section 1.2, Schedule 
of Activities, Tables 
3, 4, and 5 
Renumbering and editing of footnotes 
To align and clarify footnotes, primarily 
because some had been misaligned when the 
previous amendment was prepared 
Section 1.2, Schedule 
of Activities, Table 5 
Add Extension Period Study Day and 
Week 
To clarify the expected schedule and 
procedures for patients who transfer to this 
study from Study WTX101-201 
Section 4.1 Overall 
Design 
Revised Figure 1 as Weeks 18 and 24 
were in an incorrect position and to 
clarify assessment time points for 
patients who enter the Extension Period 
For clarification 
All sections 
Minor editorial updates and corrections 
For clarification, and to ensure accuracy and 
consistency throughout the protocol 
 
10.7.8. 
Amendment 2 (Global), 25 Mar 2021 
This amendment is considered to substantially impact the scientific value of the study 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: 
The main reason for this amendment is to change the primary endpoint to reflect that a dynamic 
measure of tissue copper mobilization and elimination over time is a surrogate endpoint more 
likely to predict clinical benefit than point measurements of plasma calculated 
non-ceruloplasmin-bound copper (cNCC; the previous primary endpoint), because it will assess 
the treatment effect on tissue copper overload, the underlying cause of Wilson disease (WD).  
This amendment includes additional changes in the identity and/or the testing order of other 
endpoints to support the assessment of ALXN1840 tissue decoppering effect and its potentially 
greater benefits on the clinical outcomes of WD compared with standard of care (SoC) treatment. 
Substantial changes from protocol amendment 1 are detailed in Table 1. 


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Table 1: 
Substantial Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Substantial Changes to the Protocol 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints 
Primary endpoint changed from: 
• Percentage change from baseline 
(Day 1) to 48 weeks in non-
ceruloplasmin-bound Cu (NCC) in 
plasma. For ALXN1840-treated 
patients, the NCC in plasma will be 
corrected for the amount of Cu bound 
to the ALXN1840 tripartite complex 
(TPC) (NCCcorrected) 
to:  
• Daily mean area under the effect-time 
curve (AUEC) of directly measured 
non-ceruloplasmin-bound copper 
(dNCC) from 0 to 48 weeks 
Based on results obtained from 
completed Phase 1 and Phase 2 studies, 
it was determined that an integrative 
measure of non-ceruloplasmin-bound 
copper mobilization and elimination 
over time is a more appropriate 
surrogate endpoint to assess the 
treatment effect on tissue copper 
overload than point measurements of 
blood species of copper (eg, total 
plasma copper, labile bound copper, and 
cNCC) , which do not reflect the 
underlying burden of copper overload in 
tissues, and, therefore, do not provide 
meaningful data to direct therapeutic 
decisions.   
The previous primary endpoint has been 
moved to become a secondary endpoint 
and expanded to include absolute change 
from baseline: 
• Absolute change from baseline (Day 
1) to 48 weeks in cNCC in plasma.  
• Percentage change from baseline in 
cNCC in plasma. 
• For ALXN1840-treated patients, the 
cNCC in plasma will be corrected for 
the amount of copper bound to the 
ALXN1840 tripartite complex (TPC) 
(cNCCcorrected) 
The endpoint of percentage change from 
baseline in cNCC may be highly 
variable when the baseline levels are 
close to zero. Analysis of both absolute 
and percentage change from baseline in 
cNCC will allow more meaningful 
interpretation of the effect of 
ALXN1840 and SoC on circulating 
copper concentrations. 
Additional secondary endpoint of 
assessment of UWDRS Part III individual 
items/subscales (arising from a chair, gait, 
handwriting, and speech) added to the 
secondary objective of “Evaluate the 
effects of ALXN1840 on neurological 
status” 
Based on a recommendation by the US 
FDA, individual items/subscales of 
UWDRS Part III have been added to 
further define the range of functionally 
burdensome signs and symptoms of 
WD, so as to further understand the 
assessment of treatment effects on 
patients with WD. 
Additional endpoints added to the 
exploratory objective “Evaluate other 
directly measured PD and biomarkers of 
ALXN1840”  
Addition of exploratory objectives of 
“Explore ALXN1840 effect on initial 
decoppering phase compared to SoC 
based on directly measured PK/PD and 
biomarkers” and “Explore ALXN1840 
effect on subsequent maintenance phase 
compared to SoC based on directly 
measured PK/PD and biomarkers”  
The LBC assay was developed to 
provide a direct quantification of 
exchangeable copper in the NCC 
fraction, because the indirect method for 
estimating NCC concentrations is often 
associated with biologically implausible 
negative values. Therefore, newly 
developed endpoints have been added to 
reflect the additional assessments that 
will be performed relating to total 
copper concentration and LBC. 


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Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Extension Period endpoints aligned, so 
that the additional endpoints added to the 
primary, secondary, and exploratory 
objectives are also assessed. 
To ensure appropriate additional 
endpoints are also assessed during the 
Extension Period of the study. 
Section 1.1 Synopsis 
2.1, Study Rationale 
4.2 Scientific Rationale 
for Study Design 
Revision of text on the rationale for the 
study 
To align the study rationale with the 
change in primary endpoint. 
Section 1.1 Synopsis 
Section 9.2.1.1 Primary 
Efficacy Analysis 
9.2.1.2 Secondary 
Efficacy Analysis 
9.2.2 Type I Error 
Control 
9.2.5 Handling of 
Missing Data 
9.2.7 Sample Size 
Determination 
Revision of text relating to the statistical 
analysis of the primary endpoint and 
deletion of text relating to statistical 
analysis of the secondary endpoints 
To align details of the statistical 
analysis with the change in primary 
endpoint. 
Details of the statistical analyses to be 
performed on the secondary endpoints 
will be described in the Statistical 
Analysis Plan. 
Section 1.2 Schedule of 
Activities, Table 6 only 
Addition of text to clarify that patients 
who transferred from Study WTX101-201 
do not need to attend visits at Weeks 60 
and 84 
These visits were not required for 
patients who had previously been in 
Study WTX101-201. 
Section 1.2 Schedule of 
Activities, Table 5 only, 
Section 8.1.5 Three Most 
Troublesome Symptoms 
Text added to clarify that videos of 
patients reporting their 3 most 
troublesome symptoms are not required to 
be collected in the Extension Period of the 
study 
Videos are not required for patients in 
the Extension Period and also for 
patients who switch from SoC to 
ALXN1840 during the first year of the 
Extension Period. 
Section 1.2 Schedule of 
Activities, Table 5 
Removal of the following assessments on 
Day 295: Plasma/serum 
PK/PD/biomarkers and biobank samples, 
UWDRS Parts I, II, and III, and 
administer/dispense ALXN1840 
The Day 295 visit is performed via a 
phone call, so assessments are not 
performed. 
Section 1.2 Schedule of 
Activities, Table 5 and 
Table 6 
Addition of administer/dispense 
ALXN1840 on Days 1513, 1681, and 
1849 (Table 5) and Day 1849 (Table 6) 
To correct the SoA to when ALXN1840 
is administered/dispensed. 
Section 2.2.1 Wilson 
Disease 
2.2.2 ALXN1840 
2.3.1 Potential Benefits 
4.2 Scientific Rationale 
for Study Design 
Addition/update of the description of the 
proposed mechanism of action of 
ALXN1840 
To include text on the proposed 
mechanism of action of ALXN1840. 
Section 6.5.1.1 
Prohibited Medications 
Added text prohibiting the use of an 
experimental or unapproved/unlicensed 
therapy 
To ensure that use of experimental or 
unapproved/unlicensed drugs is 
excluded during the study. 
Section 7.2 Patient 
Discontinuation/ 
Withdrawal from the 
Study 
Revision of the requirement that patients 
may be discontinued from the study if 
they enroll in a clinical study of an 
experimental or unapproved/unlicensed 
therapy to state that they must be 
withdrawn if they receive an experimental 
or unapproved/unlicensed therapy. 
To clarify that if patients receive an 
experimental or unapproved/unlicensed 
therapy (eg, for treatment of 
COVID-19), they must be withdrawn 
from the study. 
Section 8.1.1 
Assessment of Copper 
Added details of the assessment of copper 
using AUEC 
To align with the change in primary 
endpoint. 


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Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 8.3.1 Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Text corrected to confirm that medical 
occurrences that occur after consent but 
before study drug are recorded as pre-
treatment adverse events 
To clarify that medical occurrences that 
occur after consent is given but before 
administration of study drug should be 
reported as pre-treatment adverse 
events, not medical history. 
Section 9.2.1.2 
Secondary Efficacy 
Analysis 
Text and table added defining key 
secondary endpoints according to regional 
expectations. 
Following interactions with the US 
FDA and EMA CHMP, regional 
differences in the key secondary 
endpoints and associated multiplicity 
testing were agreed. 
Section 9.2.5 Handling 
of Missing Data 
Tipping point analysis replaced with a 
2-dimensional tipping point analysis. 
The US FDA requested a more 
comprehensive tipping point analysis 
that would allow assumptions about the 
missing outcomes on the 2 groups to 
vary independently rather than just 
applying the shift to the ALXN1840 
group. 
Section 9.2.7 Sample 
Size Determination 
Numbers of patients revised to 
approximately 113 evaluable patients 
Cohort 1 and 37 evaluable patients in 
Cohort 2 
To reflect the correct ratio of patients in 
Cohorts 1 and 2, ie, 3:1. 
Section 10.2.1 
Chemistry, Table 8 
Chemistry 
Total cholesterol and triglycerides added 
to the table of chemistry assessments 
Routine lipid panel added for 
completeness. 
Text added to the footnote noting that the 
Schwartz formula is used to calculate 
creatinine clearance in patients < 18 years 
of age 
To reflect that different methods are 
used to calculate creatinine clearance in 
patients < 18 years of age and those 
18 years and older. 
Section 10.3 Appendix 
3: Definition of Adverse 
Event and Reporting of 
SAEs 
Definition of an AE, and text on reporting 
of SAEs updated. 
To be in-line with the definition in the 
latest Alexion approved protocol 
template. 
Abbreviations: AE = adverse event; AUEC = area under the effect-time curve; (d)(c)NCC = (direct) (calculated) 
non-ceruloplasmin-bound copper; CHMP = Committee for Medicinal Products for Human Use; EMA = European 
Medicines Agency; FDA = Food and Drug Administration; LBC = labile bound copper; PD = pharmacodynamic; 
PK = pharmacokinetic; SAE = serious adverse event; SoC = standard of care; TPC = tripartite complex; UWDRS = 
Unified Wilson Disease Rating Scale, WD = Wilson disease. 
Changes made in the country specific amendments 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6, as well as 
urgent safety measures relating to the COVID-19 pandemic already implemented in the study 
and notified to Competent Authorities have also been incorporated into this amendment (Table 
2). Minor administrative changes have also been made for clarification and consistency (Table 
3). 


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Table 2: 
COVID-19 Urgent Safety Measures and Changes Incorporated from 
Country Specific Amendments and Administrative Change Letters 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 10.9, Appendix 9: 
COVID-19 Urgent Safety 
Measures 
Appendix added detailing the provision 
of additional study procedures, 
laboratory assessments, safety 
monitoring and study drug dispensation 
that may be conducted as a result of the 
global COVID pandemic 
To ensure that every effort is made to 
maintain patient safety in the setting of 
COVID-19 transmission while 
continuing treatment for Wilson disease. 
Section 1.1, Synopsis 
Section 2.1, Study 
Rationale 
Section 4.1.1, Primary 
Evaluation Period 
Section 4.2, Scientific 
Rationale for Study Design 
Section 5.1, Inclusion 
Criteria 
Addition of text stating that patients 
enrolled in Germany have to be 18 
years of age or older 
Only patients aged 18 years and older 
can be enrolled in Germany, as detailed 
in Amendment 1.5 (Germany) dated 
10 Jul 2019, based on comments that 
were received from the Federal Institute 
for Drugs and Medical Devices in 
Germany (BfArM) on Protocol 
Amendment 1 dated 17 Jan 2019 and 
Amendment 1.3 (Germany) dated 
17 May 2019.  
Section 1.1, Synopsis 
Section 9.2.1.1, Primary 
Efficacy Analysis 
Details added of when the primary 
efficacy analysis will be performed. 
To ensure clarity regarding when the 
primary efficacy analysis will be 
performed, as requested by the Swedish 
Health Authority in Amendment 1.4 
(Sweden) dated 21 May 2019. 
Section 1.2 Schedule of 
Activities, Tables 4, 5, and 
6 
Section 8.2.5 Pregnancy 
Test 
Addition of requirement for female 
subjects of childbearing potential to 
perform monthly pregnancy testing at 
their home throughout the study 
Added as per Amendment 1.6 (Austria) 
dated 30 Apr 2020, because it is a legal 
requirement in Austria to include 
monthly pregnancy tests in clinical 
studies. 
Section 2.3.3 Benefit/Risk 
Conclusions 
Text added regarding the conclusions 
of the benefit/risk assessment. 
To clarify the benefit/risk, as requested 
by the Swedish Health Authority in 
Amendment 1.4 (Sweden) dated 21 May 
2019. 
Section 5.1 Inclusion 
Criteria 
Section 5.2 Exclusion 
Criteria 
Section 7.2 Patient 
Discontinuation/Withdraw
al from the Study 
Section 10.1.3 Informed 
Consent Process 
Change to reflect that the legal 
guardian of patients who are below the 
legal age for an adult in Japan must 
give consent to participate in or 
withdraw from the study 
To reflect that the age where a subject 
becomes an adult in Japan is 20 years 
old, not 18 years old, as defined in the 
Global Study Protocol, as previously 
detailed in Amendment 1.1 (Japan) 
dated 25 Mar 2019. 
Section 6.6.1, Guidance for 
Female Patients 
Addition of text on acceptable methods 
of contraception for female patients of 
childbearing potential in Japan, which 
differ from the methods accepted 
elsewhere 
Added in response to a request from the 
Japan Health Authorities, as previously 
detailed in Amendment 1.1 (Japan) 
dated 25 Mar 2019. 
Section 6.6.1, Guidance for 
Female Patients 
Addition of text on acceptable methods 
of contraception for female patients of 
childbearing potential in Canada, which 
differ from the methods accepted 
elsewhere 
Added in response to a request from 
Health Canada, previously detailed in 
Administrative Change Letter 7 
(Canada) dated 24 Jul 2020. 


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Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Section 8.5.3 Biomarkers 
and Biobank Samples 
Section 10.8 Appendix 8: 
Biobank Samples in the 
Netherlands 
Addition of an appendix detailing 
information on the management, 
storage, and analysis of biobank 
samples for the study site in the 
Netherlands 
To include the Biobank Regulations 
from the University Medical Center 
Utrecht, as previously detailed in 
Amendment 1.2 (Netherlands) dated 
22 May 2019. 
Section 10.1.1 
Added text on the competent authority 
To confirm that protocol amendments 
should be approved by the competent 
authority, in addition to the IEC/IRB, as 
detailed in Amendment 1.4 (Sweden) 
dated 21 May 2019. 
Section 10.7 Appendix 7: 
Protocol Amendment 
History 
Details of the previous protocol 
amendments, 1.1, 1.2, 1.3, 1.4, 1.5, and 
1.6 added.  
To include details of previous 
amendments. 
 
Table 3: 
Administrative Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or clarifications 
Section 1.2, Schedule of 
Activities, Tables 4, 5, and 
6 
Renumbering and editing of footnotes 
To align and clarify footnotes, primarily 
because some had been misaligned 
when amendment 1 was prepared. 
Section 1.2, Schedule of 
Activities, Table 6 
Added Extension Period Study Days 
and Weeks 
To clarify the expected schedule and 
procedures for patients who transfer to 
this study from Study WTX101-201. 
Section 4.1 Overall Design 
Revised Figure 1 as Weeks 18 and 24 
were in an incorrect position and to 
clarify assessment time points for 
patients who enter the Extension Period 
For clarification. 
All sections 
Minor editorial updates and corrections 
For clarification, and to ensure accuracy 
and consistency throughout the protocol. 
 
10.7.9. 
Amendment 2.1 (UK), 16 Apr 2021 
This amendment is considered non-substantial and applies to the UK. 
Overall Rationale for the Amendment: 
The reason for this amendment is to include language relating to 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. 
The change from protocol amendment 2 is detailed in Table 1. 
Table 1: 
Change to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
10.10 Appendix 10: 
COVID-19 Vaccine Risk 
Assessment 
Text on the COVID-19 vaccine risk 
assessment performed with respect to 
ALXN1840 added. 
A vaccine risk assessment has been 
requested by the UK MHRA for studies 
performed in the UK. 
Abbreviations: COVID-19 = coronavirus disease 2019; MHRA = Medicines and Healthcare products Regulatory 
Agency 


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10.8. 
Appendix 8: Biobank Samples in the Netherlands 
To fulfil the requirements set forth in the biobank regulations at the University Medical Center 
Utrecht (UMCU), the Netherlands, additional language is included here for this study to comply 
with the provisions of Article 10 of these regulations with regards to human biological material 
that was collected for the purpose of a specific study, subject to the Medical Research Involving 
Human Subjects Act (WMO), and that was not used (in full) for the study concerned.  
This appendix has been specifically written to document details regarding PK, PD, genetic and 
biomarker blood samples that will be stored and may be used for future research on ALXN1840. 
This appendix should be reviewed in addition to the conditions and procedures as set forth in the 
body of the main study protocol. 
10.8.1. 
Purpose of the Biobank Samples 
Blood and urine samples collected for testing of PK, PD, future genetic research, and biomarkers 
will be frozen, stored and may be used for future research linked to WD and the potential activity 
of ALXN1840, subject to the WMO. The samples will be de-identified, allowing the samples to 
be used without the researchers knowing the patient’s name or other personal identifiers. 
10.8.2. 
Processing, Analyzing and Storage of the Samples 
The process for collecting and handling the samples that are to be kept for future research is 
described in the study laboratory manual. 
These samples will be stored frozen at Alexion Pharmaceuticals, Inc. (100 College Street, New 
Haven, CT 06510 USA) or its designee for a maximum of 5 years after all data have been 
collected for the study (10 years for samples for genetic analysis). Cells will not be amplified to 
immortal (stem) cells and cell lines. 
In case of exceptional circumstances that something is discovered when analyzing the samples 
that could be in the patient’s interest, it will be reported to the biobank committee at UMCU. The 
committee will review all relevant information, and will discuss with the treating physician 
and/or the patient’s general practitioner, and the Medical Cluster Head from the Department of 
Gastroenterology. They will decide if the patient will be informed about these findings by the 
treating physician. 
This process is also explained in the informed consent form and the patient and/or his/her 
parents/guardians will provide consent for the use and storage of these samples and to be 
informed about any relevant findings. 
10.8.3. 
Release of the samples 
The terms for management of the samples are: 
1. Approval from the Medical Ethics Committee at UMCU as delegated by the Reviewing 
Committee Biobanking at UMCU. 
2. Executive Board approval at UMCU for the study including the biobanking. 
3. Samples may not be used for research other than specified in the ethical review 
application, unless obtaining a new approval by the Medical Ethics Committee at UMCU. 


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4. In case of future use of the samples, prior permission will be sought from the person at 
UMCU responsible for the biobank as described on the registration form. 
Samples are received, handled, analyzed, retained, and disposed in accordance with the 
Study WTX101-301 protocol, applicable laboratory standard operating procedures, and Alexion 
standard operating procedures. 
10.8.4. 
Procedures for coding and storage of personal data and biomaterial 
Personal data 
Patients receive a unique study code that will not identify the patient. The code linking personal 
identifiers to the samples will be kept by the investigator in a secure location at the study site. 
Patient initials and full Date of Birth information will not be used on any documents outside the 
hospital. The laboratories involved in the shipment or testing of samples do not have access to 
this information. These data are only accessible to the investigator and members of the research 
team in the hospital where the patient is treated. 
Samples will be labelled with a unique study number, sample number (code) and the study code 
described above. 
Alexion, and authorized representatives on behalf of Alexion, such as study monitors, as well as 
the Medical Ethics Committee, Health inspection, and other competent authorities, will have 
access to the source documents and other data traceable to individual patients at the hospital. 
The investigator and Alexion will store the patient’s data for at least 25 years after the end of the 
study, in accordance with applicable EU laws and national guidelines. 
Biomaterial 
a. During the research 
Biomaterial (blood samples and urine) from patients will be coded so that Alexion and their 
designees can store and analyze the samples without knowing the patient’s name or other 
personal identifiers. The patient’s biomaterial will receive a unique study number not linked to 
the person as described above.  
b. After conclusion of the research 
Blood samples for PK, PD, and biomarkers may be stored for a maximum of 5 years after the 
study, and samples for future genetic research for 10 years, and may be used for future research 
linked to the potential activity of ALXN1840. The blood samples will be discarded according to 
the standard procedures of the laboratory. 
All other blood and urine samples collected during the study will be destroyed after the tests 
described in the protocol have been performed. 
10.8.5. 
Consent procedure 
Where required by local regulations, explicit consent for the biobank storage and future research 
is required, and patients and/or their parents/guardians (where applicable) are specifically asked 
for their consent for retention and analysis of the biomaterial for future use for the purposes 
described in the informed consent form. In case the samples would be used for other purposes 
than described in the informed consent form, the patient’s (and/or parents/guardians) further 


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consent will first be obtained. In addition, where required by local regulations, there is a separate 
withdrawal consent process for patients and/or their parents/guardians who initially consented to 
the storage of their samples for future use, but who change their mind during or after the study. 
 


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10.9. 
Appendix 9: COVID-19 Urgent Safety Measures 
The COVID-19 pandemic has the potential to restrict access to ALXN1840 and SoC treatment 
and safety monitoring visits for study patients. During this pandemic period, Alexion has set up 
mitigation measures providing additional options whereby study procedures, laboratory 
assessments, safety monitoring and study drug dispensation may be conducted (Table 13). These 
include visits at the patient’s home, by an investigator or home healthcare provider, in-person, by 
telephone or by video conference, at another study site located near the patient’s home, or an 
alternative center located near the patient’s home. These visits are conducted under the orders of 
the study site Investigator by trained qualified staff and in accordance with all national, state, and 
local laws or regulations.  
Patients with WD may be at risk of complications if treatment is missed or delayed. Alexion has 
not identified a safety signal with ALXN1840 that would prevent its use during a viral infection 
and does not recommend suspending treatment in patients receiving ALXN1840 or SoC. The 
risk to benefit assessment favors continuity of treatment for WD, when possible.  
An Urgent Safety Measure was notified to both competent authorities and IRBs/ECs, where 
applicable. Informed consents forms were updated as necessary to permit release of medical 
records for patients transferring to another study site and to enable remote data verification 
where permitted. 
The future of this pandemic is uncertain. These changes in the conduct of the study are effective 
but are intended to be temporary. Alexion intends to revert back to the original measures 
described in the current protocol after the end of the pandemic period. Alexion is making every 
effort to maintain patient safety in the setting of COVID-19 transmission while continuing 
treatment for WD. Any questions concerning the mitigation measures in place should be 
discussed with the Alexion Medical Monitor. 
 


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Table 13: 
COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) for Study WTX101-301 
Study Impact 
Clinical Study Temporary Measures 
Justification for COVID-19 Mitigation  
Site Staff via 
Home 
Visit/Phone/Vide
o 
Alternative staff 
at home 
Alternative 
study/local 
site 
Courier 
Abbreviated 
physical 
examination 
PI/Sub-I 
  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
Vital signs 
(Weight, temp, 
BP and HR) 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider, at another study site located near the patient’s home, 
or an alternative center located near the patient’s home. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
12-lead ECG 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at another study site located near the patient’s 
home, or an alternative center located near the patient’s home. This 
alternative measure will limit impact of the pandemic on the parameter 
assessment. 
DNA sample 
In-Clinic after 
restriction is lifted 
  
  
  
NA 
Pregnancy 
testa 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Courier may be 
used for shipment 
of lab kits from 
site to patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider, at another study site located near the patient’s home, 
or an alternative center located near the patient’s home. Site staff and 
home healthcare providers will be trained on the study laboratory manual 
to ensure proper collection, processing, shipping of samples. If local labs 
are used for collection of safety samples, results and reference ranges will 
be collected. This alternative temporary measure will limit impact of the 
pandemic on the parameter assessment. 
Urinalysis 
 PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Courier may be 
used for shipment 
of lab kits from 
site to patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider, at another study site located near the patient’s home, 
or an alternative center located near the patient’s home. Site staff and 
home healthcare providers will be trained on the study laboratory manual 
to ensure proper collection, processing, shipping of samples. If local labs 
are used for collection of safety samples, results and reference ranges will 
be collected. This alternative temporary measure will limit impact of the 
pandemic on the parameter assessment. 


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Table 13: 
COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) for Study WTX101-301 
Study Impact 
Clinical Study Temporary Measures 
Justification for COVID-19 Mitigation  
Site Staff via 
Home 
Visit/Phone/Vide
o 
Alternative staff 
at home 
Alternative 
study/local 
site 
Courier 
Chemistry, 
coagulation, 
hematology 
panela 
 PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Courier may be 
used for shipment 
of lab kits from 
site to patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider, at another study site located near the patient’s home, 
or an alternative center located near the patient’s home. Site staff and 
home healthcare providers will be trained on the study laboratory manual 
to ensure proper collection, processing, shipping of samples. If local labs 
are used for collection of safety samples, results and reference ranges will 
be collected.  This alternative temporary measure will limit impact of the 
pandemic on the parameter assessment. 
AEsa 
PI/Sub-I 
Home healthcare 
provider to query 
patient about 
changes from last 
visit. Contact 
Investigator if any 
changes.  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider. This alternative temporary measure will limit impact 
of the pandemic on the parameter assessment. 
Concomitant 
medicationsa 
PI/Sub-I 
Home healthcare 
provider to query 
patient about 
changes from last 
visit. Contact 
Investigator if any 
changes.  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider. This alternative temporary measure will limit impact 
of the pandemic on the parameter assessment. 
MELD and 
modified 
Nazer 
NA 
  
  
  
NA 
Fibrosis-4 
NA 
  
  
  
NA 
Transient 
elastography 
In-Clinic after 
restriction is lifted 
  
  
  
NA 
Plasma/serum 
PK/PD/ 
biomarkers 
and biobank 
samples 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Courier may be 
used for shipment 
of lab kits from 
site to patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider, at another study site located near the patient’s home, 
or an alternative center located near the patient’s home. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 


Protocol Amendment 3 (Global) 
 
WTX101-301 
27 Apr 2022 
Page 108 of 112 
 
Alexion Confidential 
 
Table 13: 
COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) for Study WTX101-301 
Study Impact 
Clinical Study Temporary Measures 
Justification for COVID-19 Mitigation  
Site Staff via 
Home 
Visit/Phone/Vide
o 
Alternative staff 
at home 
Alternative 
study/local 
site 
Courier 
24-hour urine 
copper and 
molybdenum 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
  
Courier may be 
used for shipment 
of lab kits from 
site to patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home by site staff or home 
healthcare provider. This alternative temporary measure will limit impact 
of the pandemic on the parameter assessment. 
Investigational 
Product (IP) 
PI/Sub-I/SC/Other 
certified staff 
Home healthcare 
provider may 
transport IP from 
site to patient 
  
Courier may be 
used for shipment 
of IP from site to 
patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider, at another study site located near the patient’s home, 
or an alternative center located near the patient’s home. IP may be 
transported by site staff, home healthcare provider, or shipped to patient 
via courier in a refrigerated (ALXN1840, Trientine) or ambient (Zinc, 
Penicillamine) container. This alternative temporary measure will limit 
impact of the pandemic on the IP supply to the patient. 
UWDRS II 
Site staff 
Phone/Video  
  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home by site staff. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. . 
UWDRS I & 
III 
Video by 
Neurologist if 
feasible 
  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home by site staff. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
BPRS 
Site staff 
Phone/Video  
  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home by site staff. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
CGI-S, CGI-I 
Site staff 
Phone/Video  
  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home by site staff. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
25F Walk Test 
Home visit by site 
staff if feasible 
  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home by site staff. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
9-HPT 
Home visit by site 
staff if feasible 
  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home by site staff. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 


Protocol Amendment 3 (Global) 
 
WTX101-301 
27 Apr 2022 
Page 109 of 112 
 
Alexion Confidential 
 
Table 13: 
COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) for Study WTX101-301 
Study Impact 
Clinical Study Temporary Measures 
Justification for COVID-19 Mitigation  
Site Staff via 
Home 
Visit/Phone/Vide
o 
Alternative staff 
at home 
Alternative 
study/local 
site 
Courier 
Digit Span 
Home visit by site 
staff if feasible 
  
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home by site staff. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
3 Most 
Troublesome 
Symptoms 
Patient to 
complete 
Home healthcare 
provider may 
provide completed 
questionnaire to 
site 
  
Courier may be 
used for shipment 
of questionnaires 
from site to 
patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider This alternative temporary measure will limit impact 
of the pandemic on the parameter assessment. 
EQ-5D 
Patient to 
complete 
Home healthcare 
provider may 
provide completed 
questionnaire to 
site 
  
Courier may be 
used for shipment 
of questionnaires 
from site to 
patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider. This alternative temporary measure will limit impact 
of the pandemic on the parameter assessment. 
TSQM-9 
Patient to 
complete 
Home healthcare 
provider may 
provide completed 
questionnaire to 
site 
  
Courier may be 
used for shipment 
of questionnaires 
from site to 
patient 
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider. This alternative temporary measure will limit impact 
of the pandemic on the parameter assessment. 
Re-consent 
Site staff 
Phone/Video  
Home healthcare 
provider may 
provide signed 
consent to site 
  
  
Due to COVID-19 pandemic restrictions, patient study visits may need to 
be completed remotely at the patient’s home, by site staff or home 
healthcare provider. This alternative temporary measure will limit impact 
of the pandemic on the re-consent of patients if needed. 
a. 
Critical for safety monitoring 
 


Protocol Amendment 3 (Global) 
 
WTX101-301 
27 Apr 2022 
Page 110 of 112 
 
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11. 
REFERENCES 
Beinhardt S, Leiss W, Stattermayer AF, et al. Long-term outcomes of patients with Wilson 
disease in a large Austrian cohort. Clin Gastroenterol Hepatol. 2014;12(4):683-689. 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28:586-604. 
Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurologic syndrome in patients with 
Wilson's disease with initial penicillamine therapy. Arch Neurol. 1987;44(5):490-493. 
Brewer GJ, Hedera P, Kluin KJ, et al. Treatment of Wilson disease with ammonium 
tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and 
follow-up with zinc therapy. Arch Neurol. 2003;60(3):379-385. 
Brewer GJ, Askari F, Dick RB, et al. Treatment of Wilson's disease with tetrathiomolybdate: V. 
Control of free copper by tetrathiomolybdate and a comparison with trientine. Transl Res. 
2009;154(2):70-77. 
Brewer GJ, Askari F, Lorincz MT, et al. Treatment of Wilson disease with ammonium 
tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study 
of treatment of the neurologic presentation of Wilson disease. Arch Neurol. 2006;63(4):521-527. 
Chen HW, Yan JJ, Chen WC, et al. Predictive and prognostic value of human copper transporter 
1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based 
doublet chemotherapy. Lung Cancer. 2012;75(2):228-234. 
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-857. 
Czlonkowska A, Tarnacka B, Moeller JC, et al. Unified Wilson's Disease Rating Scale - a 
proposal for the neurological scoring of Wilson's disease patients. Neurol Neurochir Pol. 
2007;41(1):1-12. 
Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiyiannakis L, Mieli-Vergani G. Wilson's 
disease in children: 37-year experience and revised King's score for liver transplantation. Liver 
Transpl. 2005;11(4):441-448. 
Dziezyc K, Karlinski M, Litwin T, Czlonkowska A. Compliant treatment with anti-copper agents 
prevents clinically overt Wilson's disease in pre-symptomatic patients. Eur J Neurol. 
2014;21(2):332-337. 
EASL. European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: 
Wilson's disease. J Hepatol. 2012;56(3):671-685. 
Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson 
disease. Liver Int. 2003;23(3):139-142. 
Ferenci P, Stremmel W, Czlonkowska A, et al. Age and sex but not ATP7B genotype effectively 
influence the clinical phenotype of Wilson disease. Hepatology. 2019;69(4):1464-1476. 
Frydman M. Genetic aspects of Wilson's disease. J Gastroenterol Hepatol. 1990;5(4):483-490. 


Protocol Amendment 3 (Global) 
 
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27 Apr 2022 
Page 111 of 112 
 
Alexion Confidential 
 
Gorst-Rasmussen A, Tarp-Johansen MJ. Multiway Tipping Point Analyses in Longitudinal 
Clinical Trials with Missing Data. ASA Biopharm Reg Ind Stats Workshop. Poster 05. 
25 Sep 2020. 
Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annu Rev Nutr. 2002;22:439-
458. 
Hoelscher S, Leinweber B, Hefter H, et al. Evaluation of the symptomatic treatment of residual 
neurological symptoms in Wilson disease. Eur Neurol. 2010;64(2):83-87. 
Kalita J, Kumar V, Ranjan A, Misra UK. Role of Oxidative Stress in the Worsening of 
Neurologic Wilson Disease Following Chelating Therapy. Neuromolecular Med. 
2015;17(4):364-372. 
Kalita J, Kumar V, Chandra S, Kumar B, Misra UK. Worsening of Wilson disease following 
penicillamine therapy. Eur Neurol. 2014;71(3-4):126-131. 
Lehmacher W, Wassmer G. Adaptive sample size calculations in group sequential trials. 
Biometrics. 1999;55(4):1286-1290. 
Leinweber B, Moller JC, Scherag A, et al. Evaluation of the Unified Wilson's Disease Rating 
Scale (UWDRS) in German patients with treated Wilson's disease. Mov Disord. 2008;23(1):54-
62. 
Maselbas W, Chabik G, Czlonkowska A. Persistence with treatment in patients with Wilson 
disease. Neurol Neurochir Pol. 2010;44(3):260-263. 
Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term 
outcome of Wilson's disease: a cohort study. Gut. 2007;56(1):115-120. 
Ogra Y, Ohmichi M, Suzuki KT. Mechanisms of selective copper removal by tetrathiomolybdate 
from metallothionein in LEC rats. Toxicology. 1996;106(1-3):75-83. 
Pfeiffenberger J, Lohse CM, Gotthardt D, et al. Long-term evaluation of urinary copper 
excretion and non-caeruloplasmin associated copper in Wilson disease patients under medical 
treatment. J Inherit Metab Dis. 2019;42(2):371-380. 
Pfeiffer RF. Wilson's Disease. Semin Neurol. 2007;27(2):123-132. 
Poujois A, Woimant F. Wilson's disease: A 2017 update. Clin Res Hepatol Gastroenterol. 
2018;42(6):512-520. 
Reilly M, Daly L, Hutchinson M. An epidemiological study of Wilson's disease in the Republic 
of Ireland. J Neurol Neurosurg Psychiatry. 1993;56(3):298-300. 
Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). 
Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York. John Wiley and Sons; 
1987. 
Schilsky ML. Diagnosis and treatment of Wilson's disease. Pediatr Transplant. 2002;6(1):15-19. 
Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated 
guidelines for reporting parallel group randomized trials. Ann Intern Med. 2010;152(11):726-
732. 


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Sugitani T, Bretz F, Maurer W. A simple and flexible graphical approach for adaptive group-
sequential clinical trials. J Biopharm Stat. 2016;26(2):202-216. 
UNOS UNfOS. Policy Notice. Policy Clarification to KPD Histocompatibility Requirements – 
Test Date. 2015. 
Van Reenen MJB, Oppe M, Kreimeier S, Greiner W. EuroQol Group. EQ-5D-Y User Guide. 
Basic information on how to use the EQ-5D-Y instrument. Version 1.0. 2014. 
Wassmer G, Brannath W. Group Sequential and Confirmatory Adaptive Designs in Clinical 
Trials. New York: Springer; 2016. 
Weiss G, Forster S, Irving A, et al. Helicobacter pylori VacA suppresses Lactobacillus 
acidophilus-induced interferon beta signaling in macrophages via alterations in the endocytic 
pathway. mBio. 2013;4(3):e00609-00612. 
Weiss KH, Gotthardt DN, Klemm D, et al. Zinc monotherapy is not as effective as chelating 
agents in treatment of Wilson disease. Gastroenterology. 2011;140(4):1189-1198.e1181. 
Weiss KH, Askari FK, Czlonkowska A, et al. Bis-choline tetrathiomolybdate in patients with 
Wilson's disease: an open-label, multicentre, phase 2 study. Lancet Gastroenterol Hepatol. 
2017;12:869-876. 
Yeh KC, Kwan KC. A comparison of numerical integrating algorithms by trapezoidal, Lagrange, 
and spline approximation. J Pharmacokinet Biopharm. 1978;6(1):79-98. 
Zhang JW, Liu JX, Hou HM, et al. Effects of tetrathiomolybdate and penicillamine on brain 
hydroxyl radical and free copper levels: a microdialysis study in vivo. Biochem Biophys Res 
Commun. 2015;458(1):82-85. 
 
 

SAP_001.pdf: 
Alexion Pharmaceuticals 
US/Japan Statistical Analysis Plan 
Protocol Number: WTX101-301 dated 25 Mar 2021 (Amendment 2) 
06 Aug 2021, Version 6.0 
Proprietary and Confidential 
Page 1 of 66 
Alexion Pharmaceuticals, Inc. 
STATISTICAL ANALYSIS PLAN 
Primary Evaluation Period 
for US/Japan Submission 
PROTOCOL NUMBER: WTX101-301 
A PHASE 3, RANDOMIZED, RATER-BLINDED, 
MULTI-CENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF ALXN1840 
ADMINISTERED FOR 48 WEEKS VERSUS STANDARD 
OF CARE IN PATIENTS WITH WILSON DISEASE 
AGED 12 YEARS AND OLDER WITH AN EXTENSION 
PERIOD OF UP TO 60 MONTHS
Authors: 
 
Date: 06-Aug-2021 
Version: 6.0 Final 
NCT #:  NCT03403205


Alexion Pharmaceuticals 
US/Japan Statistical Analysis Plan 
Protocol Number: WTX101-301 dated 25 Mar 2021 (Amendment 2) 
06 Aug 2021, Version 6.0 
Proprietary and Confidential 
Page 2 of 66 
1. 
APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
06-Aug-2021 | 11:02:30 EDT
06-Aug-2021 | 10:18:26 EDT
06-Aug-2021 | 10:11:29 EDT


Alexion Pharmaceuticals 
US/Japan Statistical Analysis Plan 
Protocol Number: WTX101-301 dated 25 Mar 2021 (Amendment 2) 
06 Aug 2021, Version 6.0 
Proprietary and Confidential 
Page 3 of 66 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES .......................................................................................2 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................3 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................8 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................9 
4. 
DESCRIPTION OF THE PROTOCOL .....................................................................11 
4.1. 
Changes from Analyses Specified in the Protocol .....................................................12 
4.2. 
Changes from Analyses Specified in the Previous Version of the SAP .....................12 
5. 
DEFINITIONS ...........................................................................................................13 
5.1. 
Efficacy .......................................................................................................................13 
5.1.1. 
Primary Endpoint(s) ....................................................................................................13 
5.1.2. 
Secondary Endpoints ..................................................................................................13 
5.1.2.1. 
Unified Wilson Disease Rating Scale (Parts I, II, and III) .........................................14 
5.1.2.2. 
Clinical Global Impression-Improvement Scale and the Clinical Global 
Impression-Severity Scale ..........................................................................................14 
5.1.2.3. 
Model for End-Stage Liver Disease Score .................................................................14 
5.1.2.4. 
cNCC/cNCCcorrected, cNCC/cNCCcorrected Responder ..................................................15 
5.1.3. 
Exploratory Endpoints ................................................................................................16 
5.1.3.1. 
Three Most Troublesome Symptoms ..........................................................................18 
5.1.3.2. 
Fibrosis-4 Index/Transient Elastography ....................................................................18 
5.1.3.3. 
Modified Nazer Score .................................................................................................19 
5.1.3.4. 
Brief Psychiatric Rating Scale-24 ...............................................................................19 
5.1.3.5. 
EuroQoL-5 Dimensions ..............................................................................................19 
5.1.3.6. 
Treatment Satisfaction Questionnaire for Medication ................................................20 
5.1.3.7. 
Timed 25F Walk Test .................................................................................................20 
5.1.3.8. 
Nine-Hole Peg Test .....................................................................................................21 
5.1.3.9. 
Nonverbal Stroop Interference Test ............................................................................21 
5.1.3.10. 
Digit Span Test ...........................................................................................................21 


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5.1.3.11. 
Plasma Total Molybdenum, Plasma Ultrafiltrate Molybdenum, Plasma Total 
Copper, Plasma Ultrafiltrate Copper, dNCC, LBC, Ceruloplasmin, and 
Ceruloplasmin-bound Copper .....................................................................................22 
5.1.3.12. 
Time to First Confirmed Increase, Time to Minimum and Maximum, and 
Time for Return to Predose Baseline ..........................................................................22 
5.1.3.13. 
24-Hour Urine Copper and Molybdenum ...................................................................22 
5.2. 
Safety ..........................................................................................................................22 
5.2.1. 
Adverse Events ...........................................................................................................22 
5.2.2. 
Vital Signs ..................................................................................................................23 
5.2.3. 
Laboratory Assessments .............................................................................................23 
5.2.4. 
Physical Examinations ................................................................................................23 
5.2.5. 
Electrocardiogram .......................................................................................................23 
5.2.6. 
Other Events of Special Interest .................................................................................23 
6. 
DATA SETS ANALYZED (STUDY POPULATIONS) ...........................................24 
6.1. 
Full Analysis Set .........................................................................................................24 
6.2. 
Per Protocol Set ..........................................................................................................24 
6.3. 
Safety Set ....................................................................................................................24 
6.4. 
Pharmacokinetic Set ...................................................................................................24 
6.5. 
Pharmacodynamic and Biomarker Set ........................................................................24 
7. 
STATISTICAL ANALYSIS ......................................................................................25 
7.1. 
Study Patients .............................................................................................................25 
7.1.1. 
Disposition of Patients ................................................................................................25 
7.1.2. 
Protocol Deviations ....................................................................................................25 
7.1.3. 
Demographics, Disease Characteristics, and History .................................................26 
7.1.3.1. 
Demographics .............................................................................................................26 
7.1.3.2. 
Disease Characteristics ...............................................................................................26 
7.1.3.3. 
Medical / Surgical History, and WD History .............................................................28 
7.1.4. 
Prior and Concomitant Medications / Therapies ........................................................29 
7.2. 
Efficacy Analyses .......................................................................................................29 
7.2.1. 
Primary Analysis ........................................................................................................30 
7.2.1.1. 
Handling of Dropouts or Missing Data ......................................................................31 
7.2.1.2. 
Subgroup Analysis ......................................................................................................33 
7.2.1.3. 
Multicenter Studies .....................................................................................................35 


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06 Aug 2021, Version 6.0 
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7.2.1.4. 
Hypothesis Testing and Significance Level ...............................................................36 
7.2.1.5. 
Sensitivity Analyses ....................................................................................................38 
7.2.2. 
Secondary Analyses ....................................................................................................38 
7.2.3. 
Exploratory Analyses ..................................................................................................39 
7.2.4. 
Extension Period Analyses .........................................................................................42 
7.2.5. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................42 
7.3. 
Safety Analyses ..........................................................................................................43 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure .............................................43 
7.3.1.1. 
Study Duration ............................................................................................................43 
7.3.1.2. 
Treatment Compliance ................................................................................................43 
7.3.1.3. 
Exposure .....................................................................................................................43 
7.3.2. 
Adverse Events ...........................................................................................................44 
7.3.2.1. 
Overall Summary of Adverse Events .........................................................................45 
7.3.2.2. 
AEs by System Organ Class and Preferred Term .......................................................45 
7.3.2.3. 
AEs by System Organ Class .......................................................................................46 
7.3.2.4. 
AEs by Preferred Term ...............................................................................................46 
7.3.2.5. 
AEs by System Organ Class, Preferred Term, and Relationship ...............................46 
7.3.2.6. 
AEs by System Organ Class, Preferred Term, and Severity ......................................46 
7.3.2.7. 
Deaths, Other Serious Adverse Events, and Adverse Events of Special 
Interest ........................................................................................................................46 
7.3.2.8. 
Other Significant Adverse Events ..............................................................................47 
7.3.3. 
Other Safety Analyses ................................................................................................48 
7.3.3.1. 
Analyses for Laboratory Tests ....................................................................................48 
7.3.3.2. 
Evaluation of Drug Induced Serious Hepatotoxicity ..................................................49 
7.3.3.3. 
Vital Signs ..................................................................................................................50 
7.3.3.4. 
Electrocardiogram .......................................................................................................50 
7.3.3.5. 
Relationship Between Copper and Safety Endpoints .................................................50 
8. 
REFERENCES ...........................................................................................................52 
9. 
APPENDICES ............................................................................................................56 
9.1. 
Protocol Schedule of Activities ..................................................................................56 
9.2. 
Changes from Analyses Specified in the Previous Version of the SAP .....................56 
9.3. 
Sample Size, Power, and Randomization ...................................................................57 
9.3.1. 
Sample Size Justifications ..........................................................................................57 


Alexion Pharmaceuticals 
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06 Aug 2021, Version 6.0 
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9.3.2. 
Sample Size Re-estimation .........................................................................................58 
9.3.3. 
Randomization ............................................................................................................58 
9.4. 
Technical Specifications for Derived Variables .........................................................58 
9.4.1. 
Adverse Events ...........................................................................................................58 
9.4.2. 
Age ..............................................................................................................................59 
9.4.3. 
Analysis Relative Day ................................................................................................59 
9.4.4. 
Baseline Value ............................................................................................................59 
9.4.5. 
Body Mass Index (BMI) .............................................................................................59 
9.4.6. 
Change from Baseline .................................................................................................59 
9.4.7. 
Medications and Therapies .........................................................................................60 
9.4.8. 
UWDRS ......................................................................................................................60 
9.4.9. 
Visit Windowing .........................................................................................................65 
9.5. 
Additional Details on Statistical Methods ..................................................................65 
9.5.1 
Analysis Considerations Related to COVID-19 .........................................................65 
 


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Protocol Number: WTX101-301 dated 25 Mar 2021 (Amendment 2) 
06 Aug 2021, Version 6.0 
 
Proprietary and Confidential 
Page 7 of 66 
LIST OF TABLES 
Table 1: 
Abbreviations and acronyms ........................................................................................9 
Table 2: 
Modified Nazer Score .................................................................................................19 
Table 3: 
Correlations Between Copper and Key Secondary Endpoints (Change from 
Baseline) .....................................................................................................................42 
Table 4: 
Correlations Between Copper and Key Secondary Endpoints (Measured 
Values) ........................................................................................................................42 
Table 5: 
Correlations Between Copper and Safety Endpoints ..................................................51 
Table 6: 
Age and Reference Date .............................................................................................59 
 
 


Alexion Pharmaceuticals 
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Protocol Number: WTX101-301 dated 25 Mar 2021 (Amendment 2) 
06 Aug 2021, Version 6.0 
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LIST OF FIGURES 
Figure 1: 
Proposed Multiple Testing Strategy. ..........................................................................37 
 


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06 Aug 2021, Version 6.0 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and acronyms in Table 1 are used in this Statistical Analysis Plan 
(SAP). 
Table 1: 
Abbreviations and acronyms 
Abbreviation or acronym 
Explanation 
ADL 
Activities of Daily Living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUEC 
area under the effect-time curve 
BMI 
body mass index 
BPRS-24 
Brief Psychiatric Rating Scale-24 
BSA 
body surface area 
CCR 
color congruent ratio 
CGI 
Clinical Global Impression  
CGI-I 
Clinical Global Impression-Improvement Scale 
CGI-S 
Clinical Global Impression-Severity Scale 
CI 
confidence interval 
CIR 
color incongruent ratio 
cNCC 
calculated non-ceruloplasmin-bound copper 
cNCCcorrected 
calculated non-ceruloplasmin-bound copper corrected for copper bound 
in tetrathiomolybdate-copper-albumin complexes 
COVID-19 
Coronavirus Disease 2019 
Cp 
ceruloplasmin 
CpC 
ceruloplasmin-bound copper 
CPni 
conditional power for non-inferiority 
CPs 
conditional power for superiority 
CRF 
case report form  
CTCAE 
Common Terminology Criteria for Adverse Events 
Cu 
copper 
CV 
coefficient of variation 
DNA 
deoxyribonucleic acid 
dNCC 
directly measured non-ceruloplasmin-bound copper 
dNCC AUEC0-48W 
area under the effect-time curve of directly measured non-
ceruloplasmin-bound copper from 0 to 48 weeks 
ECG 
electrocardiogram 
eDISH 
evaluation of drug induced serious hepatotoxicity 
EOS 
end of study 
EQ-5D 
EuroQOL-5 Dimensions 
EQ-5D-5L 
EuroQOL-5 Dimensions-5 Levels 
EQ VAS 
EuroQol Visual Analogue Scale 
ET 
Early Termination 
FA 
Full Analysis  
FIB-4 
fibrosis-4 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyltransferase 


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Table 1: 
Abbreviations and acronyms 
Abbreviation or acronym 
Explanation 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
INR 
international normalized ratio 
LBC 
labile bound copper 
LLN 
lower limit of normal  
LLOQ 
lower limit of quantification 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
MMRM 
mixed model for repeated measures 
Mo 
molybdenum 
NCC 
non-ceruloplasmin-bound copper 
NCI 
National Cancer Institute 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PP 
Per Protocol 
PTAE 
pretreatment adverse event 
PUF 
plasma ultrafiltrate 
PY 
patient-years 
QoL 
Quality of Life 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SCr 
serum creatinine 
SE 
standard error 
SoC 
standard of care 
SSR 
sample size re-estimation 
TEAE 
treatment-emergent adverse event 
TPC 
tripartite complex 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication-9 
ULN 
upper limit of normal  
UWDRS 
Unified Wilson’s Disease Rating Scale 
VAS 
Visual Analogue Scale 
WD 
Wilson Disease 
WHO 
World Health Organization 
9-HPT 
Nine-Hole Peg Test 


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4. 
DESCRIPTION OF THE PROTOCOL 
This SAP relates to Alexion Pharmaceuticals Inc. Protocol WTX101-301 (A Phase 3, 
Randomized, Rater-Blinded, Multi-Center Study to Evaluate the Efficacy and Safety of 
ALXN1840 Administered for 48 Weeks Versus Standard of Care in Patients with Wilson 
Disease Aged 12 and Older with an Extension Period of up to 60 Months), Amendment 2 dated 
25 March 2021. 
This is a randomized, rater-blinded, multicenter study assessing the efficacy and safety of 
ALXN1840 versus standard of care (SoC). In the Primary Evaluation Period, efficacy and safety 
were assessed for an individualized ALXN1840 dosing regimen compared with SoC 
administered for 48 weeks in patients with Wilson Disease (WD) who are aged 12 years and 
older (18 years and older in Germany). 
Patients meeting all inclusion and no exclusion criteria were enrolled into the study and studied 
as outpatients. Eligible patients with WD were enrolled into 1 of 2 cohorts, in a ratio of 3:1 
(Cohort 1: Cohort 2). 
 Cohort 1: Patients who had received SoC therapy (i.e., chelation therapy with 
penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc 
therapy) for > 28 days prior to first dose 
 Cohort 2: Patients who were treatment naïve or who had received SoC therapy 
for ≤ 28 days prior to first dose 
Approximately 180 patients were enrolled and randomized by cohort in a 2:1 ratio to treatment 
with ALXN1840 or SoC (either as continued therapy in Cohort 1 or as continued or initial 
therapy in Cohort 2) to obtain data from approximately 150 evaluable patients (100 ALXN1840, 
50 SoC) for the primary analysis. Treatments were assigned randomly, stratified by cohort. 
Patients who were randomized to receive ALXN1840 were required to withhold treatment with 
SoC for ≥ 48 hours immediately prior to first study assessment on Day 1. Patients who were 
randomized to ALXN1840 received ALXN1840 as delayed-release tablets for oral 
administration at doses ranging from 15 mg every other day (QOD) to 60 mg once daily (QD). 
Efficacy and safety assessments were performed at scheduled visits, while adverse events (AEs) 
and concomitant medications were monitored continuously throughout the study. Patients 
randomized to SoC initiated treatment or continued treatment on their current regimen where 
possible, without compromising the safety of individual patients. 
The Primary Evaluation Period consisted of an up to 28-day Screening Period, a 1-day 
Enrollment Visit, a 48-week Treatment Period, and a Follow-up Visit 4 weeks after the last dose 
for patients who do not elect to continue in the Extension Period. 
Patients in Study WTX101-301 who completed the 48-week Treatment Period and patients who 
completed participation in Study WTX101-201 will be offered the opportunity to participate in 
an up to 60-month Extension Period within Study WTX101-301 to evaluate the long-term safety 
and efficacy of ALXN1840. 
This SAP describes the analytical plan for the randomized Primary Evaluation Period. A separate 
SAP will be generated for the non-randomized exploratory open label Extension Period. 
Refer to the Study WTX101-301 protocol for additional details. 


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4.1. 
Changes from Analyses Specified in the Protocol 
 LBC responder rate at 48 weeks will not be analyzed. 
 Physical examination results will not be tabulated independently. Abnormalities will be 
reported as part of Medical History or as adverse events. 
4.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
More details of the changes can be found in Section 9.2. 


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5. 
DEFINITIONS 
5.1. 
Efficacy  
5.1.1. 
Primary Endpoint(s) 
The primary efficacy analysis will be conducted on the data from the Primary Evaluation Period 
for all patients. The primary endpoint is the daily mean area under the effect-time curve (AUEC) 
of directly measured non-ceruloplasmin-bound copper (dNCC) from 0 to 48 weeks (dNCC 
AUEC0-48W). dNCC is the directly quantified copper not bound to ceruloplasmin, obtained by 
inductively coupled plasma mass spectrometry after immunocapture and removal of 
ceruloplasmin. The mean of dNCC AUEC0-48W will be compared between ALXN1840 and SoC. 
Based on results obtained from the completed Phase 1 and Phase 2 studies, it was determined 
that an integrative measure (AUEC) of non-ceruloplasmin-bound copper mobilization and 
elimination over time is a more appropriate surrogate endpoint to assess the treatment effect on 
tissue copper overload. In contrast, point measurements of blood species of copper (eg, total 
plasma copper, labile bound copper, and calculated non-ceruloplasmin-bound copper [cNCC]), 
do not reflect the underlying burden of copper overload in tissues, and, therefore, do not provide 
meaningful data to direct therapeutic decisions. 
5.1.2. 
Secondary Endpoints 
The key secondary endpoints are: 
 Change from baseline in the Unified Wilson’s Disease Rating Scale (UWDRS) Part II 
total score. 
 Change from baseline in UWDRS Part III Functional Subscale score 
 Change from baseline in UWDRS Part III individual functional items: arising from a 
chair, gait, handwriting, and speech. 
The non-key secondary endpoints are: 
 Change from baseline in UWDRS Part III total score 
 Clinical Global Impression-Improvement Scale (CGI-I) 
 Change from baseline in Clinical Global Impression-Severity Scale (CGI-S) 
 Change from baseline in Model for End-Stage Liver Disease (MELD) score 
 Absolute change and percentage change from baseline (Day 1) to 48 weeks in cNCC in 
plasma. For ALXN1840-treated patients, the cNCC in plasma will be corrected for the 
amount of copper bound to the ALXN1840 tripartite complex (TPC) (cNCCcorrected) 
 cNCC/cNCCcorrected responder rate at 48 weeks. 
Descriptions and algorithms for some of the secondary endpoints are described in Section 5.1.2. 


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5.1.2.1. 
Unified Wilson Disease Rating Scale (Parts I, II, and III) 
The UWDRS (Czlonkowska, 2007; Leinweber, 2008) 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 [10 items in total]), and UWDRS Part III 
(a detailed neurological examination, items 12 to 34 [23 items in total]). The UWDRS Part I and 
III will be assessed by a neurologist who is blinded to the treatment randomization, while 
UWDRS Part II may be reported to a non-blinded member of the study team, by the patient, 
family member or caregiver. 
The UWDRS will be assessed at Day 1, Week 4, Week 12, Week 24, Week 36, and Week 
48/ET. The UWDRS may also be assessed at the Screening Visit and EOS for patients who 
enrolled under the original protocol prior to the implementation of Protocol Amendment 1. Refer 
to Appendix 9.4 for further details on calculating the UWDRS scores. 
The UWDRS has not been formally evaluated in adolescents. However, the components are not 
fundamentally different between adults and adolescents. Patients aged 12 years and older are 
expected to be able to comply with UWDRS assessments (Rohay, 2020). 
5.1.2.2. 
Clinical Global Impression-Improvement Scale and the Clinical Global 
Impression-Severity 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. Although originally developed for patients with mental disorders (Guy, 1976) 
the CGI rating scales have been adapted to use generalized language (Busner, 2007), which 
supports their application to any clinically assessed disease setting. 
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient’s illness 
at the time of the assessment, relative to the clinician’s past experience with patients who have 
the same diagnosis. Considering total clinical experience, a patient is assessed 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-S will be performed at 
Day 1, Week 4, Week 12, Week 24, Week 36, and Week 48/ET. The CGI-S may also be 
assessed at Week 8, Week 18 and EOS for patients who enrolled under the original protocol 
prior to the implementation of Protocol Amendment 1. 
The CGI-I 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. The CGI-I will be performed at the 
same visits as CGI-S with the exception of Day 1. 
5.1.2.3. 
Model for End-Stage Liver Disease Score 
The MELD (Alcorn, 2015) is a scoring system for assessing the severity of chronic liver disease 
in patients 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 


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international normalized ratio (INR). The initial MELD score, MELD(i) is calculated according 
to the following formula: 
MELD(i) = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine 
(mg/dL)] + 6.43 
Creatinine, bilirubin, and INR values less than 1.0 are set to 1.0 and creatinine values greater 
than 4.0 are set to 4.0 when calculating MELD(i). Additionally, creatinine, bilirubin, and INR are 
rounded to the 10th decimal place prior to performing the calculation. The initial MELD score is 
then rounded to the nearest integer. The maximum MELD score is 40. 
A modification to the MELD score exists for MELD scores greater than 11 (Alcorn, 2015) and 
this will be applied to remain up-to-date with the current guidance. Thus, if MELD(i) is greater 
than 11, MELD is recalculated as follows: 
MELD = MELD(i) + 1.32*(137-sodium [mmol/L]) – 0.033*MELD(i)*(137-sodium [mmol/L]) 
Sodium values less than 125 mmol/L will be set to 125 and values greater than 137 mmol/L will 
be set to 137. 
The MELD score will be calculated each time the appropriate clinical chemistry parameters are 
obtained at the Screening Visit, Day 1, Week 4, Week 6, Week 8, Week 12, Week 18, Week 24, 
Week 36, Week 48/Early Termination (ET), and End of Study (EOS). If any of the parameters 
required to compute MELD score are unavailable at any given visit, the MELD score will not be 
derived for that patient visit. 
5.1.2.4. 
cNCC/cNCCcorrected, cNCC/cNCCcorrected Responder 
cNCC will be calculated as follows (EASL, 2012; Roberts et al., 2008): 
𝑐𝑁𝐶𝐶[µ𝑚𝑜𝑙/𝐿] = 𝑃𝑙𝑎𝑠𝑚𝑎 𝑇𝑜𝑡𝑎𝑙 𝐶𝑢 [µ𝑔/𝐿] −(3.15 ∗𝑐𝑒𝑟𝑢𝑙𝑜𝑝𝑙𝑎𝑠𝑚𝑖𝑛 [𝑚𝑔/𝐿]) 
63.5 [µ𝑔/µ𝑚𝑜𝑙]
 
For ALXN1840-treated patients, the cNCC in plasma will be corrected for the amount of copper 
bound to the ALXN1840 TPC using the square root-based cNCC correction method 
(cNCCcorrected) as determined based on data from the WTX101-201 study as follows  
(Plitz, 2017): 
𝑐𝑁𝐶𝐶𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑= (√𝑐𝑁𝐶𝐶− 0.993√𝑀𝑜)
2 
In the calculation of cNCC and cNCCcorrected the following rules apply: 
 For plasma total copper concentration values < lower limit of quantification (LLOQ), 
cNCC will be considered missing; 
 Serum ceruloplasmin concentration values < LLOQ are set to 0; 
 Plasma total molybdenum concentration values < LLOQ are set to 0; 
 In cases where cNCC calculation produces a negative result, cNCC will be considered 
missing and cNCCcorrected will not be derived; 
 cNCCcorrected will be set to 0 when 0.993√𝑀𝑜 > √𝑐𝑁𝐶𝐶. 


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cNCC/cNCCcorrected responder is defined as patients who achieved or maintained normalized 
cNCC/cNCCcorrected concentration (0.8-2.3 µM) (Brewer 2009) within (at or before) 48 weeks or 
reached a reduction of at least 25% in cNCC/cNCCcorrected within 48 weeks. Thus, a patient will 
be considered a cNCC/cNCCcorrected responder if they met at least one of the following criteria: 
 Achieved normalized cNCC/cNCCcorrected concentration for two consecutive 
measurements within 48 weeks, for patients who had elevated cNCC concentrations at 
baseline; 
 Maintained normalized cNCC/cNCCcorrected concentration within 48 weeks, for patients 
who had normal cNCC concentrations at baseline; 
 Reached a reduction of at least 25% in cNCC/cNCCcorrected for two consecutive 
measurements within 48 weeks. 
Nonresponder will be defined as patients who did not meet the responder criteria. 
5.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
 Individualized assessment of each patient’s 3 most troublesome symptoms; 
 Change from baseline in the Fibrosis-4 (FIB-4) Index and by transient elastography; 
 Change from baseline in Modified Nazer Score; 
 Change from baseline in Brief Psychiatric Rating Scale-24 (BPRS-24); 
 Change from baseline in Euro Quality of Life (QoL) 5 Dimensions (EQ-5D); 
 Evaluation of Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9); 
 Change from baseline in the timed 25 Foot Walk Test; 
 Change from baseline in the 9-Hole Peg Test (9-HPT); 
 Change from baseline in the nonverbal Stroop Interference Test; 
 Change from baseline in the Digit Span Test; 
 Evaluation of plasma total copper, plasma ultrafiltrate (PUF)-copper, dNCC, labile bound 
copper (LBC), ceruloplasmin (Cp), and ceruloplasmin-bound Cu (CpC) concentration-
time profiles; 
 Daily mean AUEC of plasma dNCC (from 0 to 24, and 24 to 48 weeks); 
 Daily mean AUEC of LBC from 0 to 48 weeks; 
 Daily mean AUEC of plasma total copper from 0 to 48 weeks; 
 Absolute and percentage change from baseline (Day 1) to 48 weeks in dNCC; 
 Absolute and percentage change from baseline (Day 1) to 48 weeks in LBC; 
 Time to first confirmed increase in plasma dNCC, and total copper concentration; 


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 Time to minimum and maximum concentration (TEmax) and the maximum concentration 
of (Emax): 
 − Plasma dNCC 
 − Plasma total copper 
 − Plasma LBC 
 − Ratio plasma dNCC:total copper 
 − Ratio plasma LBC:total copper 
 − Urinary molybdenum 
 − Ratio urinary molybdenum:urinary copper 
 − Ratio urinary molybdenum:dosed molybdenum 
 − Plasma Cp 
 − Plasma CpC 
 − Ratio plasma Cp:total copper 
 − Ratio plasma CpC:total copper 
 − Ratio plasma CpC:Cp; 
 Time for return to predose baseline for the following parameters: 
 − Plasma dNCC 
 − Plasma total copper 
 − Plasma LBC 
 − Ratio plasma dNCC:total copper 
 − Ratio plasma LBC:total copper 
 − Urinary molybdenum 
 − Ratio urinary molybdenum:urinary copper 
 − Ratio urinary molybdenum:dosed molybdenum 
 − Plasma Cp concentration 
 − Plasma CpC concentration 
 − Ratio plasma Cp:total copper 
 − Ratio plasma CpC:total copper 
 − Ratio plasma CpC:Cp; 
 Change from baseline of total molybdenum and PUF-molybdenum (Mo) in plasma; 
 Change from baseline of 24-hour urinary copper and urinary molybdenum; 


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 Change from baseline in the UWDRS Part I score and UWDRS total score; 
 Change from baseline in the UWDRS Part II-FDA suggested scoring; 
 Change from baseline in the UWDRS Part III Functional Subscale-FDA suggested 
scoring 
 Change from baseline in the UWDRS Part III Individual Items-FDA suggested scoring: 
arising from a chair, gait, handwriting, and speech 
 Change from baseline in the UWDRS Part II ADL subscale score 
 UWDRS Part II responder rate at 48 weeks (proportion of patients who achieve clinically 
meaningful improvement) 
 UWDRS Part III responder rate at 48 weeks (proportion of patients who achieve 
clinically meaningful improvement) 
Descriptions and algorithms for the exploratory efficacy endpoints in the Primary Evaluation 
Period are described in Sections 5.1.3.1 to Section 5.1.3.13. 
5.1.3.1. 
Three Most Troublesome Symptoms 
At randomization each patient will record their 3 most troublesome symptoms. These symptoms 
will be recorded in the case report form (CRF) as well as the impact these symptoms have on the 
patient’s activities of daily living (ADL). The 3 most troublesome symptoms will be assessed at 
Day 1; they will be subsequently re-presented to the patient at Week 12, Week 24, and 
Week 48/ET when the patient will be asked if their symptoms have improved, remained the same 
or worsened relative to Day 1. The influence of patients with missing data at either Week 12, 
Week 24 or Week 48 will be explored by assuming responses of (i) ‘remained the same’ and (ii) 
‘worsened’. 
5.1.3.2. 
Fibrosis-4 Index/Transient Elastography 
The FIB-4 Index (Vallet-Pichard, 2007) is a formula used to predict liver fibrosis based on 
standard biochemical values (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
and platelet count) and age. The FIB-4 Index will be calculated by a Central Laboratory. The 
formula is as follows: 
[Age (years) * AST (U/L)] / [Platelets (109/L) * sqrt(ALT {U/L})] 
Transient elastography is a non-invasive imaging method that evaluates the degree of liver 
fibrosis or fatty deposits in the liver, by determining the speed of sound waves through the liver 
utilizing a sonogram. 
The FIB-4 Index will be assessed at Day 1, Week 4, Week 6, Week 8, Week 12, Week 18, 
Week 24, Week 36, Week 48/ET, and EOS. Transient elastography will be performed at Day 1 
and Week 48/ET. If any of the parameters required to compute the FIB-4 Index are unavailable 
at any given visit, FIB-4 Index will be set to missing for that patient visit. 


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5.1.3.3. 
Modified Nazer Score 
The modified Nazer Score (Dhawan, 2005) is an assessment of liver status and consists of a 
composite of 5 laboratory parameters: bilirubin, AST, INR, leukocytes (white cell count), and 
albumin. The score has a total range of 0 to 20, and lower values indicate a healthier liver status. 
The modified Nazer Score will be determined at the Screening Visit, Day 1, Week 4, Week 6, 
Week 8, Week 12, Week 18, Week 24, Week 36, Week 48/ET, and EOS. If any of the 
5 parameters required to compute the modified Nazer Score are unavailable at any given visit, 
the modified Nazer Score will not be derived at that patient visit. The score for an individual 
analyte (bilirubin, AST, INR, leukocytes, and albumin) should be derived from Table 2 , and 
then all 5 scores will be added to obtain the final score. 
Table 2: 
Modified Nazer Score 
Score 
Bilirubin (µmol/L) 
AST (IU/L) 
INR 
Leukocytes 
(109/L) 
Albumin 
(g/L) 
0 
0-100 
0-100 
0-1.29 
0-6.7 
> 44 
1 
101-150 
101-150 
1.3-1.6 
6.8-8.3 
34-44 
2 
151-200 
151-300 
1.7-1.9 
8.4-10.3 
25-33 
3 
201-300 
301-400 
2.0-2.4 
10.4-15.3 
21-24 
4 
> 300 
> 400 
> 2.4 
> 15.3 
< 21 
Abbreviations: AST = aspartate aminotransferase; INR = international normalized ratio  
5.1.3.4. 
Brief Psychiatric Rating Scale-24 
The BPRS-24 (Ventura, 1993) is a 24-item instrument that allows the rater to measure 
psychopathology severity. 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, etc.) who has completed the training required to administer the 
instrument. 
The BPRS-24 will be obtained at Day 1, Week 24, and Week 48/ET. The BPRS-24 may also be 
assessed at the Screening Visit and EOS for patients who enrolled under the original protocol 
prior to the implementation of Protocol Amendment 1. The total score across the 24 items will be 
used as the endpoint for analysis. A minimum of 20/24 items are required to be completed at any 
given visit; the total score will then be taken for the non-missing items and scaled up to the 
24-item score for the purposes of data summary and analysis. If fewer than 20/24 items are 
completed at any given visit, the BPRS-24 total score will be set to missing for that patient visit. 
5.1.3.5. 
EuroQoL-5 Dimensions 
The EQ-5D (EuroQol Group, 2015) consists of 2 different assessments: the EQ-5D-5L 
Descriptive System and the EuroQol Visual Analogue Scale (EQ VAS). The descriptive system 
comprises measures of health-related QoL 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. For the scoring in the EQ-5D-5L Descriptive System, the respondent is asked to 
indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate 
statement in each of the 5 dimensions. This decision results in a 1-digit number expressing the 


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level selected for that dimension. The digits for 5 dimensions can be combined in a 5-digit 
number describing the respondent’s health state. 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 judgment. 
The EQ-5D will be administered at Day 1, Week 4, Week 12, Week 24, Week 36, and 
Week 48/ET. The EQ-5D may also be assessed at Week 8 and Week 18 for patients who 
enrolled under the original protocol prior to the implementation of Protocol Amendment 1. 
5.1.3.6. 
Treatment Satisfaction Questionnaire for Medication 
The TSQM-9 is used to assess the overall level of satisfaction or dissatisfaction with medication 
patients are taking (Atkinson, 2004; Atkinson, 2005; Bharmal, 2009). 
The TSQM-9 has 9 questions making up 3 components: effectiveness score, convenience score, 
and global satisfaction score. Details on deriving the component scores are given below 
including how to handle a single missing question within a component. If more than one question 
is missing for a component, the component score cannot be derived. 
Effectiveness score is comprised of Questions 1 to 3, each of them ranging from 1 to 7. The 
score is calculated as follows: (Q1+Q2+Q3-3)/18*100. If one of the questions is missing, the 
score is calculated as follows (including the missing item): (Q1+Q2+Q3-2)/12*100. 
Convenience score is comprised of Questions 4 to 6, each ranging from 1 to 7. The score is 
calculated as follows: (Q4+Q5+Q6-3)/18*100. If one of the questions is missing, the score is 
calculated as follows (including the missing item): (Q4+Q5+Q6-2)/12*100. 
Global satisfaction is comprised of Questions 7 to 9, where Questions 7 and 8 range from 1 to 5 
and Question 9 ranges from 1 to 7. The score is calculated as follows: (Q7+Q8+Q9-3)/14*100. If 
either Question 7 or 8 is missing, the score is calculated as follows (including the missing item): 
(Q7+Q8+Q9-2)/10*100. If Question 9 is missing, the score is calculated as follows: (Q7+Q8-
2)/8*100. 
The TSQM-9 will be administered at Week 4, Week 12, Week 24, Week 36, and Week 48/ET. 
The TSQM-9 may also be assessed at Week 8 and Week 18 for patients who enrolled under the 
original protocol prior to the implementation of Protocol Amendment 1. 
5.1.3.7. 
Timed 25F Walk Test 
The Timed 25F Walk Test (Hobart, 2013; Coleman, 2012) is a quantitative mobility and leg 
function performance test based on a timed 25-foot walk. Scoring for the Timed 25F Walk Test 
is the average of the 2 trials in seconds captured in the CRF. The walking times will then be 
transformed and analyzed as walking speed (more normally distributed) in feet per second by 
dividing 25 feet by the time in seconds required to complete the walk. Patients may use assistive 
devices when doing this task. The test will be performed at Day 1, Week 12, Week 24, and Week 
48/ET. If one of the trials is missing at any given visit, the time taken for the complete trial will 
be used as the test result. 


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5.1.3.8. 
Nine-Hole Peg Test 
The 9-HPT (Mathiowetz et al, 1985) is a brief, standardized, quantitative test of upper extremity 
function. Both the dominant and non-dominant hands are tested twice. The patient is seated at a 
table with a small, shallow container holding 9 pegs and a wood or plastic block containing 9 
empty holes. On a start command when a stopwatch is started, the patient picks up the 9 pegs, 
one at a time as quickly as possible, puts them in the 9 holes, and, once they are in the holes, 
removes them again as quickly as possible one at a time, replacing them into the shallow 
container. Two consecutive trials with the dominant hand are immediately followed by 
2 consecutive trials with the non-dominant hand. The result for the 9-HPT is the average of the 
4 trials in minutes. At least 1 complete test per hand is required to provide an overall result for 
the 9-HPT for that patient visit; if both tests are missing for either hand, then the overall result 
for that patient visit will be set to missing. The 9-HPT will be performed at Day 1, Week 12, 
Week 24, and Week 48, and ET. 
5.1.3.9. 
Nonverbal Stroop Interference Test 
In psychology, the Stroop effect (Koch, 2012) is a demonstration of interference in the reaction 
time of a task. There will not be any verbal communication during this test; the test will be 
taught with nonverbal directions, using gestures and demonstrations. The test will be performed 
at Day 1, Week 12, Week 24, and Week 48/ET. Patients are presented with 32 color congruent 
cards and 72 color incongruent cards and are tasked with categorizing these cards correctly 
according to the nonverbal instruction provided. The number of cards correctly and incorrectly 
categorized and the time taken to complete the test are recorded onto the record form. The 
endpoint for analysis is the Stroop Interference Effect, which is calculated for each patient using 
the color congruent ratio (CCR) and color incongruent ratio (CIR) as follows: 
 
𝐶𝐶𝑅 =
Number of seconds to complete all color congruent cards
Number of correct color congruent cards – Number of incorrect color congruent cards; 
 
𝐶𝐼𝑅 =
Number of seconds to complete all color incongruent cards
Number of correct color incongruent cards – Number of incorrect color incongruent cards; 
 
Stroop Interference Effect = CIR – CCR. 
Based on age of the patient, the Stroop Effect Scaled Score is then derived from the Stroop 
Interference Effect score to have a mean of 50 and standard deviation of 10. Scores between 35 
and 65 are considered normal. Higher scores indicate worse performance generally. 
5.1.3.10. Digit Span Test 
The complete Digit Span Test (Wechsler, 2008) is measured for forward and reverse-order 
(backward) recall of digit sequences and digit span sequencing. Digit sequences are presented 
beginning with a length of 2 digits and 2 trials are presented at increasing list length. Testing 
ceases when the patient fails to accurately report either trial at 1 sequence length or when the 
maximal list length is reached (9 digits, 8 backwards). The Digit Span Test will be performed at 


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Day 1, Week 12, Week 24, and Week 48/ET. Patients who cannot speak clearly enough to 
perform the test will be assigned the lowest possible outcome score. 
5.1.3.11. Plasma Total Molybdenum, Plasma Ultrafiltrate Molybdenum, Plasma Total 
Copper, Plasma Ultrafiltrate Copper, dNCC, LBC, Ceruloplasmin, and 
Ceruloplasmin-bound Copper 
Plasma concentrations of total molybdenum, PUF-Mo, plasma total copper, PUF-Cu, dNCC, 
LBC, Cp, and CpC will be measured at the Screening Visit, Day 1, Week 4, Week 6, Week 8, 
Week 12, Week 18, Week 24, Week 36, and Week 48/ET. 
5.1.3.12. Time to First Confirmed Increase, Time to Minimum and Maximum, and Time 
for Return to Predose Baseline 
Time to first confirmed increase is defined as weeks from baseline to the second timepoint of the 
2 consecutive timepoints above baseline. Time to minimum is defined as weeks from baseline to 
the timepoint with minimum postbaseline values within the Primary Evaluation Period. Time to 
maximum is defined as weeks from baseline to the timepoint with maximum postbaseline values 
within the Primary Evaluation Period. Time for return to predose baseline is defined as weeks 
from baseline to the first timepoint with postbaseline values less or equal to the predose baseline. 
The maximum observed concentration values will also be reported. 
5.1.3.13. 24-Hour Urine Copper and Molybdenum 
Twenty-four hour urine copper and molybdenum will be measured at Day 1, Week 4, Week 12, 
Week 24, Week 36, and Week 48/ET. 
5.2. 
Safety 
The safety endpoints in this study are the safety and tolerability of individualized dosing of 
ALXN1840 over time. Safety will be assessed by analysis of AEs. AE data collected will include 
onset, duration, seriousness, intensity, and relatedness to study drugs. Deaths and other serious 
adverse events (SAEs) will also be evaluated and will be collected on a separate CRF. Changes 
in physical examinations, vital signs (resting heart rate, semi-supine systolic and diastolic blood 
pressure, respiratory rate, temperature, and weight), and laboratory values will also be evaluated 
and assessed. Time points for recording of safety parameters is provided in Table 4 of the 
Protocol. 
5.2.1. 
Adverse Events  
The occurrence of AEs at each visit will be recorded on designated CRF pages. Each AE is to be 
characterized (ie, verbatim term) and information provided regarding its seriousness, start and 
stop dates, severity, outcome, and causal relationship with the study drug. The safety evaluation 
will include an assessment of all AEs, SAEs, AE severity, and AE causality. AE severity will be 
evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 (published 27 Nov 2017) (NCI, 2017). AE causality will be 
evaluated by Investigators to be either not related or related. Further details are given in Protocol 
Section 8.3, Protocol Appendix 3, and in Appendix 9.4. 


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5.2.2. 
Vital Signs 
Vital sign measurements will be taken after the patient has been resting for at least 5 minutes, 
and will include systolic and diastolic blood pressure (mmHg), heart rate (beats/minute), 
respiratory rate (breaths/minute), height, weight, and temperature (°C or °F). The timepoints for 
recording of vital signs is provided in Table 4 of the Protocol. 
5.2.3. 
Laboratory Assessments 
Clinical laboratory measures include chemistry, hematology, coagulation, copper and 
molybdenum analyses testing, and urinalysis (with microscopy). For females of childbearing 
potential, a serum or urine pregnancy test (ie, beta-human chorionic gonadotropin) will be 
performed. For postmenopausal females, follicle-stimulating hormone will be performed. 
Additionally, deoxyribonucleic acid (DNA) data will be available for some patients as it is 
optional. The specific laboratory assessments are provided in Appendix 2 of the Protocol. 
5.2.4. 
Physical Examinations 
Physical examinations will include an assessment of the following: general appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, and musculoskeletal (including spine and extremities) systems. 
An abbreviated physical examination consists of a body system relevant examination based upon 
Investigator (or designee) judgment and patient symptoms. At least 1 body system must be 
checked for an abbreviated examination. 
5.2.5. 
Electrocardiogram 
Single 12-lead electrocardiogram (ECG) will be obtained in triplicate using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) 
intervals. 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. 
5.2.6. 
Other Events of Special Interest 
Any new neurological symptom or clinically significant worsening of an ongoing neurological 
symptom after initiation of study drug (ALXN1840 or SoC) will be designated to be an adverse 
event of special interest (AESI), whether serious or nonserious. If a patient has an AESI, in 
addition to assessments deemed clinically relevant by the Investigator, the following additional 
assessments should be performed to the extent possible to help assess the AE and patient status: 
UWDRS Part III, nonverbal Stroop Interference Test, Digit Span Test, and the CGI-I and CGI-S. 


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6. 
DATA SETS ANALYZED (STUDY POPULATIONS) 
6.1. 
Full Analysis Set 
The Full Analysis (FA) Set includes all randomized patients who received at least 1 dose of 
randomized treatment. Patients will be analyzed as randomized. 
6.2. 
Per Protocol Set 
The Per Protocol (PP) Set includes all patients who are randomized and had at least baseline and 
48-week efficacy assessments for dNCC in the Primary Evaluation Period. Patients with major 
protocol deviations that are likely to impact the primary efficacy analysis will be excluded from 
the PP Set. Major protocol deviations, and the PP Set, will be defined, documented, and agreed 
within Alexion prior to database lock. 
6.3. 
Safety Set 
The safety analysis will be performed on the Safety Analysis Set. This dataset includes all 
patients who received at least 1 dose of randomized treatment. Patients will be summarized 
according to the treatment actually received. 
6.4. 
Pharmacokinetic Set 
Patients meeting the definition of the FA Set and who have any baseline and postbaseline data 
for plasma molybdenum will be included in the pharmacokinetic (PK) set. 
6.5. 
Pharmacodynamic and Biomarker Set 
Patients meeting the definition of the FA Set and who have any baseline and postbaseline 
measurable concentration data reported for any plasma copper (pharmacodynamics; PD) and 
ceruloplasmin (biomarker) will be included in the PD and Biomarker set. 


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7. 
STATISTICAL ANALYSIS 
For the statistical analyses below, descriptive statistics (n, mean, median, SD, minimum, and 
maximum) will be provided for each continuous variable, and frequencies and percentages will 
be provided for each categorical variable. Certain continuous variables may also include 95% 
confidence intervals (CIs) and certain categorical variables will be summarized as proportions 
with 95% CIs. All data will be displayed unless otherwise indicated. Analyses will be conducted 
using Statistical Analysis Software (SAS©) version 9.4 or higher. 
In general, analyses will be presented by randomized treatment within cohort and overall where 
specified. Cohort will be derived using the patient’s prior WD medication history. Patients with 
SoC treatment > 28 days (treatment experienced) prior to first dose will be in Cohort 1 and 
patients with SoC treatment ≤ 28 days or who are SoC treatment naïve prior to first dose will be 
in Cohort 2. 
7.1. 
Study Patients 
7.1.1. 
Disposition of Patients 
The number and percentage of all patients enrolled, randomized, included in the FA, PP, Safety, 
PK and PD sets, and those who have come from Study WTX101-201 or WTX101-203 will be 
summarized. The reasons for exclusion from the analysis sets will also be provided. Frequency 
counts and percentages of patients excluded prior to randomization will be provided for patients 
who failed to meet study entry requirements during Screening at the start of the study. 
The number and percentage of patients who completed, or prematurely discontinued from the 
study will be described by randomized treatment group within each cohort, for rollover patients 
and overall. For patients who discontinued the study, the number and percentage will be 
summarized by their reason for premature discontinuation and withdrawal of consent. A 
summary will be provided of patients by region, country, and site. Additionally, a summary of 
patients who did not meet inclusion or who met exclusion criteria will be provided. 
Descriptive statistics of the number of days in the study will be summarized. The date of first and 
last use of study medication in each period, and the study termination date will be listed. 
Individual reasons for premature discontinuation and withdrawal of consent from the study will 
be presented in a listing. All enrolled patients will be listed indicating their analysis set along 
with the reason for exclusion. A listing of screen failure patients will also be provided. 
Additionally, a listing of the inclusion/exclusion criteria and a listing of patients and the 
inclusion criteria they failed to meet and the exclusion criteria they met will be provided. 
7.1.2. 
Protocol Deviations 
All protocol violations will be determined and appropriately categorized prior to database lock. 
The number and percentage of patients with any important/not important protocol violations, as 
well as the number and percentage of patients with violations within each category, will be 
presented. A listing will also be provided. 


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7.1.3. 
Demographics, Disease Characteristics, and History 
All demographic and baseline characteristics information will be summarized on the FA Set. 
Summary statistics will be presented by randomized treatment within cohort, for rollover patients 
and overall. Continuous variables will be presented using descriptive statistics, and categorical 
variables will be presented using frequencies and percentages. Age will be calculated relative to 
date of informed consent and will be summarized as both a continuous and categorical variable. 
Time since WD treatment start date (months) will be calculated as months occurring between 
date of informed consent and the start date from WD treatment history CRF and will be 
summarized using descriptive statistics. Listings will also be provided. 
7.1.3.1. 
Demographics 
The following demographic variables will be summarized: 
 Age (years),  
 Age in years group (≥12-<18, ≥18), (≥12-<18, ≥18-<65, ≥65), (<25, ≥25) 
 Sex (Male, Female),  
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown), 
 Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other Pacific Islander, Other), 
 Country/Region (United States, United Kingdom, Germany, Japan, Rest of World), 
 Height (cm), 
 Weight (kg), 
 Body mass index (kg/m2) 
7.1.3.2. 
Disease Characteristics 
The following disease characteristics will be summarized: 
 Time since WD treatment start date (months), 
 Cumulative duration of prior WD treatment (months),  
 Prior WD therapy: (i) Zinc monotherapy vs Penicillamine or Trientine (± Zinc); (ii) Zinc 
monotherapy vs Penicillamine (± Zinc) vs Trientine (± Zinc ) 
 Cirrhosis (Yes, No), 
 CGI severity, 
 Psychiatric symptom (Yes, No): at least 1 symptom present on BPRS-24 
 dNCC, 
 Plasma total copper, 
 Plasma total molybdenum, 
 PUF-Cu, 
 PUF-Mo, 
 Cp, 
 CpC, 
 24-hour urinary copper concentration, 
 24-hour urinary molybdenum concentration 
 LBC, 
 MELD score, 


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 Modified Nazer Score, 
 UWDRS Part II total score (original score and FDA suggested score) 
 UWDRS Part III total score,  
 UWDRS Part III Functional Subscale (original score and FDA suggested score), 
 UWDRS Part III individual symptoms (original score and FDA suggested score of arising 
from a chair, gait, speech, and handwriting),  
 UWDRS ADL Subgroup at Baseline, 
 EQ-5D visual analogue scale (VAS), 
 EQ-5D-5L. 
In addition, the following baseline laboratory measures will be summarized: 
 ALT, 
 ALT groups (> 2× upper limit of normal [ULN], ≤ 2 × ULN), 
 AST, 
 Total bilirubin, 
 Total bilirubin groups (>ULN, ≤ ULN), 
 Gamma-glutamyl transferase (GGT), 
 Platelets, 
 Leukocytes, 
 Creatinine, 
 Total Cholesterol, HDL, LDL, 
 Triglycerides, 
 Renal Function Status at Baseline: 
o Normalized glomerular filtration rate (GFR) (mL/min/1.73 m2) 
 G1: GFR > 90 mL/min/1.73 m2 
 G2: GFR 60 to 89 mL/min/1.73 m2 
 G3a: GFR 45 to 59 mL/min/1.73 m2 
 G3b: GFR 30 to 44 mL/min/1.73 m2 
 G4: GFR 15 to 29 mL/min/1.73 m2 
 G5: GFR < 15 mL/min/1.73 m2 or treatment by dialysis 
o Absolute GFR (mL/min) 
 G1: GFR ≥ 90 mL/min 
 G2: GFR 60 to < 90 mL/min 
 G3: GFR 30 to < 60 mL/min 
 G4: GFR < 30 mL/min not requiring dialysis 
 G5: GFR < 15 mL/min requiring dialysis treatment 


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Renal Function Status at Baseline: 
Patients will be classified into 6 different stages of kidney disease based on normalized GFR 
estimated from the serum concentration of creatinine at baseline. Patients will also be classified 
based on the absolute GFR (EMA/CHMP/83874, 2014). 
Patients will also be classified into 6 different stages of kidney disease based on normalized GFR 
estimated from the serum concentration of creatinine at baseline. 
The normalized GFR can be calculated using Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation for participants with Age ≥ 18 years (Levey et al., 2009, 
Stevens and Levey, 2009 and Frequently Asked Questions, National Kidney Foundation, 2014): 
Normalized GFR (mL/min/1.73 m2)  
= 141× min(SCr/κ, 1)α × max(SCr/κ, 1)-1.209 × (0.993)Age×(1.018 if female)×(1.159 if African 
American),  
where SCr = standardized serum creatinine assay is given in milligrams per deciliter (mg/dl), the 
parameter κ is 0.7 for females and 0.9 for males, the parameter α is -0.329 for females and -0.411 
for males,  min indicates the minimum of 1 or SCr/κ, and max indicates the maximum of 1 or 
SCr/κ. 
For children and adolescent participants (Age <18 years), the equation provided by Schwartz, 
2009 (“bedside” formula) provides a better estimate of the normalized GFR (Frequently Asked 
Questions, National Kidney Foundation, 2014): 
Normalized GFR (mL/min/1.73 m2) = 0.41×[Height (cm)/ SCr (mg/dl)] 
The relationship between normalized GFR and absolute GFR can be obtained using body surface 
area (BSA) as presented in Frequently Asked Questions, National Kidney Foundation, 2014:  
Absolute GFR (mL/min) = Normalized GFR (mL/min/1.73 m2)×BSA/1.73 
where BSA = Body Surface Area. 
For adults, the BSA can be estimated using weight and height of the participant as follows 
(DuBois and DuBois, 1916, National Kidney Disease Education Program, 2009, and Frequently 
Asked Questions, National Kidney Foundation, 2014):  
Age ≥ 18 years: BSA (m2) = 0.007184×(Weight (kg))0.4250×(Height (cm))0.7250 
For young and adolescent participants, the BSA can be determined using formula by Haycock et 
al., 1978, and also presented in  Schwartz, 2009:  
Age < 18 years: BSA (m2) = 0.024265×(Weight (kg))0.5378×(Height (cm))0.3964 
Patients with end-stage renal disease on dialysis (Chronic Kidney Disease Stage 5) or creatinine 
clearance < 30 mL/min are excluded from the study. 
7.1.3.3. 
Medical / Surgical History, and WD History 
Medical history will be summarized by counts and percentages and displayed by system organ 
class and Preferred Term within each system organ class. System Organ Class and Preferred 
Term will be coded using the most up-to-date version of the Medical Dictionary for Regulatory 
Activities (MedDRA), version 21.1 or higher, available at the start of the study. This dictionary 


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will be used throughout the life of the study and will not be updated during study conduct. The 
number and percentage of patients will be presented for ongoing conditions and previous 
conditions separately by System Organ Class and Preferred Term. A by-patient listing will also 
be created. 
All details of WD diagnosis will be listed in full. WD treatment history will be summarized by 
counts and percentages for Cohort 1 and Cohort 2 by prior SoC, where prior SoC is defined as 
the later of the treatment at the time of Screening or most recent treatment prior to Screening and 
is categorized as penicillamine, trientine hydrochloride, zinc, or combination. 
7.1.4. 
Prior and Concomitant Medications / Therapies 
The World Health Organization (WHO) Drug Dictionary version from March 2018 or later will 
be used to code the medications. Medications will be summarized by Anatomical Therapeutic 
Chemical (ATC) level 3 class and generic drug name. 
Prior and concomitant medications will be summarized for the FA Set by randomized treatment 
within treatment cohort, for rollover patients and overall. The number and percentage of patients 
receiving any concomitant medication will be summarized, as well as the number and percentage 
receiving any concomitant medication by ATC drug class and generic drug name. Patients 
reporting use of more than one medication at each level of summarization (any medication 
received, ATC class, and generic drug name) will be counted only once. ATC class terms will be 
displayed by descending order of incidence, as well as generic drug names within each ATC 
class. Prior medications used to treat WD and an additional analysis of all prior medications will 
be summarized similarly. 
Prior medications will be defined as medications that were discontinued prior to the start of study 
drug. Concomitant medications will be defined as medications that either started prior to first 
dose of study drug and were continuing at the time of first dose of study drug or started on or 
after the date of the first dose of study drug. If it cannot be determined whether a medication was 
stopped prior to the start of study drug dosing due to partial or missing medication start or end 
dates, it will be considered a concomitant medication. 
Prior and concomitant medications will be presented in a by-patient data listing by patient and 
medication name. 
7.2. 
Efficacy Analyses 
In general, all primary and key secondary efficacy endpoints will be assessed in both the FA and 
PP Sets. The non-key secondary and exploratory efficacy endpoints will only be assessed in the 
FA Set. The principal analysis for all efficacy endpoints will be performed on the overall 
population (Cohort 1 and Cohort 2 combined) in the FA set. Corresponding supportive analyses 
will be performed in Cohort 1 and Cohort 2. All efficacy endpoint data will be summarized 
descriptively by visit, by randomized treatment (with cohorts combined), and by visit by 
randomized treatment within each cohort. Supporting listings will also be presented. Least square 
(LS) means ± standard error (SE), when calculated, will be displayed graphically over time by 
randomized treatment group for primary and secondary endpoints. 
For endpoints which do not have a baseline assessment (eg, CGI-I, TSQM-9 scores), the results 
at each time point will be summarized. 


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7.2.1. 
Primary Analysis 
The primary estimand is the difference in daily mean dNCC AUEC0-48W between ALXN1840 
and SoC in patients with WD, regardless of less-than-complete adherence or use of another 
medication that affects plasma dNCC, with no benefit derived from treatment after death. 
Treatment: ALXN1840 and SoC 
Population: Patients with WD who meet all inclusion and no exclusion criteria. 
Variable/endpoint: daily mean dNCC AUEC0-48W 
Intercurrent Events: For patients who die, a composite strategy will be applied reflecting no 
benefit derived from treatment after death. The baseline value of plasma dNCC will be carried 
forward from the point of discontinuation to Week 48. 
For patients with less-than-complete adherence, including discontinuation of treatment for any 
reason other than death, the treatment policy strategy will be applied. The missing values of 
plasma dNCC will be imputed based on the response for SoC patients. 
For patients who use another medication that affects plasma dNCC the treatment policy strategy 
will be applied. 
Population Level Summary: Comparison of the mean of dNCC AUEC0-48W between treatment 
groups. 
Overall Analysis: 
The primary endpoint is the daily mean dNCC AUEC0-48W. The AUEC for dNCC concentration 
will be calculated using the trapezoidal rule. 
𝐴𝑈𝐸𝐶0−𝑡𝑛= ∑
𝑐𝑖−1+𝑐𝑖
2
 (𝑡𝑖−𝑡𝑖−1 )
𝑛
𝑖=0
 , n= number of measured timepoints 
The AUEC is then divided by the number of days to yield daily mean dNCC AUEC0-48W. The 
group means for daily mean dNCC AUEC0-48W will be compared between ALXN1840 and SoC 
using an analysis of covariance (ANCOVA) statistical model; treatment arm, baseline dNCC, 
and cohort, will be included in the model. Tests will be performed at a significance level of 0.05 
(2-sided). 
Model-based estimates of the difference between randomized treatments (ALXN1840 – SoC) in 
dNCC AUEC0-48W, along with a 2-sided 95% CI and p-value will be provided. If the lower 2-
sided 95% CI exceeds 0 µM, then superiority will be concluded. 
Accounting for Sample Size Re-estimation: 
In the present study, the interim analysis for sample size re-estimation (SSR) was performed 
using the data from the first approximately 35% patients evaluable for the primary analysis. The 
decision was to keep the original sample size, with no adaptation. When no adaptation occurs (ie, 
interim decision to keep the original planned sample size), then the conventional statistic can be 
used to determine statistical significance (Wassmer, 2016). 


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In contrast, if an adaptation had occurred (ie, interim decision to increase the sample size), then 
the final analysis would have used the weighted statistic proposed by Cui, Hung, and Wang 
(1999) in which the independent increments of the Z statistics of the 2 stages are combined by 
prespecified weights that are based on the planned proportion of total number of patients. The 
planned proportions were 0.35 and 0.65 for the 2 stages, and the independent incremental Z 
statistics for the 2 stages combined with weights that equal the square root of 0.35 for Stage 1 
and square root of 0.65 for Stage 2. Patients assessed for the primary efficacy endpoint prior to 
the time the interim analysis would make up the Stage 1 sample, and those patients assessed after 
the interim analysis would make up the Stage 2 sample. Based on the Stage 1 and Stage 2 patient 
samples, the 2-independent stage-wise test statistics for superiority, 𝑍1 and 𝑍2, would be 
computed. If an adaptation had occurred, the final test statistics would be: 
𝑍CHW = √𝑤 𝑍1 + √1 −𝑤 𝑍2 
where 𝑤= 0.35, the planned information fraction at the time of the interim analysis. Since no 
adaptation occurred, the conventional statistics will be used. 
7.2.1.1. 
Handling of Dropouts or Missing Data 
For intermediate missing data, interpolation will be used to fill out missing values. 
For patients who die during study, their baseline plasma dNCC concentration will be carried 
forward. 
For patients who drop out due to other reasons, multiple imputation will be used to impute 
missing dNCC concentration assuming data are missing not at random. In this case, responses for 
both treatment groups will be imputed with multiple imputation based on the response for SoC 
patients (jump to reference method). Cohort, baseline, and previous visit value will be included 
in the imputation model. The following steps will be followed: 
Step 1: Missing values at each visit will be imputed 10 times via SAS PROC MI, and 
imputed values will be retained in the imputed datasets. 
Step 2: For each imputed dataset, daily mean dNCC AUEC0-48W will be derived using the 
trapezoidal rule (Yeh, 1978). 
Step 3: ANCOVA analysis will performed for each of the 10 imputed dataset, with LS 
means (SE) for each treatment arm saved from each of the 10 analyses. 
Step 4: 10 sets of analysis results will be combined using Rubin’s rules (Rubin, 1987) via 
SAS PROC MIANALYZE. The treatment differences, CIs and p-values will be estimated 
by MODELEFFECTS and STDERR statement.


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Tipping Point Analysis: 
A tipping point analysis will be conducted for the primary endpoint, by splitting the patients into 
2 subgroups: “observed” and “missing”. “Observed” patients are those with baseline and Week 
48 assessment in plasma dNCC concentration, while “missing” refers to all other randomized 
patients. An efficient 2-dimensional tipping point analysis will be accomplished by performing 
two 1-dimensional analyses: (a) vary assumptions about the missing outcomes in the ALXN1840 
arm, while fixing those about the SoC arm, and (b) vary assumptions about the missing outcomes 
in the SoC arm, while fixing those in the ALXN1840 arm. The combination of assumed missing 
data values that maintain the statistically significant conclusion are bound by the two one-way 
tipping points (Gorst-Rasmussen, 2020). 
Step 1: Within the “observed” subgroup, ANCOVA analysis will be performed on the daily 
mean dNCC AUEC0-48W in the 2 treatment arms, with cohort and baseline dNCC as covariates. 
The LS means and SEs for ALXN1840 and SoC, respectively, and the residual error estimate, 
will be extracted. 
a. ALXN1840 varied, SoC fixed 
Step 2: 
i. 
For “missing” SoC patients, the daily mean dNCC AUEC0-48W concentration is generated 
randomly as a deviate from a normal distribution with mean equal to the LS mean for 
“observed” SoC patients, and SD equal to the residual error estimate, as obtained in 
Step 1. 
ii. 
For “missing” ALXN1840 patients, the LS mean for daily mean dNCC AUEC0-48W in 
Step 1 will be decreased by a small increment (δ=10%), to reflect a marginally worse 
AUEC0-48W value. For these patients, the daily mean dNCC AUEC0-48W  will be generated 
randomly as a deviate from a normal distribution with mean equal to (100% − δ) of the 
LS mean for “observed” ALXN1840 patients, and SD equal to the residual error estimate, 
as obtained in Step 1. 
iii. 
Combine “observed” and “missing” patients into complete dataset. Analyze complete 
dataset using ANCOVA with cohort and baseline dNCC as covariates, to give LS means 
and SEs for ALXN1840 and SoC, with treatment effect estimate and associated SE. 
Step 3: 
i. 
Step 2 will be repeated 10 times for the same increment δ, giving rise to 10 sets of LS 
means, treatment effect estimates, and associated SEs. 
ii. 
The 10 treatment effect estimates will be combined via PROC MIANALYZE using 
Rubin’s method. 
Step 4: Steps 2 and 3 will be repeated with larger increments (δ = 20%, 30%,…, 90%) to reflect 
an even-poorer outcome with ALXN1840 treatment. 
Step 5: The treatment effect estimates, associated SEs, and CIs generated for all increments 
(δ = 10%, 20%,…, 90%) will be summarized in a table, and the first point at which superiority 
fails (if it exists) will be highlighted. 


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b. ALXN1840 fixed, SoC varied 
Step 2: 
i. 
For “missing” ALXN1840 patients, the daily mean dNCC AUEC0-48W is generated 
randomly as a deviate from a normal distribution with mean equal to the LS mean for 
“observed” ALXN1840 patients, and SD equal to the residual error estimate, as obtained 
in Step 1. 
ii. 
For “missing” SoC patients, the LS mean for daily mean dNCC AUEC0-48W  in Step 1 
will be increased by a small increment (δ=10%), to reflect a marginally better AUEC0-48W 
value. For these patients, the daily mean dNCC AUEC0-48W will be generated randomly 
as a deviate from a normal distribution with mean equal to (100% + δ) of the LS mean for 
“observed” SoC patients, and SD equal to the residual error estimate, as obtained in 
Step 1. 
iii. 
Combine “observed” and “missing” patients into complete dataset. Analyze complete 
dataset using ANCOVA with cohort and baseline dNCC as covariates, to give LS means 
and SEs for ALXN1840 and SoC, with treatment effect estimate and associated SE. 
Step 3: 
i. 
Step 2 will be repeated 10 times for the same increment δ, giving rise to 10 sets of LS 
means, treatment effect estimates, and associated SEs. 
ii. 
The 10 treatment effect estimates will be combined via PROC MIANALYZE using 
Rubin’s method. 
Step 4: Steps 2 and 3 will be repeated with larger increments (δ = 20%, 30%,…, 200%) to reflect 
an even-better outcome with SoC treatment. 
Step 5: The treatment effect estimates, associated SEs, and CIs generated for all increments 
(δ = 10%, 20%,…, 200%) will be summarized in a table, and the first point at which superiority 
fails (if it exists) will be highlighted. 
7.2.1.2. 
Subgroup Analysis 
For exploratory purposes, the primary and secondary efficacy endpoints will also be evaluated in 
clinically relevant subgroups. As a general rule, a subgroup is analyzed only if the number of 
patients is ≥ 3 in each treatment arm.  
 Previous treatment for WD (within Cohort 1, 2, and total). 
i. 
Zinc monotherapy vs penicillamine or trientine (± Zinc) 
ii. 
Zinc monotherapy vs penicillamine (± Zinc) vs trientine (± Zinc) 
 Previous treatment for WD (Cohort 2 only) 
o Completely naïve (ie, zero days prior treatment for WD) vs minimally treated (ie, 1 to 
≤ 28 days treatment prior treatment for WD). 
 SoC treatment during Primary Evaluation Period: 
i. 
Zinc monotherapy vs penicillamine or trientine (± Zinc) 


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ii. 
Zinc monotherapy vs penicillamine (± Zinc) vs trientine (± Zinc) 
 Age in years group (≥ 12-< 18, ≥ 18), (≥ 12-<18, ≥18-< 65, ≥ 65), (<25, ≥ 25) 
 
Patients who have an incomplete or intolerant response to prior WD treatment. 
Incomplete and intolerant responders will be combined into a single subgroup. 
o “Incomplete” responder is defined as a patient who meets at least 1 of the 
following criteria: 
1. UWDRS Part II total score at Baseline: > 0 
2. UWDRS Part III total score at Baseline: > 0 
o “Intolerant” responder is defined as a patient who meet at least 1 of the following 
criteria: 
1. Wilson Disease treatment history “Reason for discontinuation” which 
indicates intolerance, as reviewed by the Medical Monitor. This review 
will be blinded to patient and treatment identifiers, and be completed prior 
to database lock. 
2. Adverse event observed prior to first dose on Day 1 with “Action taken 
with SoC” as “Drug withdrawn”. 
 Symptomatic vs pre-symptomatic. Presence of symptoms will be assessed by the 
following criteria independently: 
 Cirrhosis at Baseline (Yes/No) 
 UWDRS Part II total score at Baseline: > 0 or = 0 
 UWDRS Part III total score at Baseline: >0 or = 0 
 Symptomatic vs pre-symptomatic adolescents (≥ 12 - <18 years). Presence of symptoms 
will be assessed by the following criteria independently: 
 Cirrhosis at baseline (Yes/No) 
 UWDRS Part II total score at Baseline: > 0 or = 0 
 UWDRS Part III total score at Baseline: >0 or = 0 
 Sex (Male, Female) 
 Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other Pacific Islander, Other) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown) 
 Country/Region (United States, EU, United Kingdom, Germany, Japan, Rest of World) 
 BMI Group : <25 kg/m2, 25-30 kg/m2, >30 kg/m2  
 Liver impairment status at entry defined as MELD score above (>) or below (≤) the 
median MELD score at Baseline 
 UWDRS Part II total score at Baseline: > 0 or = 0 


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 UWDRS Part III total score at Baseline: > 0 or = 0 
 UWDRS Part III Functional Subscale: > 0 or = 0 
 UWDRS ADL Subgroups at Baseline 
 No reported ADL limitations 
 Functionally independent 
 Functionally dependent 
 Cirrhosis at Baseline (Yes/No) 
 Psychiatric symptoms at Baseline (Yes/No) - at least 1 symptom present on BPRS-24 
 Overall Mean Daily Dose Group  (< 15 mg, 15- < 30 mg, ≥ 30 mg) 
 Renal Function Status at Baseline  
 G1 
 G2 
 G3a/G3b/G4/G5 combined 
 ALT at Baseline: > or ≤ ULN  
7.2.1.3. 
Multicenter Studies 
Subgroup analyses will be performed for country/region (ie, United States, EU, United Kingdom, 
Germany, Japan, Rest of World). 
7.2.1.3.1. Japanese Specific Analysis 
Subgroup analyses for Japan will be based on Japanese patients, which are defined as patients 
enrolled in the country of Japan and enrolled in the Primary Evaluation Period. The layout of the 
tables and figures will be the same as the global tables and figures for Study WTX101-301. The 
table/figure number will be the same as the original number, however, a “J” will be added to the 
end. To the end of original title of the table/figure, “(Japanese)” will be added. The analysis will 
be performed for the following sections: 
 Disposition of patients 
 Demographics and baseline characteristics 
 Primary efficacy endpoints 
 Secondary efficacy endpoints 
 Exploratory endpoints 
 AEs. 
A descriptive efficacy analysis will be performed on the Japanese patients in the FA Set. No 
formal hypothesis tests or p-values on the Japanese patients alone will be conducted or reported, 
due to the small number of patients in Japan. Instead, summary statistics will be computed and 


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displayed by treatment within cohorts in the same format as global tables. The subgroup analysis 
listed in Section 7.2.1.2 will not be needed for Japanese specific analysis. 
The safety analysis will only include AEs, which will be performed on the Japanese patients in 
the Safety Set. 
Figures will be created based on the Japanese patients, if applicable. 
Listings will not be created for Japanese specific analysis. 
7.2.1.4. 
Hypothesis Testing and Significance Level 
The efficacy assessments will be performed for the following primary and key secondary 
endpoints: 
 Endpoint 1 (primary): Daily mean dNCC AUEC0-48W  
 Endpoint 2: Change from baseline in the UWDRS Part II 
 Endpoint 3: Change from baseline in UWDRS Part III Functional Subscale 
 Endpoint 4: Change from baseline in UWDRS Part III Arising from a chair 
 Endpoint 5: Change from baseline in UWDRS Part III Gait 
 Endpoint 6: Change from baseline in UWDRS Part III Handwriting 
 Endpoint 7: Change from baseline in UWDRS Part III Speech 
The corresponding null hypotheses will be labeled as follows: 
 𝐻1: Null hypotheses of no effect for Endpoint 1 (dNCC AUEC0-48W). 
 𝐻2: Null hypotheses of no effect for Endpoint 2 (UWDRS Part II). 
 𝐻3: Null hypotheses of no effect for Endpoint 3 (UWDRS Part III Functional Subscale). 
 𝐻4: Null hypotheses of no effect for Endpoint 4 (UWDRS Part III Arising from a chair). 
 𝐻5: Null hypotheses of no effect for Endpoint 5 (UWDRS Part III Gait). 
 𝐻6: Null hypotheses of no effect for Endpoint 6 (UWDRS Part III Handwriting). 
 𝐻7: Null hypotheses of no effect for Endpoint 7 (UWDRS Part III Speech). 
A multiplicity adjustment will be applied to address the following 2 sources of multiplicity: (1) 
analysis of the primary/key secondary endpoints, and (2) SSR rule at the interim analysis. The 
proposed multiplicity adjustment guarantees strong control of the overall Type I error rate 
control with respect to these sources of multiplicity at two-sided 𝛼= 0.05. The multiplicity 
adjustment relies on a prospectively defined multiple testing procedure. This procedure will be 
applied in conjunction with the combination function approach  
(Wassmer, 2016) at the interim and final analyses to ensure strong Type I error rate control. The 
combination function approach will be applied using the modification proposed in Sugitani et.al 
(Sugitani,2016). 
To address multiplicity induced by the first source of multiplicity in this study, namely, 
multiplicity induced by the analysis of the primary/key secondary endpoints, a multiple testing 
procedure will be applied. This procedure will be set up using the graphical method 
(Bretz,  2009). The multiplicity adjustment strategy will be applied using the serial testing 
algorithm (Dmitrienko, 2013). Figure 1 illustrates the proposed multiple testing strategy. 


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Figure 1: 
Proposed Multiple Testing Strategy. 
 
The hypothesis weights are set up as follows: 
 All of the weight is initially assigned to the hypothesis 𝐻1, ie, 𝑤1 = 1. 
 The other hypothesis weights are set to 0, ie, 𝑤𝑖= 0, 𝑖= 2, … ,7. 
The values of the transition parameters are defined as: 
 𝑔12 = 1  
 𝑔23 = 1 
 𝑔34 = 1/4, 𝑔35 = 1/4, 𝑔36 = 1/4, 𝑔37 = 1/4, 
 𝑔45 = 1/3, 𝑔46 = 1/3, 𝑔47 = 1/3, 
 𝑔56 = 1/3, 𝑔57 = 1/3, 𝑔54 = 1/3, 
 𝑔67 = 1/3, 𝑔64 = 1/3, 𝑔65 = 1/3. 
 𝑔74 = 1/3, 𝑔75 = 1/3, 𝑔76 = 1/3. 
To account for the second source of multiplicity (data-driven decision rule at the interim 
analysis), the multiple testing procedure will be applied separately to the 2 study stages: 
 Stage 1 includes all patients who are included in the interim database. 
 Stage 2 includes all patients who are not included in the interim database. 
The multiple testing procedure will account for the interim decision rule to support inferences at 
the final analysis. For example, if a decision is made to increase the sample size in the study, the 
evidence of treatment effectiveness from the 2 study stages will be pooled with predefined 


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weights using the modified combination function principle. The standard analysis will be 
performed at the final analysis if the sample size is not adjusted at the interim analysis. 
Let 𝑝1 through 𝑝7 denote the two-sided treatment effect p-values for the null hypotheses of 
interest computed from the Stage 1 data. Similarly, let 𝑞1 through 𝑞7 denote the two-sided 
treatment effect p-values for the null hypotheses computed from the Stage 2 data. If an 
adaptation at the interim analysis occurred, the inferences for the hypotheses 𝐻1 through 𝐻7 
would be performed at the final analysis as follows: The combined p-value for the hypothesis 𝐻𝑖 
is denoted by 𝑟𝑖, 𝑖= 1, … ,7, and is derived using the weighted inverse-normal combination 
function, i.e., 
𝑐(𝑥, 𝑦) = 1 −Ф (√𝑤Ф−1(1 −𝑥) + √1 −𝑤Ф−1(1 −𝑦)), 
where Ф(𝑥) denotes the cumulative distribution function of the standard normal distribution, and 
𝑤= 0.35 and 1 −𝑤= 0.65 are the predefined weights assigned to Stages 1 and 2. 
The combined p-value for the hypothesis 𝐻𝑖 would be computed as follows: 
𝑟𝑖= 𝑐(𝑝𝑖, 𝑞𝑖). 
The resulting combined p-values would be passed to the multiple testing procedure to perform 
inferences at the final analysis, ie, the adjusted p-values will be computed for the null hypotheses 
and each null hypothesis will be rejected at the final analysis if its adjusted p-value does not 
exceed a two-sided 𝛼= 0.05. The proposed multiplicity adjustment guarantees overall Type I 
error rate control in the strong sense with respect to both sources of multiplicity in the study. 
There will be no Type I error adjustment made for non-key and exploratory efficacy endpoints. 
Since no adaptation for sample size increase occurred at the interim analysis, this second source 
of multiplicity will not be relevant to the final analysis. 
7.2.1.5. 
Sensitivity Analyses 
Sensitivity analyses for the primary endpoint only will be performed using different imputation 
methods on the missing data mentioned in the Section 7.2.1.1. 
7.2.2. 
Secondary Analyses 
Similar to the primary estimand, the key secondary estimand is the difference in UWDRS score 
between ALXN1840 and SoC in patients with WD, regardless of less-than-complete adherence 
or use of another medication that affects plasma dNCC, with no benefit derived from treatment 
after death. This estimand applies to all key secondary endpoints. 
The secondary endpoints will be analyzed via mixed model for repeated measures (MMRM) 
analysis with the principal contrast being between SoC versus ALXN1840-treated patients at 
Week 48. Fixed-effect terms will be included for randomized treatment (ALXN1840 or SoC), 
cohort, visit, baseline by visit interaction, randomized treatment by visit interaction, and baseline 
level as a covariate. The treatment by visit interaction will remain in the model regardless of 
significance. An unstructured covariance matrix will be used to model the within-patient error 
and the Kenward Roger approximation will be used to estimate the degrees of freedom. If the fit 
of the unstructured covariance structure fails to converge, the following covariance structures 


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will be tried in order until convergence is reached: Toeplitz with heterogeneity, autoregressive 
with heterogeneity, Toeplitz, and autoregressive. 
The key secondary endpoints include: 
 Change from baseline in the UWDRS Part II total score. 
 Change from baseline in the UWDRS Part III Functional Subscale. 
 Change from baseline in the UWDRS Part III individual functional items: arising 
from a chair, gait, speech, and handwriting) 
Other non-key secondary endpoints include: 
 CGI-I scale 
 Change from baseline in CGI-S scale 
 Change from baseline in hepatic status assessed by the MELD score; 
 Change from baseline in the UWDRS Part III total score. 
 Change and percentage change from baseline (Day 1) in cNCC in plasma. For 
ALXN1840-treated patients, the cNCC in plasma will be corrected for the amount of 
copper bound to the ALXN1840 TPC (cNCCcorrected) 
 cNCC/cNCCcorrected responder rate at 48 weeks 
For cNCC/cNCCcorrected responder rate at 48 weeks, patients without 48-week values will be 
considered as nonresponders. These data will be analyzed via logistic regression with terms for 
randomized treatment, cohort, and baseline cNCC level. 
7.2.3. 
Exploratory Analyses 
The following exploratory endpoints will be analyzed via MMRM analysis with the principal 
contrast being between SoC versus ALXN1840-treated patients at Week 48. The parameters of 
total Cu, total Mo, Cp, PUF-Cu, PUF-Mo, 24-hour urine Cu, 24-hour urine Mo, and speciation 
profile parameters may be log transformed prior to analysis: 
 Change from baseline in the FIB-4 Index; 
 Change from baseline in Modified Nazer Score; 
 Change from baseline in BPRS-24; 
 Change from baseline in EQ-5D using the UK health states (including the EQ-5D-5L 
Descriptive System and the EQ VAS); 
 Plasma total Cu, PUF-Cu, dNCC, LBC, Cp, and CpC concentration-time profiles in 
plasma; 
 Total Mo and PUF-Mo concentration-time profiles in plasma; 
 Change in 24-hour urinary Cu and urinary Mo; 
 Change from baseline in the Timed 25F Walk Test; 
 Change from baseline in UWDRS Part I and total score; 
 Change from baseline in UWDRS Part II - FDA suggested scoring; 


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 Change from baseline in UWDRS Part III individual items - FDA suggested scoring: 
arising from chair, gait, speech, and handwriting. 
 Change from baseline in UWDRS Part III Functional Subscale-FDA suggested scoring 
The following endpoints will be analyzed using ANCOVA model on the change between 
Week 48 and baseline. For 9-HPT, nonverbal Stroop Interference Test, and Digit Span Test, an 
ANCOVA model on the change between baseline and Week 12 and between baseline and 
Week 24 will also be applied. A fixed-effect term will be included for randomized treatment 
(ALXN1840 or SoC) and the baseline value will be included as a covariate. LS means will be 
provided for each randomized treatment group at Week 48 together with the difference in LS 
means and associated 2-sided 95% CI and p-value. 
 Change from baseline in transient elastography; 
 Change from baseline in the 9-HPT; 
 Change from baseline in the nonverbal Stroop Interference Test; 
 Change from baseline in the Digit Span Test. 
The 3 most troublesome symptoms will be analyzed at Weeks 12, 24 and 48 using cumulative 
logit modelling using PROC LOGISTIC in SAS. 
The odds ratio and 95% 2-sided CI will be displayed, along with the 2-sided p-value. 
Model-based estimates of the proportion of patients in each randomized treatment group with 
responses of ‘improved’, ‘remained the same’, or ‘worsened’ will be computed. 
The daily mean AUEC of plasma dNCC (from 0 to 24 and 24 to 48 weeks), daily mean AUEC of 
plasma total copper from 0 to 48 weeks, and daily mean AUEC of LBC from 0 to 48 weeks will 
be analyzed in the same manner as the primary endpoint, via ANCOVA analysis with the 
principal contrast being between SoC versus ALXN1840 treated patients at Week 48. 
Descriptive summary and Kaplan-Meier Analysis will be applied to time to first confirmed 
increase in plasma dNCC and total copper concentration, time to minimum and maximum of 
PK/PD parameters and biomarkers, and time for return to predose baseline for PK/PD parameters 
and biomarkers. 
 Time to first confirmed increase in plasma dNCC and total copper concentration 
 Time to minimum and maximum concentration and the maximum concentration of: 
 − Plasma total copper concentration 
 − Plasma dNCC concentration 
 − Plasma LBC concentration 
 − Ratio plasma dNCC:total copper concentration 
 − Ratio plasma LBC:total copper concentration 
 − Urinary molybdenum concentration 
 − Ratio urinary molybdenum:copper concentration 


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 − Ratio urinary molybdenum:dosed molybdenum concentration 
 − Plasma Cp concentration 
 − Plasma CpC concentration 
 − Ratio plasma Cp:total copper concentration 
 − Ratio plasma CpC:total copper concentration 
 − Ratio plasma CpC:Cp 
 Time for return to predose baseline for the following PK/PD parameters: 
 − Plasma total copper 
 − Plasma dNCC 
 − Plasma LBC 
 − Ratio plasma dNCC:total copper 
 − Ratio plasma LBC:total copper 
 − Urinary molybdenum 
 − Ratio urinary molybdenum:copper 
 − Ratio urinary molybdenum:dosed molybdenum 
 − Plasma Cp concentration 
 − Plasma CpC concentration 
 − Ratio plasma Cp:total copper 
 − Ratio plasma CpC:total copper 
 − Ratio plasma CpC:Cp 
LBC responder rate will be analyzed the same as the cNCC responder rate analysis described in 
Section 7.2.2. Note, TSQM-9 will be summarized descriptively. 
 
Relationship Between Copper and Key Secondary Endpoints: 
Pearson’s correlation coefficient will be estimated to provide summaries of the relationship 
between copper quantification methods and all key secondary endpoints. For plasma total copper 
AUEC0-48W and dNCC AUEC0-48W, the key secondary endpoints will be measured as change 
from baseline to Week 48 (Table 3). 


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Table 3: 
Correlations Between Copper and Key Secondary Endpoints (Change from 
Baseline) 
 
dNCC AUEC0-48W 
PTC AUEC0-48W 
Change from baseline to Week 48 in the UWDRS Part II total 
score 
X 
X 
Change from baseline to Week 48 in the UWDRS Part III 
Functional Subscale 
X 
X 
Change from baseline to Week 48 in arising from a chair 
X 
X 
Change from baseline to Week 48 in gait 
X 
X 
Change from baseline to Week 48 in handwriting 
X 
X 
Change from baseline to Week 48 in speech 
X 
X 
Abbreviations: dNCC = directly measured non-ceruloplasmin-bound copper; PTC = plasma total copper 
For plasma total copper, dNCC, plasma LBC, cNCC/cNCCcorrected, the correlations with key 
secondary endpoints will be calculated for all visits in the following time windows (Table 4): 
 Postbaseline period: Week 4 to Week 48 
 24-Week copper mobilization period: Week 4 to Week 24  
 Post 24-Week copper maintenance period: Post Week 24 to 48 (> Week 24 - Week 48) 
Table 4: 
Correlations Between Copper and Key Secondary Endpoints (Measured 
Values) 
 
PTC 
dNCC 
Plasma LBC 
cNCC/cNCCcorrected 
UWDRS Part II total score 
X 
X 
X 
X 
UWDRS Part III Functional 
Subscale 
X 
X 
X 
X 
Arising from a chair 
X 
X 
X 
X 
Gait 
X 
X 
X 
X 
Handwriting 
X 
X 
X 
X 
Speech 
X 
X 
X 
X 
Abbreviations: dNCC = directly measured non-ceruloplasmin-bound copper; PTC = plasma total copper; 
LBC = labile bound copper; cNCC = calculated non-ceruloplasmin-bound copper calculated 
non-ceruloplasmin-bound cNCCcorrected = copper corrected for copper bound in tetrathiomolybdate-copper-albumin 
complexes 
7.2.4. 
Extension Period Analyses 
Extension Period Analyses will be fully described in a separate SAP. 
7.2.5. 
Pharmacokinetic and Pharmacodynamic Analyses 
Raw plasma concentration values, including plasma total molybdenum, PUF-Mo, total copper, 
PUF-Cu, dNCC, LBC, Cp, and CpC as well as urine total molybdenum and copper will be 
summarized by randomized treatment within treatment cohort and time point using descriptive 
statistics, to include the geometric mean and coefficient of variation (CV; %). When calculating 
the geometric mean, values of 0 will be discarded. 
Concentration-time profiles in plasma will be displayed in graphical format for each patient and 
will be plotted by dose. The mean concentration-time profiles including all patients in the PK 
and PD/biomarker populations will also be plotted. Concentration-time profiles for plasma total 
molybdenum, PUF-Mo, total copper, PUF-Cu, dNCC, LBC, Cp, and CpC as well as urine total 


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molybdenum and copper will be displayed in units of ng/mL and µmol/L, calculated by dividing 
the concentrations by the relative atomic mass (average molecular weight) of copper (63.546) or 
molybdenum (95.95). 
A by-patient listing will also be provided in units of ng/mL and µmol/L. 
7.3. 
Safety Analyses 
Safety and tolerability over the course of the study period is a secondary endpoint and will not be 
subject to formal analysis. Rather, descriptive statistics will be used to summarize the safety data 
by randomized treatment within cohort and overall. The Safety Set will be used for the 
evaluation of safety in the Primary Evaluation Period. 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure 
Study duration will be summarized for all enrolled patients by treatment within each cohort. 
Treatment compliance and exposure will be summarized for the Safety Set by treatment within 
each cohort. Supportive listings will also be provided. 
7.3.1.1. 
Study Duration 
Study duration is defined as the time from informed consent to the end of the Primary Evaluation 
Period (ie, Week 48) or study discontinuation date, whichever occurs first. 
7.3.1.2. 
Treatment Compliance 
The treatment compliance will be defined as: 
Compliance (%) = (number of dose received)/(total number of dose scheduled) × 100. 
Furthermore, the compliance will be summarized in the following ways: 
 Compliance (%) 
 Compliance (< 80%, ≥ 80%) 
Treatment compliance will be summarized using descriptive statistics by visit, by randomized 
treatment within cohort and overall. Compliance up to Week 48 (Primary Evaluation Period) will 
be summarized for all patients. If a patient prematurely discontinues during the Primary 
Evaluation Period, his or her compliance will be based on the period up to the point of 
discontinuation from the study. Additionally, drug interruptions or missed doses as the result of a 
physician decision or AE will be factored into the number of doses scheduled, whereas drug 
interruptions or missed doses for any reason will be factored into calculating the number of doses 
received. A supporting listing will also be produced. 
7.3.1.3. 
Exposure 
The number of patients exposed to the study drug will be summarized in terms of counts for the 
overall duration of the study, and by periods specified in International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) E3 guideline. The number 
of patients will also be summarized by the overall mean daily dose groups (< 15 mg, ≥ 15 to 
< 30 mg, ≥ 30 mg) for the overall duration and in each specified time period listed below. 


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 1 day or less 
 2 days to 1 week 
 1 week to 1 month 
 1 month to 6 months 
 6 months to 1 year 
 > 1 year 
The duration (days) of exposure to treatment will be calculated as date of last exposure to 
treatment – date of first dose + 1. 
Patient-years (PY) of exposure will be derived individually for each patient. PY will be defined 
for each patient as the total time (in years) from first dose to the last available dose of study drug. 
Dose adjustments and/or interruptions will not be factored into this derivation. Results will be 
analyzed using descriptive statistics and the frequency and percentage of patients in the dose 
categories (< 15 mg, 15- < 30 mg, ≥ 30 mg). 
The gap in drug exposure will not be included in the calculation of duration of exposureDosing 
will be described by mean daily dose, final daily dose, minimum daily dose, maximum daily 
dose, and total accumulative dose. 
 Mean daily dose = sum (each dose × each dose frequency × each period)/total treatment 
period 
 Final daily dose is defined as the last dispensed dose in titration studies 
 Minimum daily dose is defined as the minimum daily dose over the Treatment Period 
 Maximum daily dose is defined as the maximum daily dose over the Treatment Period  
 Total accumulative dose is the sum of doses over the total Treatment Period 
The dosing regimen was individualized and varied across protocols. The mean daily dose (mg), 
minimum daily dose (mg) and maximum daily dose (mg) will be summarized using descriptive 
statistics. All available dosing data will be presented in a listing. Where available, reasons for 
dose adjustment will also be presented in a listing. 
Listings of exposure, drug interruptions and missed doses will also be presented. 
7.3.2. 
Adverse Events 
The verbatim terms as reported in the CRF by Investigators to identify AEs will be coded using 
the MedDRA, Version 20.0 or higher and summarized by primary System Organ Class and 
Preferred Term. 
AE severity will be evaluated using the NCI CTCAE version 5.0 (published 27 Nov 2017). 
AE causality is determined by the Investigator using the following assessment categories: 
unrelated or related. 
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset after the first 
dose of randomized treatment or existing events that worsened in severity after the first dose of 
randomized treatment. Events reported with a partial onset date (eg, month and year are reported 
but the day is missing) will be considered to be treatment-emergent if it cannot be confirmed that 


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the event onset was prior to the first dose of study drug based on the available date entries. 
Additionally, for patients who were originally randomized to SoC in the Primary Evaluation 
Period and switch to ALXN1840 in the Extension Period, any AEs which initiate after the switch 
or existing events that worsen in severity will be attributed to ALXN1840. 
Although no formal statistical comparison of AEs will be done, exposure-adjusted incidence 
rates in addition to raw cumulative incidence proportions will be provided for all analyses of 
safety data. The exposure years will be included in the AE summary tables. Estimated treatment 
differences and confidence intervals for treatment arm comparisons will be reported for all 
analyses of safety data. Descriptive analysis to compare treatment groups with respect to risk (eg, 
with a risk difference, along with a confidence interval) will be reported for AESIs. 
7.3.2.1. 
Overall Summary of Adverse Events 
An overall summary of TEAEs will be presented, including frequency of patients experiencing 
the event (n) and relative frequency (n/N*100, where N is the number of patients in the Safety 
Set). The summary will include categories indicating how many events are TEAEs, 
treatment-emergent SAEs, and treatment-emergent non-SAEs. Within TEAEs, the following 
subcategories will also be summarized: 
 Severity of TEAEs (Grade 1 through Grade 5) 
 Related TEAEs (not related, related) 
 TEAEs leading to withdrawal of study drug 
 TEAEs leading to death  
 AESIs 
A summary of events (n) and number of patients with events (n, %) for pretreatment-emergent 
adverse events (PTAEs) will also be included with its relevant subcategories. 
A listing of all TEAEs by treatment cohort and patient will be presented. Separate listings will be 
produced for SAEs, AEs leading to study drug withdrawal, AEs resulting in death, AEs leading 
to withdrawal from the study and PTAEs. 
7.3.2.2. 
AEs by System Organ Class and Preferred Term 
The number of TEAEs and the number and percentage of patients with events will be presented 
by System Organ Class and Preferred Term. Patients are counted once in each System Organ 
Class and Preferred Term. Percentages will be based on the Safety Set. System Organ Class will 
be listed in descending frequency as will Preferred Terms within each System Organ Class. If 
needed, terms will also be ordered alphabetically. 
Treatment-emergent SAEs, treatment-emergent non-SAEs, TEAEs leading to withdrawal of 
study drug, TEAEs leading to death, treatment-emergent AESIs, PTAEs, and TEAEs occurring 
in ≥ 5% or ≥ 10% of patients will be summarized using the same approach. 


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7.3.2.3. 
AEs by System Organ Class 
The number of TEAEs and the number and percentage of patients with events will be presented 
by System Organ Class. Patients are counted once in each System Organ Class. Percentages will 
be based on the total number of treated patients in the treatment cohort. 
7.3.2.4. 
AEs by Preferred Term 
The number of TEAEs and the number and percentage of patients with events will be presented 
by Preferred Term. Patients are counted once in each Preferred Term. Percentages will be based 
on the total number of treated patients in the treatment cohort. 
7.3.2.5. 
AEs by System Organ Class, Preferred Term, and Relationship 
The number of TEAEs and the number and percentage of patients with events will be presented 
by System Organ Class and Preferred Term as described in Section 7.3.2.2 by relationship 
(related, not related). If a patient has more than one occurrence of an AE, the strongest 
relationship to study treatment will be used in the summary table. If relationship to study drug is 
missing, the AE will be assumed to be related. A similar analysis will be conducted for 
treatment-emergent SAEs. 
The number of related TEAEs and the number and percentage of patients with related TEAEs 
will be summarized by System Organ Class and Preferred Term, and separately by Preferred 
Term only. The same analyses will be produced for related treatment-emergent SAEs. 
Lastly, the number of TEAEs by System Organ Class, Preferred Term and relationship, without 
taking into account the highest relationship, will be analyzed. A similar analysis will be 
conducted for treatment-emergent SAEs. 
7.3.2.6. 
AEs by System Organ Class, Preferred Term, and Severity 
The number of TEAEs and the number and percentage of patients with events will be presented 
by System Organ Class, Preferred Term, and severity. If a patient has more than one occurrence 
of an AE, the highest severity reported will be used. If severity is missing, the AE will be 
assumed to be severe. The number of TEAEs by system organ class, Preferred Term, and 
severity, without taking into account the highest severity, will also be analyzed. 
Additionally, a summary of related TEAEs by System Organ Class, Preferred Term, and severity 
using the highest severity will be presented. 
7.3.2.7. 
Deaths, Other Serious Adverse Events, and Adverse Events of Special Interest  
SAEs and AESIs will be reportable from the time the patient signs the informed consent through 
the EOS Visit or until the Investigator and Alexion Pharmaceuticals determine that follow-up is 
no longer necessary. SAEs that are suspected to be drug related may be reported even if they 
occur more than 30 days after the patient is no longer on the study. 
Any new neurological symptom or clinically significant worsening of an ongoing neurological 
symptom after initiation of study drug therapy will be designated to be an AESI, whether serious 
or nonserious. This includes all AEs in the MedDRA SOC “Nervous system disorders” or any 
AE where the “Is this an AESI?” check box is checked in the CRF. 


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AESIs will be assessed by a panel of 3 independent neurologists not participating in the study. 
The panel will assess the probability that clinically significant worsening or a new clinically 
significant neurological symptom is related to disease progression or caused by the study drug 
(ALXN1840 or SoC). They will be blinded to the treatment given to the patient. All available 
relevant patient information will be provided to this panel to aid in their assessment. The 
assessment of AESIs by the panel will be independent of and in addition to the usual assessments 
of the AE, including assessments of severity (intensity) and causality, by both the Principal 
Investigator and Alexion. A summary and listing of assessments given by the Neurological 
Adverse Event Panel will be presented. 
A separate independent Hepatic Adjudication Panel, comprising experts in hepatology and 
drug-induced liver injury will be appointed by the Sponsor. 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. A summary and listing of assessments given by the 
Hepatic Adjudication Panel will be presented. 
7.3.2.8. 
Other Significant Adverse Events  
Other significant TEAEs encompass those for abnormal liver function tests (a.k.a. hepatic 
events), hematopoietic cytopenias, and dyslipidemia. These include any new AE, or worsening 
of an ongoing AE, after initiation of study drug therapy that meet the criteria described below: 
 Hepatic events: All AEs in the SMQ for Drug related hepatic disorder 
(comprehensive search), or any adverse event where the “Is this a Hepatic AE?” 
check box is ticked. 
 Hematopoietic cytopenias: All AEs in the SMQ “Haematopoietic cytopenias”. 
 Dyslipidemia: All AEs in the SMQ “Dyslipidaemia”. 
Relationships to duration of study therapy and dose of study therapy may be explored along with 
examination within relevant subgroups, eg, WD severity at study entry prior, prior therapies 
received, age, and sex. WD severity at study entry may be assessed by the following: 
 Cirrhosis status (yes, no) 
 MELD score at baseline above (>) or below (≤) median 
 Modified Nazer Score at baseline above (>) or below (≤) median 
 Total Bilirubin (mol/L) > ULN 
 Platelets (109/L) < lower limit of normal (LLN) 
 UWDRS Part II total score at baseline >0 or = 0 
 UWDRS Part III total score at baseline >0 or = 0 
 CGI-S at baseline above (>) or below (≤) median 
 LBC (µmol/L) at baseline above (>) or below (≤) median 
 Leukocytes (109/L) < LLN 
 Neutrophils (109/L) < LLN 


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Prior therapies received may be assessed as follows: 
 Cohort 1 will be categorized by prior SoC, where prior SoC is defined as the most 
recent treatment prior to or at time of Screening (whichever is later), and is 
categorized as penicillamine, trientine hydrochloride, zinc, or combination. 
 Cohort 2 will be categorized into patients who are treatment naïve and those who 
have received SoC therapy for ≤ 28 days prior to first dose. 
7.3.3. 
Other Safety Analyses 
7.3.3.1. 
Analyses for Laboratory Tests 
Actual values and changes from treatment baseline will be summarized descriptively for patients 
with available data for each laboratory parameter by randomized treatment within treatment 
cohort, for rollover patients and overall. Missing laboratory data will not be imputed, and only 
scheduled assessments will be included in by-visit summaries. A summary for “Last 
Assessment” will be included for the last available postbaseline result for each patient. A 
summary of “Worst Postbaseline” from all postbaseline data will also be included for the 
Primary Evaluation Period and for the Extension Period separately. All data, including that 
which is only collected at Screening, will be included in by-patient data listings. Laboratory 
measurements will be listed separately by patient, laboratory test, and unit. 
Clinical laboratory measurements, including serum chemistry, hematology, urinalysis, and 
coagulation, will be summarized. Descriptive statistics will be presented for results and changes 
from baseline at each visit where parameters were scheduled to be collected per the clinical study 
protocol. 
Where applicable, laboratory results will be classified as “low,” “normal,” or “high” with respect 
to the parameter-specific reference ranges (ie, below the lower limit of the normal range, within 
the normal range, or above the upper limit of the normal range). Contingency tables will be 
presented for each laboratory parameter to summarize the shift from the baseline category to all 
visits and to the worst postbaseline measurement, defined as the value numerically farthest 
outside of the normal range across all postbaseline visits through the end of the study. 
Summary results will include the count and percentage of patients within each shift category by 
scheduled visit. Laboratory values outside the normal range will also be summarized and 
assessed for trends indicating a safety signal. Additionally, a summary and listing of liver 
enzyme elevation and a listing of DNA results will be presented. 
Clinically Significant Laboratory Test Abnormalities 
The following lab tests will be graded according the CTCAE V5.0 at ADaM level. 
 Hematology: Absolute neutrophil count (neutrophil) (NEUT), total leukocytes 
(Leukocytes) (WBC), hemoglobin (HGB) (only do the grading for Anemia, no 
grading for Hemoglobin increased), platelet count (PLAT), Lymphocyte (LYM)  
 Coagulation: International normalized ratio (INR) 
 Chemistry: Alanine aminotransferase (ALT), albumin (ALB), alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), total bilirubin (BILI), creatinine 


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(CREAT), gamma-glutamyltransferase (GGT), glucose (GLUC) (only grading for 
Hypoglycemia, no grading for Hyperglycemia), creatine kinase (CK), cholesterol 
(CHOL), and Triglycerides (TRIG). 
Laboratory toxicity grade 0 will be derived for the shift table as: any non-missing results outside 
the range of the CTCAE criteria will be summarized as “Grade 0”. Laboratory tests with missing 
either LLN or ULN or both will not be graded. Abnormal laboratory tests values will be 
summarized by CTCAE Laboratory Toxicity Grade. Shift from baseline tables of the number and 
percentage of patients in each of the CTCAE categories will also be presented for each treatment 
group for each parameter and visit time window (scheduled visits only). An overall shift 
summary will also be provided comparing baseline to worst postdose toxicity observed across all 
scheduled visits. 
Lipid profile plots will be produced for individual patients, showing total cholesterol, HDL, 
LDL, and triglycerides, and ALT as a multiple of the respective baseline (BLN) values, and 
multiple of ULN values.  
7.3.3.2. 
Evaluation of Drug Induced Serious Hepatotoxicity  
A Hy’s law case refers to an increase in aminotransferase > 3 × the reference ULN, with 
bilirubin > 2 × ULN. Possible Hy’s law cases can be visualized with use of Evaluation of Drug 
Induced Serious Hepatotoxicity (eDISH) plots, a log-log scatter plot where the x-axis is the peak 
postbaseline ALT as a multiple of ULN, and the y-axis is the peak postbaseline total bilirubin as 
a multiple of ULN (Guo, 2009). 
The following series of figures, adapted from Tesfaldet et al (Tesfaldet ,2016), will be produced 
for each treatment arm (ALXN1840 and SoC) separately for the Safety Analysis Set. 
1. Distribution of ULN of liver serum enzymes. The ULN reference values used in each test 
(bilirubin, ALT, AST, ALP) and their respective frequencies in percentiles. 
2. Distribution of baseline liver serum enzymes, for each test by cohort.  
3. Distribution of baseline liver serum enzymes (× ULN), for each test by cohort. 
4. Status of baseline liver serum enzymes as function of ULN by cohort. Baseline status 
categorized as Normal, > 1 ×, > 1.5 ×, > 2 ×, > 3 ×, > 5 ×, > 10 ×. 
5. eDISH plot by treatment arm. 
6. eDISH plot by quadrant. 
7. Panel of eDISH quadrant shift plots at baseline. Patients are color coded to correspond to 
the quadrant they belong in the eDISH plot. The data presented in the panel corresponds 
to each patients’ baseline value as a multiple of the ULN. 
8. Panel of shift plots by eDISH quadrants. Patients are color coded to correspond to the 
quadrant they belong in the eDISH plot. The data is presented as multiples of the baseline 
value rather than the ULN. The shift in peak postbaseline laboratory value is compared to 
each patients’ baseline value. 


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9. Panel of eDISH shift plots by eDISH quadrants. The panels represent the on-treatment 
eDISH quadrants whereas the colored symbols represent the eDISH quadrants of the 
baseline values (not postbaseline) as multiples of ULN. 
10. Time course of liver tests as ×baseline value and ×ULN by cohort. 
7.3.3.3. 
Vital Signs 
Changes from baseline in vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) at each visit will be summarized descriptively by randomized treatment within 
treatment cohort, for rollover patients and overall. Missing vital signs data will not be imputed 
and only scheduled assessments will be summarized in tables; unscheduled assessments will be 
presented in by-patient data listings. A summary for “Last Assessment” will be included for the 
last available postbaseline result for each patient. Summaries of shifts in blood pressure and heart 
rate from baseline values will also be created to allow detection of clinically relevant changes; 
these will be shifts of ± 20 mmHg for systolic or diastolic blood pressure and ± 20 beats per 
minute for resting heart rate. A listing of vital signs will be presented by randomized treatment, 
treatment cohort, patient, vital sign, and visit. 
7.3.3.4. 
Electrocardiogram 
All ECG data will be fully listed and changes from baseline in ECG data (heart rate, PR interval, 
RR interval, QRS duration, QT interval) will also be summarized descriptively by scheduled 
visit. 
QT intervals will be corrected for heart rate according to Bazett (QTcB = QT/[RR1/2]) and 
Fridericia (QTcF = QT/[RR1/3]). At each time point, the number and percentage of patients 
falling into the following categories according to the ICH E14 Guidelines will be presented: 
 QTc actual values: ≤ 450 ms, > 450 to  480 ms, > 480 to  500 ms, and > 500 ms 
 QTc increases from baseline of > 30 msec and > 60 msec 
Changes from baseline in QTc will also be summarized. Further, ECG data will be classified by 
the Investigator as “normal,” “abnormal, not clinically significant,” “abnormal, clinically 
significant” or “indeterminate” at each timepoint assessed. Contingency tables will be presented 
to summarize the shift from the baseline category to the worst postbaseline value. Summary 
results will include the count and percentage of patients within each shift category. 
7.3.3.5. 
Relationship Between Copper and Safety Endpoints 
Pearson’s correlation coefficient will be estimated to provide summaries of the relationship 
between plasma total Cu, plasma LBC, cNCC, dNCC, 24-Hour urine copper, and plasma total 
Mo with safety endpoints. The correlations with safety endpoints will be calculated for all visits 
in the following time windows (Table 5) 
 Week 4 only 
 Postbaseline period: Week 4 to Week 48 
 24-week Cu mobilization period: Week 4 to Week 24 
 Post 24-week Cu maintenance period: Post Week 24 to 48 (> Week 24 - Week 48) 


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Table 5: 
Correlations Between Copper and Safety Endpoints 
 
Plasma 
Total 
Copper 
dNCC 
Plasma 
LBC 
cNCC/ 
cNCCcorrecte
d 
24-Hour 
Urine 
Copper 
Plasma 
Total 
Molybdenu
m 
MELD 
X 
X 
X 
X 
X 
X 
Modified 
Nazer 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
CGI-I 
X 
X 
X 
X 
X 
X 
ALT  
X 
X 
X 
X 
X 
X 
AST  
X 
X 
X 
X 
X 
X 
GGT  
X 
X 
X 
X 
X 
X 
Neutrophils  
X 
X 
X 
X 
X 
X 
 
eukocytes  
X 
X 
X 
X 
X 
X 
Albumin  
X 
X 
X 
X 
X 
X 
Hemoglobin  
X 
X 
X 
X 
X 
X 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CGI-I = Clinical Global 
Impression-Improvement Scale; CGI -S= Clinical Global Impression-Severity Scale; 
cNCC = non-ceruloplasmin-bound copper; cNCCcorrected = calculated non-ceruloplasmin-bound copper corrected 
for copper bound in tetrathiomolybdate-copper-albumin complexes; GGT = gamma-glutamyltransferase; 
LBC = labile bound copper; MELD = Model for End-Stage Liver Disease 
 
 


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Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). 
Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111. 
 
Rohay J. Measurement Properties of, and Endpoints from, the Unified Wilson Disease Rating 
Scale (UWDRS). IQVIA. 2020. 
 
Rubin DB. Multiple imputation for nonresponse in surveys. New York. John Wiley and Sons; 
1987. 
 
Schwartz, GJ and Work, DF, Measurement and estimation of GFR in children and adolescents. 
Clin J Am Soc Nephrol. 2009;4(11):1832–1843. 
Stevens LA, Levey AS. Measured GFR as a confirmatory test for estimated GFR. J Am Soc 
Nephrol 20(11):2305-2313, 2009. 
Sugitani T, Bretz F, Maurer W. A simple and flexible graphical approach for adaptive group-
sequential clinical trials. J Biopharm Stat. 2016;26(2):202-216. 
 
Tamhane AC, Dmitrienko A. Analysis of multiple endpoints in clinical trials. In multiple testing 
problems in pharmaceutical statistics, Dmitrienko A, Tamhane AC, Bretz F (editors). Chapman 
and Hall/CRC Press: New York. 2009; 131-163. 
 
Tesfaldet et al. Enhanced visualization of treatment emergent liver effects in integrated eDSH & 
baseline shift plot. FDA/PHUSE US Computational Science Symposium 2016: 
https://www.lexjansen.com/css-us/2016/PP18_Final.pdf 
 
Plitz T. WTX101: Development and validation of NCCcorrected, a method to measure free 
plasma copper in patients treated with WTX101 or other Cu lowering agents. Unpublished 
report, 2017. 
 
Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: An inexpensive and accurate marker of 
fibrosis in HCV infection. Comparison with Liver Biopsy and FibroTest. Hepatology. 2007; 
46(1), 32-36. 
 
Ventura J, Lukoff D, Nuechterlein KH, Liberman RP, Green M, Shaner A. Brief Psychiatric 
Rating Scale (BPRS) expanded version (4.0) scales, anchor points and administration manual. 
International Journal of Methods in Psychiatric. 1993;3: 227–244. 
 
Wassmer G, Brannath W. Group sequential and confirmatory adaptive designs in clinical trials. 
New York: Springer, 2016. 
 


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Wechsler, D. Wechsler Adult Intelligence Scale–Fourth Edition. Pearson; San Antonio, TX: 
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and spline approximation. J Pharmacokinet Biopharm. 1978;6(1):79-98. 


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9. 
APPENDICES 
9.1. 
Protocol Schedule of Activities 
Refer to Table 4 in the Protocol. 
9.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
The following updates have been made to the SAP version 5.0 approved 15 Apr 2021: 
 Responder rate at 48 weeks for UWDRS Part II and Responder rate at 48 weeks for 
UWDRS Part III added to list of Exploratory Endpoints and Appendix (Section 5.1.3 
and Section 9.4.8, respectively). 
 The relationship between normalized GFR and absolute GFR has been updated 
(Section 7.1.3.2) 
 Clarification added that presence of psychiatric symptoms at Baseline refers to at 
least 1 symptom present on BPRS-24 (Section 7.1.3.2 and Section 7.2.1.2). 
 Clarification added in tipping point analysis that when ALXN1840 fixed, SoC 
varied, the δ varies from 10% to 200% (Section 7.2.1.1). 
 Added condition that a subgroup is analyzed only if the number of patients is ≥ 3 in 
each treatment arm. (Section 7.2.1.2). 
 Added additional subgroups for Ethnicity (Section 7.2.1.2). 
 Added additional subgroup for patients who have an incomplete or intolerant 
response to prior WD treatment  (Section 7.2.1.2). 
 Revised subgroups for Renal Function Status at Baseline (Section 7.2.1.2). 
 UWDRS Part III Functional Subscale-FDA suggested scoring added to list of 
Exploratory Endpoints and Exploratory Analyses (Section 5.1.3 and Section 7.2.3, 
respectively). 
 Added analyses for exposure-adjusted incidence rates (Section 7.3.2). 
 Clarification that AESIs includes all AEs in the MedDRA SOC “Nervous system 
disorders” or any AE where the “Is this an AESI?” check box is ticked 
(Section 7.3.2.7).  
 Added definition of significant TEAEs for abnormal liver function, hematopoietic 
cytopenias, and dyslipidemia (Section 7.3.2.8).  
 Added lipid profile plots (Section 7.3.3.1) 
 Added 24-Hour urine copper for correlations with safety endpoints, and updated 
Table 5 (Section 7.3.3.5). 


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9.3. 
Sample Size, Power, and Randomization 
9.3.1. 
Sample Size Justifications 
The primary endpoint is copper control assessed as the percent change from baseline to 48 weeks 
in cNCC levels; for ALXN1840-treated patients, the cNCC level will be corrected for the 
amount of copper bound to the ALXN1840 TPC. 
The hypothesis to be tested with regards to the primary endpoint is: 
𝐻0: 𝜇𝐴𝐿𝑋𝑁1840 −𝜇𝑆𝑜𝐶≥Δ vs 𝐻1: 𝜇𝐴𝐿𝑋𝑁1840 −𝜇𝑆𝑜𝐶< Δ 
where Δ=15% is the non-inferiority margin, 𝜇ALXN1840 and 𝜇𝑆𝑜C represent 48-week mean percent 
change for ALXN1840 and SoC, respectively. 
For patients who have been previously treated with SoC for > 28 days prior to first dose (ie, 
corresponding to Cohort 1 in the present study), the cNCC data in the preceding Phase 1 
Study WTX101-201, 24-week interim lock gives a mean percent change in cNCC level at 
24 weeks of 80% with estimated projected standard deviation of 20% to 30% at 48 weeks. Based 
on this anticipated degree of variability, 90 Cohort 1 patients, randomized by cohort on a 2:1 
basis, will provide between 60% and 91% power to rule out a difference of Δ = 15% in mean 
percent change in cNCC values, ALXN1840 versus SoC with a 1-sided Type I error of 2.5%. 
The number of patients in Cohort 2 is based on feasibility only, and there is no supporting power 
calculation. The intent of Cohort 2 is to provide at least some randomized data in patients who 
are treatment naïve or have been previously treated with SoC for  28 days prior to first dose to 
descriptively assess within arm changes from baseline. No formal statistical comparisons are 
planned within Cohort 2 patients alone. 
In relation to the overall analysis of cNCC percent change from baseline to 48 weeks, data from 
the WTX101 201, 24-week interim lock gives a mean percent change in cNCC level at 24 weeks 
of 78%. A total of 120 patients (90 patients in Cohort 1 and 30 patients in Cohort 2) randomized 
by cohort on a 3:1 basis will provide between 73% and 97% power to rule out a difference of 
Δ = 15%, in mean percent change in cNCC values, ALXN1840 versus SoC, in the overall patient 
population, with a 1-sided Type I error of 2.5%. 
Study WTX101-201 had a minimum cNCC value of 0.8 for study entry while this study has no 
minimum requirement. This may result in the entry of patients with negative baseline cNCC 
values into this study who will be non-evaluable for the primary analysis and/or have a smaller 
effect size. For these reasons, and to achieve a pooled safety database of at least 100 patients 
treated with ALXN1840 for at least 1 year pooling Studies WTX101-201 and WTX101-301, 
these numbers have been inflated by 25% to achieve a total of 150 evaluable patients 
(approximately 113 patients in Cohort 1 and 37 patients in Cohort 2). 
To help ensure that at least 150 evaluable patients complete 48 weeks of treatment, 
approximately 180 patients (approximately 135 patients in Cohort 1 and approximately 
45 patients in Cohort 2) will be enrolled in total, this will also provide additional safety and 
tolerability data. 
The proposed 150 evaluable patients will provide adequate power (approximately 99%) for the 
new primary endpoint, namely, daily mean dNCC AUEC0-48W. This power calculation uses 


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previously observed data on Cohort 1 patients. In Study WTX101-201, Cohort 1 patients treated 
with ALXN1840 showed AUEC of dNCC with a mean (SD) of 3.96 (2.047), while in 
Study WTX101-203, Cohort 1 patients treated with SoC showed a mean (SD) of 0.85 (0.425). 
With a significance level of 2.5% using a one-sided unequal variance t-test, 150 patients (100 to 
ALXN1840 and 50 to SoC) will provide > 99% power to reject the null hypothesis of equal 
means. 
Because the study size and power are sensitive to the assumptions used for effect size, 
variability, and withdrawal rates, an SSR will be performed. Details of the SSR are provided in 
Section 9.3.2. 
9.3.2. 
Sample Size Re-estimation 
The interim analysis for SSR will be performed using the data from only the first approximately 
31% of enrolled patients. There will be no evaluation of the interim data for early stopping for 
futility or efficacy. The sample size will not be reduced from the planned enrollment of 180 
designed to achieve 150 evaluable patients and the maximum total number of patients enrolled 
may be increased to achieve up to 225 evaluable patients. 
The SSR will be based on a conditional power for non-inferiority (CPni) using a promising zone 
with boundaries of  30% and < 80%. The CPni will be calculated using the results obtained at 
this interim analysis and will assume population mean percent change in cNCC equals the 
observed sample mean percent change in cNCC at the time of the SSR. If the CPni is below 
30%, or equal to or above 80% (ie, outside the promising zone) then no increase in sample size 
will be made. If the CPni is within the promising zone, then the sample size will be increased by 
the amount estimated needed to achieve a CPni of 80%. The decision rule is illustrated in the 
Protocol Section 9.2.8 Table 11. The SSR will be repeated based on conditional power for 
superiority using the same boundaries and decision rules described for non-inferiority. 
9.3.3. 
Randomization 
After meeting all inclusion and none of the exclusion criteria, patients will be randomized, 
stratified by cohort, via an interactive voice/web response system in a 2:1 ratio to treatment with 
ALXN1840 or SoC. Randomization may be required on or before Day -2 to allow for SoC to be 
withheld for ≥ 48 hours for patients randomized to receive ALXN1840. 
9.4. 
Technical Specifications for Derived Variables 
The following derived data will be calculated prior to analysis. The subsections below give more 
details. 
9.4.1. 
Adverse Events 
The analysis of AEs is described in detail in Section 7.3.2. 
TEAEs are events with start dates and start times on or after the date and time of the first study 
drug dose or existing events that worsened in severity after the first dose of randomized 
treatment. If the start date of an AE is partially or completely missing and the end (stop) date and 
time of the AE does not indicate that it occurred prior to first dose, then the determination of 
treatment-emergent status will be based on the following: 


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 If the start year is after the year of the first study drug dose, then the AE is 
treatment-emergent; else, 
 If the start year is the same as the year of the first study drug dose, and 
o the start month is missing, then the AE is treatment-emergent; else if 
o the start month is present and is the same or after the month of the first study drug 
dose, then the AE is treatment-emergent; else, 
 If the start date is completely missing, then the AE is treatment-emergent. 
All other AEs are considered PTAEs. 
9.4.2. 
Age 
Age will be presented as the number of years between date of birth and the reference date. The 
following age in Table 6 may be computed, with reference date indicated. 
Table 6: 
Age and Reference Date 
Age 
Reference Date 
• 
Age at Enrollment 
• 
Date of signing ICF 
The following formula should be followed for calculation of age if needed: 
Age (year) = FLOOR([reference date – date of birth]/365.25*12) 
where FLOOR( ) function returns the integer part of the result. 
In cases where only the month and year are provided for a date, the day for the date will be 
imputed as 15. Missing month will be imputed as June. In cases where the day is observed but 
the month is missing, the date will be imputed as June 15. In instances when the imputed 
reference date is earlier than the birth date, the birth date will be used as the reference date. 
9.4.3. 
Analysis Relative Day 
Analysis relative day is the day relative to the first dosing day. It will be calculated as: analysis 
date – first dose date + 1 if analysis date is after the first dose date, or else as: first dose date – 
analysis date. 
9.4.4. 
Baseline Value 
The baseline is defined as the last non-missing value collected on or prior to first dose. 
9.4.5. 
Body Mass Index (BMI) 
BMI is derived as follows: weight (kg) / [height (cm) / 100]2 
9.4.6. 
Change from Baseline 
Change from baseline will be calculated as: postbaseline assessment value – baseline assessment 
value when both values are not missing. 
Percent change from baseline is calculated as (change from baseline/baseline result * 100). 


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If either the baseline or the postbaseline result is missing, the change from baseline and/or 
percentage change from baseline is set to missing. Additionally, if the baseline is 0, the 
percentage change will be missing. 
9.4.7. 
Medications and Therapies 
Concomitant medications/therapies are any events with administration dates and times on or after 
the date and time of the first study drug dose. If the start date of a medication or therapy is 
partially or completely missing and the end (stop) date and time of the medication/therapy does 
not indicate that it occurred prior to first dose, then the determination of concomitant status will 
be based on the following: 
If the start year is after the year of the first study drug dose, then the medication/therapy is 
concomitant; else, if the start year is the same as the year of the first study drug dose and the start 
month is missing, then the medication/therapy is concomitant; else if the start month is present 
and is the same or after the month of the first study drug dose, then the medication/therapy is 
concomitant; else, if the start date is completely missing, then the medication/therapy is 
concomitant. 
All other medications/therapies are considered prior medications/therapies and could occur from 
the 30 days prior to informed consent up through the Screening Period and prior to the first dose. 
9.4.8. 
UWDRS 
As described in Section 5.1.2.1, UWDRS has 3 subscores. The algorithms for calculating the 
subscores are given below. The UWDRS total score will be the sum of the 3 subscores. 
UWDRS I: Consciousness; Maximum score of 3 
 Set to Question 1, range 0 to 3 
UWDRS Part II total score: Disability; Maximum score of 40 
 Calculate the sum of Question 2 to Question 11, each question has range 0 to 4 
 If all 10 items are populated, the subscore will be the sum calculated above. If 8 or 9 
items are populated, prorate the score by dividing by the number of answered items and 
multiplying by 10. This is done in order to estimate the value the patient could have 
achieved if they had answered all the questions. If less than 8 items are populated, score 
won’t be derived. 
o Eg, Patient has answered 8 of 10 questions and the total of their answered 
questions is 23. The pro-rated score will then be calculated as: 23/8*10=28.75 
UWDRS Part III total score: Neurological Status; Maximum score of 175 
 Calculate the following new scores for Questions 12 to 34: 
o Question 12: range 0 to 4 
Set to Q12A 
o Question 13: range 0 to 6 


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If Q13=0 then set to 0;  
else if Q13=1 then do; 
if Q13A>2 then set to Q13A  
else set to Q13A+Q13B 
end; 
o Question 14: range 0 to 1 
Set to Question 14  
o Question 15: range 0 to 16 
Set to Q15A+Q15B+Q15C+Q15D 
o Question 16: range 0 to 4 
Set to Q16 
o Question 17: range 0 to 20 
Set to Q17A+Q17B+Q17C+Q17D+Q17E 
o Question 18: range 0 to 8 
Set to Q18A+Q18B 
o Question 19: range 0 to 8 
Set to Q19A+Q19B 
o Question 20: range 0 to 4 
Set to Q20 
o Question 21: range 0 to 16 
Set to Q21A1+Q21A2+Q21B1+Q21B2 
o Question 22: range 0 to 8 
Set to Q22A+Q22B 
o Question 23: range 0 to 8 
Set to Q23A+Q23B 
o Question 24: range 0 to 8 
Set to Q24A+Q24B 
o Question 25: range 0 to 4 
Set to Q25 
o Question 26: range 0 to 8 
Set to Q26A+Q26B 
o Question 27: range 0 to 4 


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Set to Q27 
o Question 28: range 0 to 10 
If Q28=0 then set to 0;  
else if Q28=1 then do; 
if Q28A>2 then set to Q28A 
else set to Q28A+Q28B+QS28C 
end; 
o Question 29: range 0 to 10 
If Q29=0 then set to 0; 
else if Q29=1 then do; 
if Q29A1+Q29A2>2 then set to Q29A1+Q29A2  
else set to Q29A1+Q29A2+Q29B+Q29C 
end; 
o Question 30: range 0 to 24 
Set to Q30A+Q30B+Q30C+Q30D+Q30E+Q30F 
o Question 31: range 0 to 1 
Set to Q31 
o Question 32: range 0 to 1 
Set to Q32 
o Question 33: range 0 to 1 
Set to Q33 
o Question 34: range 0 to 1 
Set to Q34 
 Add up the newly calculated scores for Questions 12 to 34. If all 23 items are completely 
populated, the subscore will be that sum. If 20 to 22 items are fully populated, then 
calculate the maximum score of the answered items. Next, divide the sum of the 
responses to Questions 12 to 34 by the maximum score and multiply by 175 to obtain the 
subscore. This is done in order to estimate the value the patient could have achieved if 
they had answered all the questions. If less than 20 items are fully populated, then do not 
derive. If part of a multi-component question is answered, the maximum score of the 
answered components will be used to derive the subscore. However, partially answered 
questions will not be considered as fully populated (and therefore will be viewed as a null 
response) when counting the number of fully answered questions in order to obtain a 
minimum of 20 fully answered questions. The exception to this latter rule is for 
Questions 13, 28 and 29. If the > 2 condition is met with populated components, the 
question is considered to be fully populated regardless if the unused components are null. 
o Eg, Patient has responded to 21 questions and left Questions 21 and 22 null. The 
total of their responses to the answered questions is 97 and the maximum score of 


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the answered questions is 151. The pro-rated score will then be calculated as: 
97/151*175=112.41721854. 
o Eg, Patient has responded to 22 questions and part of Question 17 so they will be 
considered as answering 22 questions. The total of their response to the answered 
questions is 111 and the maximum score of the answered questions and answered 
components (including any partially answered questions) is 167. The pro-rated 
score will then be calculated as 111/167*175=116.317365.  
UWDRS Part II-FDA Suggested Scoring: UWDRS Part II consists of mobility, falling, 
transfer, salivation, swallowing, feeding, dressing, grooming, taking a bath or shower, and toilet 
use. These items will be rescaled to 0- 3 scale which 0 is corresponding to original score of 0 and 
1; 1 is corresponding to original score of 2; 2 is corresponding to original score of 3; and 3 is 
corresponding of original score of 4. The total UWDRS Part II-FDA suggested scoring will be 
the sum of these 10 items. 
UWDRS Part III Individual Items-Original Scoring: For items: speech, handwriting, and 
arising from chair, original scores are 0-4 scale as in the Unified Wilson’s Disease Rating Scale. 
For gait, the original score is 0-10 by summing of Part A, B, and C. 
UWDRS Part III Individual Items-Transformed Original Scoring: For gait, four sections 
(Part A Right, Part A Left, Part B, and Part C) from three sub-questions will be used to generate 
one single score which ranges from 0 to 4. Score is 0 if response to UWDRS Q29 is ‘normal’. 
The score will be the maximum score of four sections of Q29 if response is ‘not normal’.  
UWDRS Part III Individual Items - Standardized Transformed Scoring: For gait, the 
standardized transformed scores are generated by dividing the transformed original scores by 4 
and then multiplying by 10 with a range of 0 to 10. 
UWDRS Part III Individual Items-FDA Suggested Scoring: UWDRS Part III following items 
will be rescaled per FDA suggestion: 
For items: speech, handwriting, and arising from chair, score will be rescaled to 0-3 scale in 
which 0 is corresponding to original score of 0, and 1; 1 is corresponding to original score of 2; 2 
is corresponding to original score of 3; and 3 is corresponding of original score of 4. 
For gait-FDA suggested scoring, the transformed original score will be rescaled to 0-3 scale in 
which 0 is corresponding to transformed original score of 0, and 1; 1 is corresponding to 
transformed original score of 2; 2 is corresponding to transformed original score of 3; and 3 is 
corresponding of transformed original score of 4. 
UWDRS Part III Functional Subscale: UWDRS Part III Functional Subscale consists of 
speech, handwriting, arising from chair, and gait from UWDRS Part III. As described above, the 
standardized score of the first 3 items ranges from 0 to 10, and standardized transformed score of 
gait ranges from 0 to 10. The average of these scores will be used to create the Part III Functional 
Subscale with a range of 0-10. 
The subscale score and test statistic for evaluating the significance of the treatment effect will be 
derived using the global test for multiple endpoints (O’Brien, 1984; Tamhane, 2009). This test 
relies on pooling the evidence of effectiveness across the 4 items and will be employed for 
assessing the evidence to support the global alternative hypothesis that ALXN1840 is uniformly 


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better than SoC in the mean changes in the 4 scores defined above (treated as a single 
instrument). 
The following notation will be used to define the global test for the UWDRS Part III Functional 
Subscale. Let 𝜇𝑖 and 𝑡𝑖 denote the model-based treatment effect, and the test statistic, 
respectively, for evaluating the treatment difference on the 𝑖th item, 𝑖= 1, … ,4, respectively. The 
pairwise correlation between the change from baseline in the 𝑖th item and 𝑗th item will be 
denoted by 𝜌𝑖𝑗, 𝑖= 1, … ,4, 𝑗= 1, … ,4. The pairwise correlations will be estimated at the time of 
the final analysis. Lastly, 𝑛1 and 𝑛2 will denote the sample sizes in the 2 study arms. The global 
test statistic is given by: 
𝑡= ∑
𝑡𝑖
4
𝑖=1
/√∑
∑
𝜌𝑖𝑗
4
𝑗=1
4
𝑖=1
. 
Under the global null hypothesis of no effect on any of the 4 items, the test statistic follows a 𝑡 
distribution with (1 + 1/16)(𝑛1 + 𝑛2 −2)/2 degrees of freedom. The mean treatment 
difference for the UWDRS Part III Functional Subscale is given by: 
𝜇= ∑
𝜇𝑖
4
𝑖=1
/√∑
∑
𝜌𝑖𝑗
4
𝑗=1
4
𝑖=1
. 
UWDRS Part III Functional Subscale-FDA Suggested Scoring: UWDRS Part III following 
items will be rescaled per FDA suggestion: 
For items: speech, handwriting, and arising from chair, score will be rescaled to 0-3 scale in 
which 0 is corresponding to original score of 0, and 1; 1 is corresponding to original score of 2; 2 
is corresponding to original score of 3; and 3 is corresponding of original score of 4.  
For gait-FDA suggested scoring, the transformed original score will be rescaled to 0-3 scale in 
which 0 is corresponding to transformed original score of 0, and 1; 1 is corresponding to 
transformed original score of 2; 2 is corresponding to transformed original score of 3; and 3 is 
corresponding of transformed original score of 4. 
These items will be standardized to create a value between 0 to 10, and the average of these 
scores will be used to create the Part III Functional Subscale. 
UWDRS ADL Subgroup at Baseline: Patients can be classified into 3 UWDRS ADL 
subgroups based on their response to UWDRS Part II questions related to ADL: mobility, 
feeding, dressing, grooming, taking a bath or shower, and toilet use. 
- No reported ADL limitation: If a patient with score of 0 for all 6 questions (original score 0-4) 
- Functionally independent: if a patient with score of 0 or 1 for all 6 questions (original score 
0-4) 
- Functionally dependent: if a patient with score of 2 or more for at least 1 of the 6 questions 
(original score 0-4) 
Responder rate at 48 weeks for UWDRS Part II and Part III: The definition of "clinically 
meaningful change" will be defined in Clinical Outcome Assessment (COA) validation 
documents. The definition will be formed using both quantitative data collected in studies 
WTX101-201 and WTX101-301 and qualitative information from WTX101-301 
patient/physician interviews. These activities require information from the WTX101-301 primary 


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analysis period to be final. Consequently, the specific numerical values for "clinically 
meaningful change" cannot be prospectively stated. 
 
9.4.9. 
Visit Windowing 
In analysis of data summarized by study visit, all data collection will be reassigned a study visit 
where data is scheduled for collection based on the actual days relative to baseline. All visits will 
be assigned a target study day; for the determination of target days, weeks will be assumed to 
have 7 days. Baseline will have a target study day of 1. Thus, Week 4 would have a target day of 
4*7+1=29. For each assessment, the postbaseline period will be divided up using the scheduled 
visit’s target days. The lower bound of each visit interval will be evaluated as the midpoint 
between the target day and the previous visit’s target day in the following manner: study day 
interval lower bound = target study day – ([target study day – last target study day]/2). If more 
than 1 value is mapped to the same scheduled visit, the closer of those values will be considered 
for summarization. Visit windows are intended to be contiguous such that all data collected at all 
postbaseline visits, whether scheduled or unscheduled, will map to 1 of the visits. 
The visit displayed on patient data listings will be reflective of the scheduled visit label as 
reported on the CRF. Study days relative to baseline will be displayed for each visit so it is 
apparent which visit the data may have been reassigned to in the summaries. 
9.5. 
Additional Details on Statistical Methods 
To maintain study integrity and minimize bias in this open label study, draft tables, listings, and 
figures will be produced with blinded treatment assignments for review prior to database lock for 
the Primary Evaluation Period. 
9.5.1 
Analysis Considerations Related to COVID-19 
On 11 Mar 2020, Coronavirus Disease 2019 (COVID-19) was declared a pandemic by the WHO. 
This section summarizes additional analysis considerations to assess the potential impact of 
COVID-19 (Meyer, 2020). Since enrollment (last patient informed consent) was completed on 
27 Feb 2020, ie, before 11 Mar 2020, the pandemic onset should have no effect on baseline 
patient characteristics. The following additional sensitivity and supplementary analyses will be 
included to assess the impact of the pandemic disruption on the trial and to address pandemic-
related data missingness. 
1. The summary of patient disposition will include COVID-19 related discontinuations and 
withdrawals. 
2. A summary of known COVID-19 exposure or diagnosis during the Primary Evaluation 
Period will be provided by treatment group using the Safety Set. 
3. A summary of COVID-19 related important protocol deviations during the Primary 
Evaluation Period will be provided. A by-patient listing of all protocol deviations will be 
provided. 
4. A summary of the number and percentage of patients who missed a study visit or had a 
modified study visit during the Primary Evaluation Period along with the reasons 


Alexion Pharmaceuticals 
US/Japan Statistical Analysis Plan 
Protocol Number: WTX101-301 dated 25 Mar 2021 (Amendment 2) 
06 Aug 2021, Version 6.0 
Proprietary and Confidential 
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(COVID-19 related/not), will be provided by treatment group and by visit using the FA 
Set and Safety Set. For patients who had a modified study visit, the method for the 
different assessments will be summarized. 
5. Alternative data collection methods required during the pandemic may introduce
additional variability. Two sensitivity analyses will be performed to assess this
possibility. Descriptive statistics for the primary and key secondary endpoints by visit
(and by randomized treatment and cohort) can be calculated with the visits split into the
categories described below. In the first sensitivity analysis, each visit for each patient will
be categorized as either “collected as planned”, or “modified”. In the second sensitivity
analysis, each visit for each patient will be categorized as either “prepandemic”
(occurring before 11 Mar 2020), or “during pandemic”.
6. Missing data on the primary endpoint due to any COVD-19 related reasons will be
handled as described in Section 7.2.1.1 “Handling of Dropouts or Missing Data”, where
sensitivity analyses assuming missing at random, as well as missing not at random, will
be performed.