A Phase 2, Open-label Study to Assess Copper and Molybdenum Balance in Participants With Wilson Disease Treated With ALXN1840
Phase: PHASE2
Conditions: Wilson Disease
Sponsor: Alexion Pharmaceuticals, Inc.

Protocol Amendment 3.1 (US) 
18 Mar 2022 
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Alexion Confidential 
TITLE PAGE 
Protocol Title: 
A Phase 2, Open-label Study to Assess Copper and Molybdenum Balance in Participants with 
Wilson Disease Treated with ALXN1840 
Protocol Number: ALXN1840-WD-204 
Amendment Number: 3.1 (US) 
Compound: ALXN1840 (bis-choline tetrathiomolybdate) 
Study Phase: 2 
Short Title: Copper and Molybdenum Balance in Participants with Wilson Disease Treated with 
ALXN1840 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address: 
121 Seaport Boulevard 
Boston, MA 02210 
USA 
Regulatory Agency Identifier Number(s) 
EudraCT: 2020-001104-41 
IND: 119006 
Approval Date: 
Original Protocol 
12 May 2020 
Amendment 1 
18 Aug 2020 
Amendment 2 
19 Mar 2021 
Amendment 3 
31 Aug 2021 
Amendment 3.1 (US) 
18 Mar 2022 
Sponsor Signatory: 
 
 
Date 
Medical Monitor Name and Contact Information can be found in the Study Contact List. 
ALXN1840-WD-204 
NCT #: NCT04573309

Protocol Amendment 3.1 (US) 
 
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INVESTIGATOR’S AGREEMENT 
I have read the study protocol amendment 3.1 and agree to conduct the study in accordance with 
this protocol, all applicable government regulations, the principles of the ICH E6 Guidelines for 
Good Clinical Practice, and the principles of the World Medical Association Declaration of 
Helsinki. I also agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
 
____________________________________ 
Printed Name of Investigator 
 
_____________________________________ 
Signature of Investigator 
 
_______________ 
Date 
 

Protocol Amendment 3.1 (US) 
 
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Alexion Confidential 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Amendment 3.1 (US), 18 Mar 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union, the 
US Food and Drug Administration’s (FDA) regulation at 21 CFR part 312.30(b), and any 
applicable local regulations. 
Overall Rationale for the Amendment 
The main reason for preparation of this amendment was to clarify study procedures occurring 
across different sites in the US, so as to facilitate participant recruitment across different regions 
of the US, and to lessen inconvenience for participants without compromising the quality of the 
study. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or 
Clarifications 
Section 1.3 Schedule of 
Activities (SoA), Table 1 
Addition of text to the footnote to state that 
procedures specific to screening sites (only 
in the US) detailed in Section 8 
As per Section 8 (below). 
4.2 Scientific Rationale for 
Study Design 
Number of days changed from 30 days to 21 
days in the following sentence: 
• However, the physiologic turnover of 
human gastrointestinal epithelial cells is 3 
- 5 days (Darwich, 2014); therefore, the 
inhibitory effect of zinc on intestinal 
copper absorption is expected to be 
minimal 30 21 days after discontinuation 
of zinc. 
To align the number of days 
with the mention of zinc 
discontinuation elsewhere in the 
protocol. 
Section 8 Study Assessments 
and Procedures 
Addition of text applicable only to the US 
that details the possibility for sites in the US 
to only perform screening procedures and not 
any of the remaining study procedures.  
To facilitate participant 
recruitment across different 
regions of the US and to lessen 
inconvenience for participants 
without compromising the 
quality of the study. 
 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................8 
1. 
PROTOCOL SUMMARY............................................................................................9 
1.1. 
Synopsis ........................................................................................................................9 
1.2. 
Schema ........................................................................................................................13 
1.3. 
Schedule of Activities (SoA) ......................................................................................14 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Study Rationale ...........................................................................................................18 
2.2. 
Background .................................................................................................................19 
2.3. 
Benefit-Risk Assessment ............................................................................................20 
2.3.1. 
Risk Assessment .........................................................................................................20 
2.3.1.1. 
Coronavirus (SARS-CoV-2) Disease 2019 ................................................................21 
2.3.2. 
Benefit Assessment .....................................................................................................22 
2.3.3. 
Overall Benefit-Risk Conclusion ................................................................................22 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
4. 
STUDY DESIGN .......................................................................................................25 
4.1. 
Overall Design ............................................................................................................25 
4.2. 
Scientific Rationale for Study Design ........................................................................27 
4.2.1. 
Participant Input into Design ......................................................................................29 
4.3. 
Justification for Dose ..................................................................................................29 
4.4. 
End of Study Definition ..............................................................................................30 
5. 
STUDY POPULATION .............................................................................................31 
5.1. 
Inclusion Criteria ........................................................................................................31 
5.2. 
Exclusion Criteria .......................................................................................................32 
5.3. 
Lifestyle Considerations .............................................................................................33 
5.4. 
Screen Failures............................................................................................................35 
6. 
STUDY INTERVENTION ........................................................................................36 

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6.1. 
Study Intervention(s) Administered ...........................................................................36 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................36 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................37 
6.4. 
Study Intervention Compliance ..................................................................................37 
6.5. 
Concomitant Therapy .................................................................................................37 
6.5.1. 
Allowed Medicine and Therapy .................................................................................38 
6.5.2. 
Disallowed Medicine and Therapy .............................................................................38 
6.6. 
Dose Modification ......................................................................................................38 
6.7. 
Intervention After the End of the Study .....................................................................41 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................42 
7.1. 
Discontinuation of Study Intervention........................................................................42 
7.2. 
Participant Discontinuation/Withdrawal From the Study ...........................................42 
7.3. 
Lost to Follow-up .......................................................................................................43 
8. 
STUDY ASSESSMENTS AND PROCEDURES......................................................44 
8.1. 
Efficacy Assessments .................................................................................................44 
8.1.1. 
Copper and Molybdenum Balance Measurements .....................................................44 
8.1.1.1. 
Food and Fluid Collection for Copper and Molybdenum Concentrations .................44 
8.1.1.2. 
Urine Collection for Measurement of Copper and Molybdenum content ..................45 
8.1.1.3. 
Fecal Collection for Measurement of Copper and Molybdenum Content .................45 
8.2. 
Safety Assessments .....................................................................................................45 
8.2.1. 
Physical Examinations ................................................................................................45 
8.2.2. 
Vital Signs ..................................................................................................................45 
8.2.3. 
Electrocardiograms .....................................................................................................46 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................46 
8.2.4.1. 
Bowel and Urine Monitoring ......................................................................................47 
8.2.4.2. 
Intake Monitoring .......................................................................................................47 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................47 
8.2.6. 
Pregnancy ...................................................................................................................47 
8.3. 
Adverse Events and Serious Adverse Events .............................................................47 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................48 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................48 
8.3.3. 
Follow-up of AEs and SAEs.......................................................................................48 

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8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................48 
8.3.5. 
Adverse Events of Special Interest .............................................................................49 
8.3.6. 
Retained and Biobanked Sample ................................................................................49 
8.4. 
Treatment of Overdose ...............................................................................................49 
8.5. 
Pharmacokinetics ........................................................................................................49 
8.6. 
Pharmacodynamics .....................................................................................................50 
8.7. 
Genetics ......................................................................................................................50 
8.8. 
Biomarkers ..................................................................................................................50 
8.9. 
Immunogenicity Assessments ....................................................................................50 
8.10. 
Health Economics Data and/or Medical Resource Utilization ...................................50 
9. 
STATISTICAL CONSIDERATIONS .......................................................................51 
9.1. 
Statistical Hypotheses .................................................................................................51 
9.1.1. 
Primary Hypothesis ....................................................................................................51 
9.2. 
Sample Size Determination ........................................................................................51 
9.3. 
Populations for Analyses ............................................................................................51 
9.4. 
Statistical Analyses .....................................................................................................51 
9.4.1. 
Primary Analysis ........................................................................................................51 
9.4.2. 
Secondary Analyses ....................................................................................................52 
9.4.3. 
Safety Analysis ...........................................................................................................52 
9.4.4. 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses ................................53 
9.5. 
Interim Analyses .........................................................................................................54 
9.6. 
Data Monitoring Committee .......................................................................................54 
9.7. 
Safety Review Committee (SRC) ...............................................................................54 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................55 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................55 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................55 
10.1.2. 
Financial Disclosure ...................................................................................................55 
10.1.3. 
Informed Consent Process ..........................................................................................56 
10.1.4. 
Data Protection ...........................................................................................................56 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................57 
10.1.6. 
Data Quality Assurance ..............................................................................................57 
10.1.7. 
Source Documents ......................................................................................................57 

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10.1.8. 
Study and Site Start and Closure ................................................................................58 
10.1.9. 
Publication Policy .......................................................................................................58 
10.2. 
Clinical Laboratory Tests ...........................................................................................59 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................61 
10.3.1. 
Definition of AE .........................................................................................................61 
10.3.2. 
Definition of SAE .......................................................................................................62 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................62 
10.3.4. 
Reporting of SAEs ......................................................................................................64 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................65 
10.4.1. 
Definitions and Contraceptive Guidance ....................................................................65 
10.4.2. 
Collection of Pregnancy Information .........................................................................66 
10.5. 
COVID-19 Vaccine Risk Assessment ........................................................................67 
10.6. 
Abbreviations ..............................................................................................................68 
10.7. 
Protocol Amendment History .....................................................................................70 
11. 
REFERENCES ...........................................................................................................73 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................14 
Table 2: 
Schedule of Pharmacokinetic and Pharmacodynamic Assessments on 
Days 1, 25, 29, and 39 ................................................................................................17 
Table 3: 
Potential Risks and Mitigation Strategy .....................................................................21 
Table 4.  
Adaptive Protocol Features.........................................................................................27 
Table 5: 
Participant Lifestyle Considerations ...........................................................................34 
Table 6: 
Study Intervention Dosage and Mode of Administration ...........................................36 
Table 7: 
ALXN1840 Dose Modifications for Individual Participants......................................39 
Table 8: 
Populations for Analysis .............................................................................................51 
Table 9: 
Protocol-Required Safety Laboratory Assessments ...................................................60 
Table 10: Potential Risks and Mitigation Measures due to COVID-19 Vaccine .......................67 
Table 11: List of Abbreviations and Definitions of Terms .........................................................68 
 

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LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................13 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 2, Open-label Study to Assess Copper and Molybdenum Balance in 
Participants with Wilson Disease Treated with ALXN1840 
Short Title: Copper and Molybdenum Balance in Participants with Wilson Disease Treated with 
ALXN1840 
Rationale: 
The principal aim of this exploratory study is to investigate the effects of ALXN1840 on copper 
balance in participants with Wilson disease (WD). The study will specifically evaluate the effects 
of 2 different ALXN1840 doses as well as the duration of treatment on copper balance to further 
elucidate the dose response of “decoppering” versus “maintenance” dose in participants with 
WD. 
The secondary aim of the study is to characterize the steady-state absorption, distribution, 
metabolism, and excretion (ADME; mass balance) of total molybdenum which is a surrogate 
measure of ALXN1840 disposition in participants with WD. 
ALXN1840 contains the active anion tetrathiomolybdate and has been shown to cause negative 
copper balance when administered to healthy animals as well as decopper the liver in animal 
models of WD. In Study WTX101-201, which assessed the safety and efficacy of ALXN1840 in 
participants with WD, ALXN1840 demonstrated enhanced copper control as measured by 
reduced plasma non-ceruloplasmin-bound copper (NCC) corrected (NCCcorrected) for the stable 
tetrathiomolybdate- copper -albumin tripartite complex (TPC). 
Depletion of copper by ALXN1840 has been shown to occur primarily through fecal elimination 
in both healthy and WD animal models. In this study, copper balance will be calculated as the 
difference between measured copper input in food and drink and measured copper output in 
urine and feces. This method is classically considered the most objective measure of decoppering 
ability with a decoppering agent able to drive a net negative copper balance. 
As part of the secondary objective, to confirm that ALXN1840 steady state is adequately 
characterized by the plasma pharmacokinetics (PK), a molybdenum mass balance assessment 
will be performed at predicted steady state for the 15 mg/day and 30 mg/day doses: if steady 
state is achieved, molybdenum(out) will equal molybdenum(in). This approach may also detect 
potential accumulation in the liver or other tissues of participants with WD.  
 

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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Assess net copper balance with daily repeat-dose 
ALXN1840 treatment (15 mg and 30 mg) in 
participants with Wilson disease (WD) 
Mean daily copper balance where copper balance is 
measured by the calculated difference between copper 
intake (in food and drink) and copper output (in feces and 
urine) during ALXN1840 accumulation and steady-state 
periods for each dose 
Secondary 
Assess change in copper balance in response to 
ALXN1840 15 mg/day and 30 mg/day during 
ALXN1840 accumulation and at steady state 
periods versus the pretreatment baseline in 
participants with WD 
Change in mean daily copper balance as measured by the 
calculated difference between copper intake (in food and 
drink) and copper output (in feces and urine) from 
pretreatment baseline (Days -4 through -1) and 
ALXN1840 accumulation and steady-state periods for 
each dose 
Investigate the effect of ALXN1840 (15 mg/day 
and 30 mg/day) on the disposition of copper in 
participants with WD  
Copper quantified in food, drink, feces, and urine, 
including plasma total and labile bound copper (LBC) 
during ALXN1840 accumulation and steady-state periods 
for each dose 
Investigate the effect of ALXN1840 on the 
disposition of molybdenum at steady state at 15 
mg/day and 30 mg/day in participants with WD 
Molybdenum quantified in food, drink, feces, and urine, 
plasma total molybdenum at ALXN1840 steady state 
Assess steady-state total molybdenum balance as a 
measure of ALXN1840 15 mg/day and 30 mg/day 
in participants with WD 
Mean daily molybdenum balance as demonstrated through 
measurement of molybdenum intake (in food, drink and 
ALXN1840), and molybdenum output (feces and urine) 
representing ALXN1840 steady state 
Assess accumulation of molybdenum with 
ALXN1840 treatment at 15 mg/day and 30 mg/day 
in participants with WD 
Accumulation of molybdenum as determined by 
molybdenum balance 
Determine the steady-state plasma pharmacokinetic 
(PK) of total molybdenum and plasma ultrafiltrate 
(PUF) molybdenum (as surrogate measures of 
ALXN1840, 15 mg and 30 mg) in participants with 
WD 
PK parameters for plasma total and PUF-molybdenum 
Safety 
Evaluate the safety and tolerability of repeated-dose 
administration of ALXN1840 15 mg/day and 30 
mg/day in participants with WD 
Safety parameters: 
• Treatment emergent adverse events (TEAEs)/serious 
adverse events (SAEs) 
• Clinical laboratory assessments (serum chemistry, 
hematology, coagulation, and urinalysis) 
• Physical examinations 
• Heart rate, intervals (PR, QRS, QT and QTc), and 
clinically significant electrocardiogram (ECG) 
findings as determined by triplicate 12-lead ECG 
• Vital sign assessments (blood pressure and heart rate) 
Exploratory 
Determine dose response of ALXN1840 15 mg/day 
and 30 mg/day for copper balance in participants 
with WD 
Assess dose response of ALXN1840 on copper balance 
focusing on copper balance 
Determine the effect of treatment duration on 
copper balance in participants with WD 
Determine the effect of time following initiation of 
ALXN1840 treatment on copper balance 
Assess the effects of ALXN1840 on ceruloplasmin, 
ceruloplasmin-bound copper LBC profiles in 
plasma in participants with WD 
Ceruloplasmin, ceruloplasmin-bound copper, and LBC: 
Change in ceruloplasmin at Days 1, 8, 25, 29, 36, and Day 
39 compared with predose 

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Objectives 
Endpoints 
Assess dose proportionality at steady state of doses 
of ALXN1840 15 mg/day and 30 mg/day in 
participants with WD 
Based on PK parameters 
Assess effects ALXN1840 on copper:molybdenum 
ratio in plasma at steady state in participants with 
WD 
Measure plasma copper:molybdenum ratios at steady state 
compared with predose 
Assess the effects of repeat-dose ALXN1840 on 
copper:molybdenum ratio in urine and feces in 
participants with WD 
Mean daily copper:molybdenum ratio in urine and feces at 
steady state compared with predose baseline 
Note: The accumulation period refers to time from initiation of ALXN1840 (Day 1) to expected steady state at Day 
10, based on 5 times the half-life of 2 days.   
Overall Design 
This is a single-arm, open-label, repeat-dose study to evaluate the effects of ALXN1840 
administration on copper balance in participants with WD. The safety and tolerability of 
ALXN1840 in participants with WD will also be assessed. ALXN1840 PK in plasma as 
measured via total molybdenum and plasma ultrafiltrate (PUF) molybdenum will be determined 
after repeated dosing along with total molybdenum mass balance at steady state. 
Disclosure Statement: This is an open-label, 3-period study with 1 arm. 
Number of Participants: 
The sample size will be approximately 10 participants which will allow a general 
characterization of copper balance in response to ALXN1840. 
Note: “Enrolled” means all participants who sign the informed consent form (ICF), are eligible 
for the study, and are registered on Day -7 when participants are assigned a participant number. 
Intervention Groups and Duration: 
Treatment-experienced (which includes standard of care therapies or ALXN1840) and 
treatment-naïve participants are eligible for this study. Following screening and enrollment, 
participants will have a Run-in Period to support diet equilibration (Day -7 through Day -5) and 
measurement of pretreatment copper and molybdenum balance (Day -4 through Day -1). 
Following the Run-in Period, participants will be administered ALXN1840 at 15 mg/day for a 
treatment period of approximately 28 days followed by titration up to 30 mg/day on Day 29. 
Before titration to 30 mg/day, the Safety Review Committee (SRC) will review available safety 
data through Day 23 for each participant. 
Participants will have intake and output collection periods from Day -4 through Day -1, from 
Day 1 through Day 8 (initial 15 mg/day collection period), and Day 25 through Day 39. The 
collection periods will support an assessment of both copper and molybdenum balance (as a 
measure of ALXN1840 ADME) at the 15 mg/day and 30 mg/day doses and will allow 
assessment of the effects of duration of treatment on copper elimination and copper balance. 
Participants may be discharged from the clinical research unit (CRU) on Day 9 to return on Day 
22 or Day 23 (predose); all procedures will start on Day 23. To ensure flexibility, the Outpatient 
Period during Treatment Period 1 may be extended up to an additional 14 days with Investigator 
approval. In this situation, participants will be given additional investigational product to support 
daily dosing throughout the Outpatient Period. In such cases, the actual Outpatient Period 

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duration will be recorded and the participant will continue Inpatient Period 2 at Day 23. During 
the Outpatient Period, participants will use SMS text messaging to confirm study intervention 
administration. At the CRU’s discretion, participants may remain in the CRU during the 
outpatient period for safety or to maintain the integrity of the conduct of the study.  
Safety Review Committee: 
A Safety Review Committee (SRC), composed of a minimum of the Investigator, Alexion 
Medical Monitor, and Alexion Safety Physician, will meet at the end of 15 mg/day dosing to 
confirm proceeding to 30 mg/day and as necessary based on any emerging safety concerns.

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1.2. 
Schema 
Figure 1: 
Study Schematic 
 
 
1. Participants eligible for the study will be enrolled on Day -7 and initiated on a copper- and molybdenum-
controlled diet, which will be continued during Treatment Period 1 and Treatment Period 2 when in the CRU, 
through Day 39. 
2. Participants will be admitted to the CRU for Treatment Period 1 on Day -8 and may be discharged on Day 9 
or remain in the CRU for their own safety or to maintain the integrity of the conduct of the study. Participants 
who are discharged will be re-admitted on Day 22 or Day 23 for Treatment Period 2 and will remain in house 
until Day 40. To ensure flexibility, the Outpatient Period may be extended up to an additional 14 days with 
Investigator approval. In this situation, participants will be given additional investigational product to support 
daily dosing throughout the Outpatient Period. In such cases, the actual Outpatient Period duration will be 
recorded and the participant will continue Inpatient Period 2 at Day 23.  
3. Participants will be administered ALXN1840 at a dose of 15 mg/day on Day 1 through Day 28 and then 
increase to 30 mg/day on Day 29 through Day 39. During the Outpatient Period, participants will use SMS 
text messaging to confirm study intervention administration. 
4. Participants will have 3 intake and output collection periods including: 
• 
Baseline Day -4 through Day -1 
• 
Day 1 through Day 8 (I/O for 15 mg) 
• 
Day 25 through Day 39 (Days 25 through 28, I/O for 15 mg; Days 29 through 39, I/O for 30 mg) 
5. During these periods all intake (including food and drink) and output (including urine and feces) will be 
collected and assessed for copper and molybdenum.  
6. Blood sampling for PK/PD will be as follows: 
• 
PK/PD collection (24-hour): Days 1, 25, 29, and 39 
• 
Predose PK/PD sampling days: Days 4 - 7, Days 26 - 28, Days 30 - 38 
• 
End of Study Visit Day 54 +/- 2 days  
Abbreviations: AP = accumulation period; CRU = clinical research unit; EOS = End of Study; I/O = input/output; 
PD = pharmacodynamic; PK = pharmacokinetic; SS = steady state. 
 

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1.3. 
Schedule of Activities (SoA) 
Table 1: 
Schedule of Activities 
 
Screeninga C-Ib 
 
UNSd EOS or ETe 
Study Procedures  
Screening 
C-I 
Inpatient Period 1 
OPc 
 
Inpatient Period 2 
 
 
Days 
-42 to 
-9 
-21 
-8 
-7 -6 through 
-5 
-4 through 
-1 
1 2-3 4-7 8 9 10-22 23 24 25 26-28 29 30-35 36 37-38 39 40 
 
EOS 
Day 54+/-2 
Eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to unit 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge from unitf 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Outpatient visit or phone call 
 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion  
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discuss/document 
contraception 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Follicle-stimulating hormone 
(post-menopausal females 
onlyh) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/demographicsi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WD historyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior WD treatmentj 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationk 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Heightl, weight, and BMI  
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment/inclusion 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discontinue chelation therapy 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discontinue zinc therapy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of Study 
Interventionm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALXN1840 15 mg/day 
 
 
 
 
 
 
X X 
X X X 
X 
X 
X X 
X 
 
 
 
 
 
 
 
 
ALXN1840 30 mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Study intervention compliance 
 
 
 
 
 
 
 
 
 
 
 
Xn 
X 
 
 
 
 
 
 
 
 
 
 
 
PK/PD Analyseso 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PK: Plasma 
total Mo and PUF-Mo 
 
 
 
 
 
 
Xp  
X 
 
 
 
 
 
Xp 
X 
Xp 
X 
X 
X 
Xp 
X 
 
 

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Screeninga C-Ib 
 
UNSd EOS or ETe 
Study Procedures  
Screening 
C-I 
Inpatient Period 1 
OPc 
 
Inpatient Period 2 
 
 
Days 
-42 to 
-9 
-21 
-8 
-7 -6 through 
-5 
-4 through 
-1 
1 2-3 4-7 8 9 10-22 23 24 25 26-28 29 30-35 36 37-38 39 40 
 
EOS 
Day 54+/-2 
PD: Plasma total and PUF-Cu, 
LBC, ceruloplasmin, 
ceruloplasmin-bound Cu 
Safety Assessments / 
Laboratory Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistryq, hematology, 
Coagulation 
X 
 
X 
 
 
Xr 
 
 
 
X 
 
Xg 
X 
 
 
Xr 
 
X 
 
 
 
X 
 
X 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
X 
 
Xg 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
Urine/serum pregnancy tests 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Retained serum sample (safety)t 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals sign measurementsu  
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
12-lead ECG (triplicate) 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Adverse events 
X 
 
X 
X 
X 
X 
X X 
X X X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Balance assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cu/Mo-controlled mealsv 
 
 
 
X 
X 
X 
X X 
X X 
 
 
X 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
Light exercise regimen 
 
 
 
X 
X 
X 
X X 
X X X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
Urination and bowel movement 
monitoring, menstruation 
checks 
 
 
 
 
 
X 
X X 
X X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
24-hour urine for Cu and Mow 
 
 
 
 
 
X 
X X 
X X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Feces for Cu and Mox 
 
 
 
 
 
X 
X X 
X X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication and 
non-pharmacologic 
therapy/procedure 
X 
 
X 
X 
X 
X 
X X 
X X X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
 
X 
a Within 42 days of ALXN1840 administration. Details of procedures that may be performed by sites designated as “screening sites” (only in the US) are 
detailed in Section 8.   
b Participants will be admitted to the clinical research unit (CRU) at least 10 hours prior to enrollment and initiation of copper- and molybdenum-controlled diet. 
c At the CRU’s discretion, participants may remain in the CRU or be readmitted on Day 22 with all procedures starting on Day 23. 
d Unscheduled study visits may occur at any time during the study and may include any study procedure as deemed necessary by the Investigator. 
e Participants are required to return to the CRU Day 54+/-2; participants will be discontinued from ALXN1840 medication by their physician at the latest by the 
Day 54 follow-up. 
f Discharge from the unit may occur after completion of all procedures on Day 9 and on Day 40 and after the Investigator has reviewed all safety assessment 
(including safety laboratory tests) and confirmed that the participant is appropriate for discharge. 
g A single outpatient visit or phone call and safety laboratory assessment should occur between Day 14 and Day 18. A phone call may take place on a different 
day than the blood draw within the Day 14 through Day 18 period.  
h If needed to confirm menopause. 

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i Parameters include age and sex. Race and ethnicity will be collected where permitted by local regulations. 
j Wilson disease history will include diagnosis date, method of diagnosis, history of cirrhosis, details of any previous liver biopsies performed, and treatment 
received. 
k A full physical examination will be performed at Screening, at check-in for the study, and at the End of the study/Early Termination Visit. A physical 
examination should also be performed on any participants with ongoing adverse events prior to discharge from the unit. Otherwise, a symptom-driven physical 
examination may be performed at other times, at the Principal Investigator’s discretion. 
l Height at screening only. 
m While in the CRU, study intervention will be administered after an overnight fast (ie, at least 10 hours) at the same time every morning; drug is to be 
administered with 240 mL of water and meals should be delayed a minimum of 2 hours after dosing. As an outpatient, participants are expected to take 
ALXN1840 at approximately the same time daily (+/-1 hour). Participants should take the medication with a glass of water on an empty stomach; meals should 
be delayed a minimum of 2 hours after dosing.  
n During the outpatient period, participants will use SMS text messaging to confirm study intervention administration. 
o Blood sampling for PK/PD will occur before ALXN1840 administration and represents a predose trough. See Table 2 for PK/PD sampling on Days 1, 25, 29, 
and 39.  
p PK/PD collection will include timepoints described in the schedule of PK/PD assessment for Days 1, 25, 29, and 39 (Table 2).  
q Samples for serum chemistry will be obtained following a fast of at least 8 hours at the Screening Visit and at check-in. In case of rechecks, and postdose serum 
chemistry, participants may not have fasted for 6 or 8 hours before the serum chemistry sample is taken. 
r Laboratory assessment including chemistry, hematology, and coagulation parameters should be performed on Days -8, -1, 8, 23, and 28 only. 
s Menstruation check is for women only; women of childbearing potential should only be enrolled after a negative serum pregnancy test result at Screening. 
Additional urine pregnancy testing will be standard for the protocol unless serum testing is required by site policies, local regulation, or Institutional Review 
Boards (IRBs)/Independent Ethics Committees (IECs) (Section 10.2). In addition to pregnancy tests detailed at the visits in the SoA, females of childbearing 
potential 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. 
t A single 15 mL serum sample will be retained for evaluation in the event of an unexpected safety finding; retained samples may be destroyed after completion 
of the clinical study report. 
u Vital signs measurements and ECGs should be performed predose, unless otherwise specified. Vitals signs include body temperature, heart rate, respiratory 
rate, and systolic and diastolic blood pressure. 
v Copper- and molybdenum-controlled diet will be initiated after registration/inclusion.  Participants will remain on a copper/molybdenum controlled diet 
throughout both the inpatient Period 1 (Day -8 to Day 9) and inpatient Period 2 (Day 23 to Day 40); during this time participants will be strongly encouraged to 
complete all meals. While not in the CRU, participants will be encouraged to adhere to their usual copper-controlled diet. 
w For each input/output balance period, 24-hour urine samples are to be collected for measurement of copper and molybdenum. 
x For fecal samples, each individual sample will be independently collected with record of date, time, and weight of the sample. 
Abbreviations: AE = adverse event; BMI = body mass index; C-I = check-in; Cu = copper; D = day; ECG = electrocardiogram; EOS/ET = End of Study or Early 
Termination; HIV = human immunodeficiency virus; HR = heart rate; LBC = labile bound copper; Mo = molybdenum; OP = outpatient; 
PD = pharmacodynamic; PK = pharmacokinetics; PUF = plasma ultrafiltrate; UNS = unscheduled; WD = Wilson disease. 
 

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Table 2: 
Schedule of Pharmacokinetic and Pharmacodynamic Assessments on Days 1, 
25, 29, and 39 
Time point (hours)a  
−0.5 
0 
1 
2 
3 
4 
5 
6 
8 
12 
24 
Blood sampling for PK: Plasma total Mo 
and PUF-Mo 
PD: Plasma total and PUF-Cu, LBC, 
ceruloplasmin, ceruloplasmin-bound Cu 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Xb 
Note: Windows for PK/PD time points will be defined as ±10% of the nominal time point. On Days 1 and 39, 
triplicate 12-lead ECG will be collected at 4 hours postdose. When multiple procedures are scheduled to occur at the 
same time, the following order of events should be strictly adhered to whenever possible: ECG, vital signs, blood 
sampling (eg, for PK/PD), study intervention administration, and meal. 
a Time points are relative to dosing (0 hours). 
b Hour 24 PK/PD sampling is to occur just prior to the next-day dose of ALXN1840. 
Abbreviations: Cu = copper; LBC = labile bound copper; Mo = molybdenum; PD = pharmacodynamic; 
PK = pharmacokinetic; PUF = plasma ultrafiltrate. 
 

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2. 
INTRODUCTION 
ALXN1840 (bis-choline tetrathiomolybdate; formerly known as WTX101) is a novel copper 
binding agent in development for the treatment of WD.  
2.1. 
Study Rationale 
The principal aim of this exploratory study is to investigate the effects of ALXN1840 on copper 
balance in participants with WD. The study will specifically evaluate the effects of 2 different 
ALXN1840 dose levels as well as the duration of treatment on copper balance to further 
elucidate the dose response of “decoppering” versus “maintenance” dose in participants with 
WD. 
ALXN1840 contains the active anion tetrathiomolybdate and has been shown to cause negative 
copper balance when administered to healthy animals as well as decopper the liver in animal 
models of WD (Mills, 1981; Czachor, 2002). In Study WTX101-201, which assessed the safety 
and efficacy of ALXN1840 in participants with WD, ALXN1840 demonstrated enhanced copper 
control as measured by reduced plasma NCCcorrected for the stable tetrathiomolybdate- 
copper-albumin TPC (Weiss, 2017).  
Depletion of copper by ALXN1840 has been shown to occur primarily through fecal elimination 
in both healthy and WD animal models. Sheep injected with 30 mg/day of tetrathiomolybdate for 
5 days were shown to have an elevation of fecal copper during the treatment period increasing 
from a baseline of approximately 3 mg/day up to approximately 7 mg/day during the treatment 
period, before returning to baseline concentrations (Mason, 1988). Similarly, when Long-Evans 
Cinnamon (LEC) WD model rats were injected intraperitoneally with a saline solution of 
tetrathiomolybdate at a dose of 10 mg/kg body weight for 8 consecutive days, the amounts of 
both copper and molybdenum excreted into the feces increased significantly (Ogra, 2000), which 
may suggest that copper is excreted in a complex with tetrathiomolybdate into the feces. While 
fecal copper increases with tetrathiomolybdate, the amount of copper excreted into the urine 
decreased and that of molybdenum increased significantly during treatment with 
tetrathiomolybdate. Molybdenum in the urine was molybdate which does not bind copper (data 
on file). These findings are in line with other studies showing enhanced biliary and/or fecal 
excretion of copper and molybdenum upon administration of tetrathiomolybdate in rats and 
sheep (Komatsu, 2000; Ogra, 1995; Mason, 1988). 
We hypothesize that repeated doses of ALXN1840 may drive a net negative copper balance in 
participants with WD by increasing fecal excretion of copper. In this study, copper balance will 
be calculated as the difference between measured copper input in food and drink and measured 
copper output in urine and feces. This method is classically considered the most objective 
measure of decoppering ability with a decoppering agent able to drive a net negative copper 
balance (Hill,1986; Strickland, 1971; Walshe, 1973). The purpose of this study is to provide 
additional descriptive characterization of the effect of ALXN1840 on copper balance in 
participants with WD. Further data obtained may help support characterization of a 
“decoppering” versus “maintenance” dose of ALXN1840, where a decoppering dose would be a 
dose sufficient to drive a net negative copper balance and maintenance would support a more 
neutral copper balance. 

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The secondary aim of the study is to characterize the steady-state ADME (mass balance) of total 
molybdenum as a surrogate measure of ALXN1840 disposition in participants with WD. To 
confirm that steady state is adequately characterized by the plasma PK, a molybdenum mass 
balance assessment will be performed on Day 25 through Day 28 for the 15 mg/day dose and 
Day 36 through Day 39 for the 30 mg/day dose: if steady state is achieved, molybdenum(out) 
will equal molybdenum(in). 
2.2. 
Background 
ALXN1840 has been selected for development in WD due to its improved stability properties 
over ammonium tetrathiomolybdate, which has previously been studied in participants with WD 
and other indications. Ammonium tetrathiomolybdate and bis-choline tetrathiomolybdate 
nonclinical and clinical data reported to date support the efficacy and safety of ALXN1840.  
ALXN1840 rapidly forms stable tetrathiomolybdate-copper-albumin TPCs, which stabilize free 
copper leading to a reduction in the NCC concentrations after correction for free copper bound to 
TPC (NCCcorrected). 
Studies in both healthy and WD animal models showed that treatment with tetrathiomolybdate 
results in removal of copper from the liver. Tetrathiomolybdate administered to healthy mice by 
intraperitoneal injection resulted in a dose-dependent reduction in liver copper concentration 
over a treatment range of 0 - 6 mg/kg/day (human equivalent dose [HED] by body surface area 
[BSA] scaling: 0 - 1 mg/kg/day). The results of these studies indicated that only 30% ‑ 40% of 
copper remained after 5 weeks of treatment. Similar liver decoppering (approximately 
40% - 60%) was also reported in toxic milk mice (a WD animal model) at 5 mg/kg/ day for 14 
days (HED by BSA scaling: 0.4 mg/kg/day; Mills, 1981; Czachor, 2002). In LEC WD model 
rats, 25 mg/kg/day of ALXN1840 (HED by BSA scaling: 4 mg/kg/day) administered by oral 
gavage for 10 days, resulted in an approximately 50% decrease in liver copper concentration. 
Because ALXN1840 has been shown to have a similar mechanism of action in healthy and WD 
animal models, a mechanism of action study in healthy participants is being performed 
(Study ALXN1840-HV-108) to demonstrate that ALXN1840 can result in a change from 
baseline in copper balance with repeat-dose ALXN1840 (30 mg/day) treatment. 
In the Phase 2 proof-of-concept Study WTX101-201 in participants with WD, ALXN1840 
demonstrated a sustained control of free copper as measured by NCCcorrected. Importantly, 
ALXN1840 treatment resulted in improvements in disability and neurologic symptoms as 
measured by the Unified Wilson Disease Rating Scale (UWDRS, Parts II and III) and 
stabilization of liver function (Weiss, 2017). Treatment with ALXN1840 resulted in an 
acceptable safety and tolerability profile when initiated at 15 mg daily with Investigator-driven, 
individual participant titration of dose based on safety, NCCcorrected, and symptoms.  
Following single-dose administration of 60 mg ALXN1840, total molybdenum peaked at 
approximately 4.54 hours with a terminal elimination half-life measured at approximately 
51 hours. In Study WTX101-201, the PK of ALXN1840, based on total molybdenum, indicated 
that exposure in participants with WD at a dose of 30 mg appeared consistent with previous 
results from healthy participants. The half-life was estimated to be approximately 24 hours at 
steady state on Days 84 and 168 and was shorter than estimated in previous studies. Based on a 
total molybdenum PK half-life of approximately 24 - 51 hours, total molybdenum steady state 
may conservatively be reached within approximately 10 - 12 days. Nevertheless, results (as 

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measured by total molybdenum) obtained from the ALXN1840 balance study in the LEC WD rat 
model suggested that approximately 30% of a single dose of ALXN1840 remained in the liver by 
Day 7, indicating the possibility of tissue accumulation, particularly in the setting of high liver 
copper concentration (Plitz, 2019).  
If the half-life of ALXN1840 in liver were longer than that of the systemic compartment, the 
accumulation may not be readily detected in the absence of a longer treatment period and with 
characterization of the terminal elimination period. An alternative approach to assessing steady 
state using total molybdenum PK is to assess whether the total molybdenum intake is equal to the 
total molybdenum output; this approach may detect any significant ongoing accumulation in the 
liver or other tissues. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ALXN1840 are 
provided in the Investigator’s Brochure (IB). 
2.3. 
Benefit-Risk Assessment 
Detailed information about the known and expected benefits, risks, and reasonably expected 
adverse events (AEs) of ALXN1840 are presented in the IB. Information about the known or 
potential risks and benefits are detailed in the following sections. 
2.3.1. 
Risk Assessment 
Details of the potential risks and mitigation strategy are provided in Table 3. 

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Table 3: 
Potential Risks and Mitigation Strategy 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; IB = Investigator’s Brochure; PK 
= pharmacokinetics; WD = Wilson disease.  
2.3.1.1. 
Coronavirus (SARS-CoV-2) Disease 2019 
The COVID-19 pandemic is active at the time of this protocol amendment. Given this unique 
circumstance, specific consideration has been given to the potential risks and mitigation 
measures due to COVID-19 vaccine (see Section 10.5).  
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
ALXN1840 
Dose-dependent elevations in 
transaminases (ALT and AST) 
Generally mild to moderate in 
severity, asymptomatic and 
reversible with dose adjustments 
were reported, usually after 
3 - 6 weeks of treatment. 
Results obtained from studies of 
ALXN1840 and ammonium 
tetrathiomolybdate in participants 
with WD; see the IB. 
Regular monitoring of liver 
function tests.  
Dose modification or 
discontinuation (Section 6.6). 
Anemia 
Anemia has been observed in 
participants with WD, attributed to 
overtreatment and resultant copper 
depletion; see the IB. 
Monitoring complete blood count. 
Dose modification or 
discontinuation (Section 6.6). 
Low white blood cell count 
(leukopenia, bone marrow toxicity)  
Leukopenia and bone marrow 
toxicity (myelosuppression) have 
been observed in participants with 
WD, attributed to overtreatment 
and resultant copper depletion. 
Results obtained from studies of 
ALXN1840 and ammonium 
tetrathiomolybdate in participants 
with WD; see the IB. 
Monitoring of complete blood 
count. Dose modification or 
discontinuation (Section 6.6). 
Neurological dysfunction 
Neurological worsening may occur 
due to copper mobilization. 
Peripheral neuropathy may be seen 
with over decoppering; however, 
symptoms such as 
myelosuppression is typically seen 
earlier. 
Regular monitoring for neurologic 
adverse events. Dose modification 
or discontinuation (Section 6.6). 
Study Procedures 
Risks associated with the study 
design and procedures  
Participants will undergo repeated 
blood draws to measure the PK of 
the study intervention and 
metabolism. Blood draws may 
result in ecchymosis, redness, and 
minor pain to the site. On rare 
occasion, infection or 
thrombophlebitis can occur. 
Blood draws are optimized for PK. 
A cannula may be placed to 
minimize needle sticks; however, a 
catheter may not be left in place for 
longer than 72 hours and should be 
flushed a minimum of every 
8 hours. 

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2.3.2. 
Benefit Assessment  
The main objective of effective WD treatment is to provide: 
• Rapid and sustained control of copper and mitigation of clinical symptoms of WD 
through the formation of a stable tetrathiomolybdate-copper-albumin TPC. Copper 
control may prevent tissue toxicity, including neurological deterioration that has been 
reported at the initiation of treatment with chelators. This hypothesis is supported by 
results from Study WTX101-201 in participants with WD (Weiss, 2017). 
• Improved compliance over current chelator therapy through improved tolerability and the 
convenience of a simplified dosing regimen (once daily) compared to current therapeutic 
options (multiple daily dosing). 
Potential benefits of study participation for participants include: 
• Participation in a clinical study increases the participant’s understanding of the 
pathophysiology and treatment of WD. 
• Removal of total body copper as a definitive treatment for WD. 
• Participants in the study will contribute to improved care for other participants with WD 
in the future. 
2.3.3. 
Overall Benefit-Risk Conclusion 
Taking into account the measures implemented to minimize risk to participants in this study, the 
potential risks identified in association with ALXN1840 are justified by the anticipated benefits 
that may be afforded to participants with WD. 

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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Assess net copper balance with daily repeat-dose 
ALXN1840 treatment (15 mg and 30 mg) in 
participants with Wilson disease (WD) 
Mean daily copper balance where copper balance is 
measured by the calculated difference between copper 
intake (in food and drink) and copper output (in feces and 
urine) during ALXN1840 accumulation and steady-state 
periods for each dose 
Secondary 
Assess change in copper balance in response to 
ALXN1840 15 mg/day and 30 mg/day during 
ALXN1840 accumulation and at steady state 
periods versus the pretreatment baseline in 
participants with WD 
Change in mean daily copper balance as measured by the 
calculated difference between copper intake (in food and 
drink) and copper output (in feces and urine) from 
pretreatment baseline (Days -4 through -1) and 
ALXN1840 accumulation and steady-state periods for 
each dose 
Investigate the effect of ALXN1840 (15 mg/day 
and 30 mg/day) on the disposition of copper in 
participants with WD  
Copper quantified in food, drink, feces, and urine, 
including plasma total and labile bound copper (LBC) 
during ALXN1840 accumulation and steady-state periods 
for each dose 
Investigate the effect of ALXN1840 on the 
disposition of molybdenum at steady state at 
15 mg/day and 30 mg/day in participants with WD 
Molybdenum quantified in food, drink, feces, and urine, 
plasma total molybdenum at ALXN1840 steady state 
Assess steady-state total molybdenum balance as a 
measure of ALXN1840 15 mg/day and 30 mg/day 
in participants with WD 
Mean daily molybdenum balance as demonstrated through 
measurement of molybdenum intake (in food, drink, and 
ALXN1840), and molybdenum output (feces and urine) 
representing ALXN1840 steady state 
Assess accumulation of molybdenum with 
ALXN1840 treatment at 15 mg/day and 30 mg/day 
in participants with WD 
Accumulation of molybdenum as determined by 
molybdenum balance 
Determine the steady-state plasma pharmacokinetic 
(PK) of total molybdenum and plasma ultrafiltrate 
(PUF) molybdenum (as surrogate measures of 
ALXN1840, 15 mg and 30 mg) in participants with 
WD 
PK parameters for plasma total and PUF-molybdenum 
Safety 
Evaluate the safety and tolerability of repeated-dose 
administration of ALXN1840 15 mg/day and 
30 mg/day in participants with WD 
Safety parameters: 
• Treatment emergent adverse events (TEAEs)/serious 
adverse events (SAEs) 
• Clinical laboratory assessments (serum chemistry, 
hematology, coagulation, and urinalysis) 
• Physical examinations 
• Heart rate, intervals (PR, QRS, QT and QTc), and 
clinically significant electrocardiogram (ECG) 
findings as determined by triplicate 12-lead ECG 
• Vital sign assessments (blood pressure and heart rate) 
Exploratory 
Determine dose response of ALXN1840 15 mg/day 
and 30 mg/day for copper balance in participants 
with WD 
Assess dose response of ALXN1840 on copper balance 
focusing on copper balance 
Determine the effect of treatment duration on 
copper balance in participants with WD 
Determine the effect of time following initiation of 
ALXN1840 treatment on copper balance 
Assess the effects of ALXN1840 on ceruloplasmin, 
ceruloplasmin-bound copper, LBC profiles in 
plasma in participants with WD 
Ceruloplasmin, ceruloplasmin-bound copper, and LBC: 
Change in ceruloplasmin at Days 1, 8, 25, 29, 36, and 
Day 39 compared with predose 

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Objectives 
Endpoints 
Assess dose proportionality at steady state of doses 
of ALXN1840 15 mg/day and 30 mg/day in 
participants with WD 
Based on PK parameters 
Assess effects ALXN1840 on copper:molybdenum 
ratio in plasma at steady state in participants with 
WD 
Measure plasma copper:molybdenum ratios at steady state 
compared with predose 
Assess the effects of repeat-dose ALXN1840 on 
copper:molybdenum ratio in urine and feces in 
participants with WD 
Mean daily copper:molybdenum ratio in urine and feces at 
steady state compared with predose baseline  
Note: The accumulation period refers to time from initiation of ALXN1840 (Day 1) to expected steady state at Day 
10, based on 5 times the half-life of 2 days.   
 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study will be conducted as an open-label, repeat-dose study to evaluate the effects of 
ALXN1840 on copper balance in participants with WD. 
Treatment-experienced (which includes standard of care therapies or ALXN1840) and 
treatment-naïve participants are eligible for this study. Eligible patients will be classified into one 
of two cohorts: 
• Cohort 1 (treatment experienced): Patients who have received WD therapy for > 28 days 
• Cohort 2 (treatment naïve): Patients who have received WD therapy for ≤ 28 days 
Following screening and enrollment, participants will check-in to the CRU on Day -8 for the 
Run-in Period. The purpose of the Run-in Period is to support diet equilibration (Day -7 through 
Day -5) and measure pretreatment copper and molybdenum balance (Day -4 through Day -1). 
Participants will remain on a copper/molybdenum-controlled diet throughout both the Inpatient 
Period 1 (Day -8 to Day 9) and Inpatient Period 2 (Day 23 to Day 40). While not in the CRU, 
participants will be encouraged to adhere to their usual copper-controlled diet. 
Participants who are taking copper-chelating therapies (penicillamine or trientine) at the time of 
enrollment will be discontinued from their decoppering therapies starting on Day -4 to allow a 
baseline assessment of copper/molybdenum balance prior to ALXN1840 treatment. On Day 1, 
participants will be initiated on 15 mg/day of ALXN1840 for a treatment period of 
approximately 28 days followed by titration up to 30 mg/day on Day 29. Before titration to 30 
mg/day, the SRC will review available safety data through Day 23 for each participant.   
Participants will have intake and output collection periods from Day -4 through Day -1, from 
Day 1 through Day 8, and Day 25 through Day 39. The collection periods will support an 
assessment of both copper and molybdenum balance (as a measure of ALXN1840 ADME) at the 
15 mg and 30 mg doses and will allow assessment of the effects of duration of treatment on 
copper elimination and copper balance. 
Collection periods for feces and urine will vary in duration from 3 to 15 days to support 
assessment of both copper and molybdenum balance before and at steady state for both 15 mg 
and 30 mg. Equilibration periods on copper/molybdenum-controlled diets will be a minimum of 
48 hours. Copper balance will be calculated as the mean daily copper balance over each of the 4 
collection periods. The interpretation of copper balance will be based on the criteria established 
by Hill,1986 when undertaking copper balance studies with zinc treatment. For assessment of 
ALXN1840 effect on copper balance, the time period for analysis will take into consideration the 
average bowel transit of approximately 40 hours (male: 33 hours; female: 47 hours) (Camilleri, 
1986; Metcalf, 1987). 
Throughout the inpatient periods, participants will remain on a copper-controlled diet. Meal 
portions will be weighed, and meal sizes will be appropriate to support male and female caloric 
consumption. Participants will be encouraged to complete 100% of all meals throughout the 
inpatient period to support quantification of copper and molybdenum intake. If participants are 
unable to complete the full meal, the uneaten portion will be weighed to allow calculation of 
meal fraction, and copper and molybdenum intake will be adjusted based on the fractional intake 

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of the meal. In addition to food, fluid intake and type will be measured and recorded each day. 
Samples of all meals and fluids will be sent for bioanalysis to support accurate quantification of 
copper and molybdenum in fluids. In the event that items cannot be accurately quantified, items 
may be balanced during pretreatment period and post-treatment period to support the change 
from baseline assessment. 
During the inpatient collection periods, daily urine will be pooled (24-hour collection) with 
volumes recorded for each 24-hour period; participants will be strongly encouraged to void 
within 2 hours of completion of each 24-hour period (ie, dosing time). Stool samples will be 
individually collected and each sample will include a collection date, time, and weight. 
Participants may be discharged from the CRU on Day 9 and return on Day 22 or Day 23 
(predose); all procedures will start on Day 23. To ensure flexibility, the Outpatient Period during 
Treatment Period 1 may be extended up to an additional 14 days with Investigator approval. In 
this situation, participants will be given additional investigational product to support daily dosing 
throughout the Outpatient Period. In such cases, the actual Outpatient Period duration will be 
recorded and the participant will continue Inpatient Period 2 at Day 23. During the Outpatient 
Period, participants will use SMS text messaging to confirm study intervention administration. 
At the CRU’s discretion, participants may remain in the CRU during the outpatient period for 
safety or to maintain the integrity of the conduct of the study. 
Blood sampling for PK/pharmacodynamic (PD) will occur over the 24-hour dosing period on 
Days 1, 25, 29, and 39. Predose PK samples will be collected at all time points during the intake 
and output collection period to help characterize PK during accumulation (Days 1 through 9 for 
15 mg and Days 31 through 35 for 30 mg) and at steady state (Days 25 through 28 for 15 mg and 
Days 36 through 39 for 30 mg). 
This study incorporates the use of an adaptive design. Adaptive features may be implemented at 
the discretion of the Investigator to support conduct of the study. Such adaptive features do not 
require amendment of the protocol. Adaptive features and their limits are described in Table 4. 
 
 

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Table 4.  
Adaptive Protocol Features 
Features 
Limits 
1. Outpatient Period (Day 9 to Day 23) may be 
extended up to an additional 14 days with 
Investigator approval with adequate supply of 
study intervention to support daily dosing can 
be provided, and with record of exact 
duration of Outpatient Period is recorded; 
participants will reinitiate the study on 
Day 23. 
• 
Not >14 days  
2. Participants may be checked in on Day 22 
rather than Day 23 at the Investigator 
discretion.  
• 
Check-in to clinical research unit allowed 
1 day prior  
3. In this study, dosing for ALXN1840 will be 
initiated at 15 mg once daily for a minimum 
of 4 weeks, with an increase to 30 mg after 
4 weeks, unless there are safety concerns that, 
in the opinion of the Investigator(s) and/or 
Alexion, may place participants at undue risk, 
in which case, patients may remain on the 
15 mg/day dose for the duration of the study. 
• 
Dose range limit 15 mg every other day 
to 30 mg/day 
4. The dose should be decreased or interrupted if 
any of the relevant Dose Modification criteria 
are met (Table 7). 
• 
Dose range limit 15 mg every other day 
to 30 mg/day 
 
4.2. 
Scientific Rationale for Study Design 
The study is designed as an open-label exploratory study to provide a descriptive assessment of 
copper balance in participants with WD, the target population for ALXN1840 therapy. The study 
is being conducted as a repeat-dose study to assess the effect of duration of ALXN1840 
treatment and the effects of intra-patient dose increase on copper and molybdenum balance in 
participants with WD. The intra-patient dose escalation schedule is similar to that employed in 
the current Phase 3 Study WTX101-301. The similar schedule was chosen to characterize the 
decoppering effects expected early with treatment. This study is designed to supplement the 
mechanism of action study in healthy participants (Study ALXN1840-HV-108). While healthy 
participants are expected to be adequate to assess the mechanism of action of ALXN1840, 
characterization of copper balance in the WD population will help to understand if there are 
differences in the magnitude of effect between the 2 populations as this may be important to 
understand the doses that may support a net neutral versus a net negative copper balance. 
Limited nonclinical data on copper elimination with tetrathiomolybdate suggested copper 
excretion may be at least maintained or increased with repeated dosing (refer to the current IB). 

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Therefore, the duration of the study and multiple collection periods will better characterize the 
pattern of copper elimination over time. Such information may be helpful in understanding the 
decoppering and maintenance phases.  
As the study involves intensive diet control and sampling, the study is planned to be conducted 
in a small number of participants with WD who will be admitted to a CRU for 2 inpatient 
periods. Inpatient Period 1 includes a baseline and initial 15 mg/day collection period during the 
accumulation phase followed by an Outpatient Period; Inpatient Period 2 with a second 
collection period to support analysis of copper balance at 15 mg/day steady state and a 
30 mg/day accumulation and steady state. 
During the Outpatient Period, participants will be encouraged to remain on a copper-controlled 
diet; however, to avoid confounding, a diet equilibration period is included in each study period. 
Overall, collection periods are a minimum of 3 days and as long as 15 days (which will be 
subdivided for analyses). Collection periods of at least 3 days were used to help minimize the 
impact of day-to-day variability on measurements. In addition, the time period for analysis will 
take into consideration the average bowel transit of approximately 40 hours (male: 33 hours; 
female: 47 hours) (Camilleri, 1986; Metcalf, 1987). Because the periods are of different lengths, 
the study will calculate mean daily copper balance. 
While the primary endpoint for the study is an assessment of net copper balance, measurement of 
a pretreatment copper baseline will be helpful to understand the magnitude of effect of 
ALXN1840. To assess the copper baseline during the Inpatient Run-in Period, participants will 
be discontinued from their chelator therapy for approximately 4 days prior to initiating 
ALXN1840. During this period, participants will be maintained on a copper-controlled diet to 
minimize risk to the participants. In the Phase 3 study ALXN1840-WD-301, participants 
discontinue their chelator approximately 48 hours prior to initiation of ALXN1840 without 
reported complications. Among participants who discontinue chelator due to intolerance or 
noncompliance, the time from chelator discontinuation to the onset or worsening of symptoms 
varies from as little as 1 or 2 weeks to as long as months or years (Scheinberg, 1987). To prevent 
confounding of the study results, participants must be off zinc therapy for a minimum of 21 days 
prior to Day 1 because zinc works through upregulation of metallothionein (MT) in enterocytes 
resulting in elevation of fecal copper excretion. Previously, reports in the literature suggest that it 
can take up to 3 weeks or longer for zinc treatment to have an efficacious effect on copper 
balance (Brewer, 1983), so a delayed time to reversal of this effect could also occur. However, 
the physiologic turnover of human gastrointestinal epithelial cells is 3 - 5 days (Darwich, 2014); 
therefore, the inhibitory effect of zinc on intestinal copper absorption is expected to be minimal 
21 days after discontinuation of zinc. 
Following ALXN1840 administration, the active drug moiety tetrathiomolybdate rapidly binds 
copper to form TPC, mostly in the liver and blood, and presents as such in the systemic 
circulation. If TPC is not rapidly formed, tetrathiomolybdate spontaneously undergoes serial 
hydrolysis to form molybdate, the most common form of nutrient molybdenum, and is excreted 
in the urine. Total molybdenum concentration has been measured as a surrogate of ALXN1840 
PK; however, total molybdenum concentration cannot distinguish whether the molybdenum is 
protein bound (mostly as TPC), free active drug as ALXN1840, intermediate hydrolysis 
products, or molybdate. To better characterize the amount of non-TPC-bound drug and its 
unbound degradation products, plasma PUF-molybdenum has also been measured, which 

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represents the free parent drug (ALXN1840), short-lived intermediate hydrolysis products, and 
molybdate, which may have originated from the tetrathiomolybdate or from food intake as a 
micronutrient. Total molybdenum PK and free molybdenum PK serve as surrogate measures of 
ALXN1840 PK. To better characterize the ADME of ALXN1840, the PK of both total 
molybdenum and PUF-molybdenum will be characterized and described. 
This study is designed to provide an extensive assessment of copper and molybdenum balance 
over the first 40 days of treatment with ALXN1840 and support a more robust understanding of 
the effects of duration of treatment and dose of ALXN1840 on copper balance. Half-life 
estimates for total molybdenum in Study WTX101-201 were reported to be approximately 24 
hours at steady state on Days 84 and 168, while in healthy participants, total molybdenum half-
life was measured closer to 51 hours. With a half-life within this range, the sample collection 
periods include assessment of copper and molybdenum balance both during accumulation and at 
steady state for both the 15 mg/day and 30 mg/day doses. The study will include both intake and 
output collection as well as PK and copper assessments (ie, ceruloplasmin-bound copper and 
labile bound copper [LBC]) to inform the relationship between balance measurements and 
copper and molybdenum levels in the blood. 
Finally, preclinical data from ALXN1840 ADME study suggest the potential for molybdenum 
accumulation in the liver of participants with WD; therefore, an assessment of molybdenum 
balance will help determine whether steady state has been reached as defined by a molybdenum 
balance of neutral during the collection period. Because molybdenum is a necessary 
micronutrient and serves as a cofactor for a number of enzymes and may exist in intracellular 
stores, small variations in molybdenum balance could be due to molybdate rather than 
ALXN1840. 
4.2.1. 
Participant Input into Design 
Not applicable. 
4.3. 
Justification for Dose 
ALXN1840 at 60 mg single dose has been shown to have an adequate safety profile and be 
well-tolerated in healthy male and female participants in the Phase 1 bioavailability Studies 
WTX101-101 and WTX101-102. In addition, preliminary data from Study WTX101-106 have 
also shown ALXN1840 to be well tolerated in healthy Japanese and non-Japanese male and 
female participants at a single dose of 15 mg or 60 mg. While no repeat-dose studies have been 
performed in healthy participants, bis-choline tetrathiomolybdate (ALXN1840) has been tested 
in a range of oncologic indications with a maximum tolerated dose of 300 mg/day (Lowndes, 
2008). 
In the Phase 2 Study WTX101-201 conducted in participants with WD, the daily ALXN1840 
doses were 15 mg for 6 (21%) participants, 30 mg for 13 (46%) participants, and 60 mg (32%) 
for 9 participants at Week 24 when the primary endpoint assessment was conducted, or at the last 
dose received for participants with early discontinuation. The 15 to 60 mg/day dose range has 
been demonstrated to be efficacious with a favorable safety profile in treating participants with 
WD (Weiss, 2017). Based on these Phase 2 study results, the ongoing Phase 3 Study 
WTX101-301 in participants with WD has been testing the efficacy and safety of ALXN1840 at 

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a dose titration range from 15 mg to 60 mg daily with data to date supporting an acceptable 
safety profile. 
Similar to the Phase 2 study, in Study WTX101-301, participants are started at a dose of 
15 mg/day and, after review of all safety information, participants may be titrated up to 
30 mg/day after approximately 4 weeks. Based on the results of Study WTX101-201, doses 
ranging from 15 mg/day to 60 mg/day were adequate to significantly decrease non-ceruloplasmin 
corrected copper concentrations corrected for TPC (NCCcorrected) and, in many cases, return the 
NCC to normal concentrations of copper control. Given the robust improvement in copper 
control, it is hypothesized that doses within the 15 to 30 mg/day range will be adequate to drive a 
net negative copper balance. The current study will explore copper balance in response to 
treatment with ALXN1840, with the purpose of informing the dose and dosing duration required 
to result in adequate copper elimination to drive a measurable net negative copper balance. 
Copper balance will be assessed for the 15 mg/day dose at the beginning and end of the 
15 mg/day treatment period, and at the beginning of the 30 mg/day treatment period. Copper 
balance will be assessed for the 30 mg/day dose at Days 31 through 35 and Days 36 through 39. 
The multiple collection periods will support assessment of duration of treatment and dose on 
copper elimination and overall copper balance. 
In this study, dosing for ALXN1840 will be initiated at 15 mg once daily for a minimum of 
4 weeks, with an increase to 30 mg after 4 weeks, unless there are safety concerns that, in the 
opinion of the Investigator(s) and/or Alexion, may place participants at undue risk, in which 
case, participants may remain on the 15 mg/day dose for the duration of the study. Further dose 
adjustments will be made as appropriate. 
The dose should be decreased or interrupted if any of the relevant Dose Modification Criteria are 
met. Deviation from the dose modification guidelines must be agreed with the Alexion Medical 
Monitor. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Activities (SoA). The end 
of the study is defined as the date the last participant completes the last visit shown in the SoA 
(Section 1.3). 
 
 

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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 
Age 
1. Participants aged ≥18 at the time of signing the ICF. 
Type of Participants and Disease Characteristics 
2. Diagnosis of WD by Leipzig Criteria ≥ 4 documented by testing as outlined in the 2012 
European Association for the Study of Liver WD Clinical Practice Guidelines  
(Ferenci, 2003; EASL, 2012) or by historical test results for WD including some or all of the 
following: 
• Presence of Kayser Fleischer rings, 
• Neurological symptoms, 
• Serum ceruloplasmin below reference range, 
• Coombs-negative hemolytic anemia, 
• Elevated liver or urinary copper, 
• Presence of mutations in the ATP7B gene, or 
• Other, as considered appropriate, may be used instead to confirm the diagnosis of WD. 
3. Participants who in the opinion of the referring Investigator may benefit from decoppering 
therapy. 
4. Participants must be able to comply with all study-related procedures. 
5. Participants must be able to reside in the CRU for intensive metabolic monitoring of copper 
and molybdenum. 
6. Participants willing to discontinue chelator therapy for approximately 4 days prior to 
initiation of ALXN1840 to allow a baseline assessment of copper balance. 
7. Participants with adequate venous access to allow collection of required blood samples. 
8. Participants must be able to swallow intact ALXN1840 tablets. 
9. Participants willing to avoid use of minerals containing copper, zinc, or molybdenum 
throughout the study duration. 
10. 
Participants willing to adhere to copper/molybdenum-controlled diet during inpatient 
periods and willing to comply with a low copper dietary requirement during the 
Outpatient Period.  
Sex 
11. 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a. Male participants: 
• Male participants, if heterosexually active and with a female spouse or partner of 
childbearing potential or a pregnant or breastfeeding spouse or partner, must agree to 
use barrier contraception (male condom) for the duration of the study and for at least 
3 months after the end of systemic exposure of the study intervention. Male 

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participants must not donate sperm for at least 3 months after the end of systemic 
exposure of the study intervention.  
• Female spouses or partners of male participants who are of childbearing potential 
must use highly effective contraception as defined below and in Section 10.4, starting 
at least 1 menstrual cycle before (the male participant’s) first study intervention 
administration and continuing until at least 3 months after the end of their male 
partner’s systemic exposure to the study intervention.  
• Barrier contraception (male condom) is required even with documented medical 
assessment of surgical success of a vasectomy. For male participants who have had a 
vasectomy (with documented evidence of azoospermia if possible) and agree to use a 
male condom for the stated time period, no additional contraceptive method is 
required by their female partner. 
b. Female participants: 
• Female participants or female partners of male participants of childbearing potential 
(including breastfeeding females), if heterosexually active, must be willing to follow 
protocol-specified contraception guidance starting at least 1 menstrual cycle before 
first study intervention administration and continuing for at least 3 months after the 
end of systemic exposure of the study intervention. Female participants must not 
donate ova for at least 3 months after the end of systemic exposure of the study 
intervention. 
• Female participants who are documented as being of non-childbearing potential as 
defined in Section 10.4 are exempt from contraception requirements. 
• Highly effective contraceptive methods for female participants and female partners of 
male participants are described in Section 10.4. 
Informed Consent 
12. 
Participants capable of giving signed informed consent, which includes compliance with 
the requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria  
Medical Conditions 
1. Decompensated cirrhosis or model for end-stage liver disease (MELD) score > 13. 
2. Modified Nazer score > 7 (Dhawan, 2005). 
3. Clinically significant gastrointestinal bleed within past 3 months. 
4. Alanine aminotransferase (ALT) > 2 × upper limit of normal (ULN). 
5. Marked neurological disease requiring assistance with self-care or activities of daily life. 
6. Hemoglobin less than lower limit of the reference range for age and sex. 
7. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus 
(participants 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). 

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8. History or presence of/significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrinological, hematological, or neurological disorders, or 
psychiatric disorder that in the opinion of the Investigator may constitute a risk when 
taking the study intervention; or may interfere with the interpretation of data. 
Prior/Concomitant Therapy 
9. Previous treatment with ALXN1840 or other form of tetrathiomolybdate within 1 year prior 
to dosing. 
10. Previous treatment with zinc within 21 days prior to Day 1. 
Prior/Concurrent Clinical Study Experience 
11. The use of an experimental or unapproved/unlicensed therapy at the same time or within 90 
days or 5 half-lives, whichever is longer, prior to the Screening Visit. 
Diagnostic Assessments 
12. Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney 
disease [CKD] stage 5) or creatinine clearance < 30 mL/min (Levey, 2006). 
Other Exclusions 
13. Pregnant (or females who are planning to become pregnant) or breastfeeding females 
(women of childbearing potential must have a negative serum pregnancy test result at 
screening). 
14. Known sensitivity to ALXN1840, ALXN1840 excipients (anhydrous dicalcium phosphate, 
anhydrous sodium carbonate), or any of the ingredients contained in ALXN1840 or 
related compounds. 
15. In the opinion of the Investigator, the participant and/or their legal guardian is likely to be 
non-compliant or uncooperative during the study. 
16. History of illicit drug abuse, history of significant alcohol abuse within 1 year prior to the 
Screening Visit, or clinical evidence of substance and/or alcohol abuse within the 2 years 
before screening. Alcohol abuse is defined as regular weekly intake of more than 14 units 
(for both males and females), using the following National Health Service (NHS) alcohol 
tracker http://www.nhs.uk/Tools/Pages/drinks-tracker.aspx.  
17. Positive urine drug toxicology screen at Screening or on Day -8 (cannabinoids will not be 
tested). 
18. Alcohol consumption within 48 hours prior to study intervention administration or positive 
alcohol breath test at screening or on Day -8. 
19. Participants unwilling to consistently complete every meal and tolerate a controlled, limited 
menu for the duration of the study. 
5.3. 
Lifestyle Considerations 
Participants must be able and willing to adhere to the lifestyle restrictions detailed in Table 5. 

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Table 5: 
Participant Lifestyle Considerations  
Restrictions 
Timeframe Restriction 
Applies 
Restrictions End 
Food 
Participants will remain on a 
copper/molybdenum-controlled diet. Standardized 
copper- and molybdenum-controlled meals will be 
provided. Male participants will receive larger meals 
than female participants, with adequate meal size to 
ensure appropriate daily caloric intake. If a participant 
is unable to eat 100% of the food, the remaining food 
will be weighed and reported in the CRF to support 
copper/molybdenum determination as a fraction of the 
total meal. Participants will be expected to fast 
overnight. During the dosing period, participants will 
be administered ALXN1840 with 240 mL of water 
each morning; participants must remain fasted for a 
least 2 hours after dose administration. 
Dietary restrictions will 
remain in place during 
Inpatient Periods 1 and 2. 
 
Participants may return to 
routine diet after 
completion of Day 40. 
Fluids 
All participants will drink water from the same large 
water bottle dispenser. There will be no set maximum 
volume of water that the participants must consume, 
but there will be a minimal volume that they must 
consume each day (1.5 L). The precise volume that 
each participant consumes will be measured. 
Water restrictions will 
remain in place during 
Inpatient Periods 1 and 2. 
Participants may return to 
routine fluid intake after 
completion of Day 40. 
Alcohol 
48 hours before check-in 
to the CRU (Day -8 and 
Day 22/23) and until 
discharge on Day 40, and 
48 hours before each 
study 
Outpatient/Follow-up 
Visit.  
Discharge from the CRU 
and completion of EOS 
Visit. 
Physical activity 
Participants will carry out daily scheduled light 
exercise. This is to help encourage regular bowel 
movements and for health benefits to the participants.  
 
Participants must refrain from strenuous activity for 
24 hours prior to each study visit for the duration of 
the study. 
48 hours prior to check-in 
to the CRU (Day -8 and 
Day 22/23) and until 
discharge on Day 40. 
 
Restrictions end after 
completion of EOS Visit. 
Concomitant medication 
Concomitant medication guidelines are as per 
Section 6.5. 
Note: If participants have a medical need to take any 
new medication(s) prescribed to them by a doctor, 
they should follow the medical advice but inform the 
Investigator as soon as possible afterwards. 
Investigator in consultation with Alexion should 
determine participant’s continued suitability to remain 
in the study.  
Signing of informed 
consent until EOS Visit. 
 
Restrictions ends after 
completion of EOS Visit. 

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Restrictions 
Timeframe Restriction 
Applies 
Restrictions End 
Nonprescription/over-the-counter medication 
Any nonprescription/over-the-counter medication 
may be taken under the direction of the Investigator. 
Over-the-counter medications may be given if they 
are not expected to impact the outcome of the study.  
Acetaminophen should be limited to 1000 mg/day. 
Herbal remedies must be discontinued at least 7 days 
prior to first admission until study completion. 
Allowed under direction 
of Investigator. 
After the EOS Visit. 
St John’s wort 
Any herbal remedy or dietary supplement containing 
St John’s wort. 
2 weeks before the 
planned first study 
intervention is 
administered. 
After EOS Visit. 
Blood and plasma donation 
Blood donation or blood 
loss in excess of 500 mL 
in the 60 days prior to 
screening (Section 5.2). 
1 month after EOS Visit. 
Contraception 
Participants must consistently and correctly use one or 
more of the appropriate contraceptive methods 
described in Section 10.4. 
Start times for 
contraceptives vary 
according to method used 
(see Section 5.1 [inclusion 
criteria]). 
See Section 10.4. 
Abbreviations: CRF = case report form; CRU = clinical research unit; EOS = End of Study; SoA = Schedule of 
Activities.  
5.4. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details 
(eg, failed eligibility criteria), and any AEs, including any serious adverse events (SAEs) and any 
related concomitant medication, occurring during the Screening Period. 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a 
reason that is expected to resolve or has resolved may be rescreened based on discussion and 
agreement between the Investigator and the Medical Monitor. Rescreened participants are not 
required to reconsent as long as they have signed the latest version of the ICF. 
 

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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Intervention(s) Administered 
Details of ALXN1840 administered in the study are provided in Table 6. 
Table 6: 
Study Intervention Dosage and Mode of Administration 
Drug Name 
ALXN1840 (formerly WTX101) 
Type  
Drug 
Dose formulation 
Tablet 
Unit dose strength(s) 
15 mg ALXN1840 containing 7.8 mg of tetrathiomolybdic acid 
Dosage level(s) 
Repeat doses of 15 mg/day or 30 mg/day (administered as 2 × 15 mg 
ALXN1840 tablets) for 40 days 
Route of administration 
Oral 
Use 
Experimental/study intervention 
IMP and NIMP 
IMP 
Sourcing 
Provided by Alexion 
Packaging and labeling 
ALXN1840 will be provided in treatment kits that will each have a unique 
identification number and be packaged and labelled in accordance with all 
applicable regulatory requirements. At a minimum, the treatment kit label 
will provide the following information: Alexion study identification, batch 
number, directions for use, required storage conditions, caution statements 
(including “New Drug-Limited by Federal Law to Investigational Use” 
language), study identification, and expiry date. 
Current/former name(s) or 
alias(es) 
bis-choline tetrathiomolybdate 
Abbreviations: IMP = investigational medicinal product; NIMP = noninvestigational medicinal product. 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
a. The ALXN1840 treatment kits should be stored at refrigerated conditions, 2°C to 8°C 
(36°F to 46°F).  
2. Only participants enrolled in the study may receive the study intervention and only 
authorized site staff may supply or administer the study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized site staff. 
3.  Authorized site staff will instruct participants on study intervention storage and how to 
correctly dose themselves during the Outpatient Period. A sufficient number of kits 
should be dispensed to the participant to cover the need until check-in for Treatment 
Period 2. Participants will return all unused study intervention and empty kits so that 
study drug compliance may be calculated. 

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4. The Investigator and/or qualified delegate (ie, pharmacist) is responsible for study 
intervention accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
a. This responsibility includes the reporting of any product complaints to 
 within 1 business day. A product complaint is 
defined as any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, usability, safety, effectiveness, or 
performance of a product or clinical study material and/or its packaging components 
after it is has been released for distribution to an end customer that affects the 
performance of such product. 
5. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Blinding and randomization are not applicable. This is an open-label study in which all 
participants are expected to receive ALXN1840. 
6.4. 
Study Intervention Compliance 
While in the CRU, participants will receive study intervention directly from the Investigator or 
designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and in the case report form (CRF) (if the CRF is not the 
source document). The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention. 
During the Outpatient Period, participants will use SMS text messaging to confirm study 
intervention administration. Compliance with ALXN1840 during the Outpatient Period will be 
assessed by means of tablet counts of used and partially used treatment kits returned to the site 
by the participant. Any deviation from the prescribed dosing regimen including extra doses, 
missed doses, and drug interruptions will be documented in the source documents and CRF. 
Reasons for not following study intervention administration as described in the protocol should 
be clearly recorded in the source documents. 
A record of the number of ALXN1840 tablets dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Study intervention 
start and stop dates, including dates for drug delays and/or dose reductions will also be recorded 
in the CRF. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements), or other specific categories of interest, that the participant is 
receiving from 14 days prior to study enrollment (Day -7) until the EOS Visit must be recorded 
along with: 
• Reason for use 

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• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Medications specific for WD taken at any time prior to the study will also be recorded, including 
ALXN1840 received in a previous clinical study (clinical study number and subject ID should be 
noted). 
6.5.1. 
Allowed Medicine and Therapy 
• Paracetamol/acetaminophen at doses of a maximum 1000 mg per day is permitted for use 
as an exception with the approval of the Investigator. 
• As per the ALXN1840 IB, in this study, Investigators should use caution in the 
coadministration of drugs known to be substrates of cytochromes 2C9 and 2B6 (CYP2C9 
and CYP2B6). Common substrates of CYP2C9 include ibuprofen, which is permitted in 
this study. The Investigator must use ibuprofen with caution during the conduct of the 
study, and the ibuprofen dose must not exceed 1200 mg in any 24-hour period. Ibuprofen 
may only be used with approval of the Investigator. 
• Concomitant procedures are not allowed unless medically indicated and/or permitted by 
Alexion or the Investigator or delegate. 
• Concomitant medications may be used during the study if deemed medically indicated by 
the Investigator. The Investigator or designee will notify Alexion of any AEs requiring 
administration of prescription medication(s) while on study. 
6.5.2. 
Disallowed Medicine and Therapy 
Participants must abstain from taking prescription medications within 14 days or 5 half-lives 
(whichever is longer) of Day -7 or nonprescription drugs (including vitamins and dietary or 
herbal supplements) within 7 days or 5 half-lives (whichever is longer) before Day -7 and until 
completion of the follow-up visit, except as described in Section 6.5.1.  
6.6. 
Dose Modification 
Participants will be initiated on ALXN1840 at 15 mg once daily and increased to 30 mg once 
daily on Day 29. Specific criteria for dose reduction, temporary interruption of dosing, or 
restriction of dose increases of ALXN1840 are detailed in Table 7.  Repeat testing of parameters 
meeting dose modification criteria should follow the instructions in Table 7. Results from non-
scheduled safety laboratory assessments must be recorded in the CRF. 
Alexion should be notified within 24 hours of any laboratory, vital sign, electrocardiogram 
(ECG) abnormality, or AE that are considered of clinical concern by the Investigator. 
Investigators must notify Alexion immediately of study intervention discontinuation. The 
decision to discontinue study intervention should not be delayed for causality assessment. 

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Table 7: 
ALXN1840 Dose Modifications for Individual Participants  
Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety Monitoringa 
Rechallengeb,c,d 
ALT 
> 5 × ↑ 
from 
baseline 
ALT above 
reference range 
at baseline 
Temporary interruption 
 
Contact participant within 48 
hours to arrange repeat testing  
(weekly repeat testing) 
At 15 mg QOD when ALT < 2 × ↑ 
from baseline. 
> 5 × ULN 
ALT within 
reference range 
at baseline 
Temporary interruption 
Contact participant within 48 
hours to arrange repeat testing 
(weekly repeat testing) 
At 15 mg QOD when ALT < 2 × 
ULN. 
> 2 × ↑ 
from 
baseline   
ALT above 
reference range 
at baseline 
Reduce dose to previous dose level 
if up-titration has occurred or reduce 
dose to 15 mg QOD if on 15 mg 
QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
> 2 × ULN 
ALT within 
reference range 
at baseline 
Reduce dose to previous dose level 
if up-titration has occurred or reduce 
dose to 15 mg QOD if on 15 mg 
QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
Hemoglobin 
< 8 g/dL in 
the absence 
of bleeding 
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when hemoglobin 
and other hematology parameters 
(neutrophils and platelets) are at 
baseline concentration. 
> 30% ↓ 
from 
baseline 
None 
Reduce dose to previous dose level 
if up-titration has occurred or reduce 
dose to 15 mg QOD if on 15 mg 
QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
Platelets 
< 30,000 
µL 
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when platelets and 
other hematology parameters 
(neutrophils and hemoglobin) are at 
baseline concentration. 
> 30% ↓ 
from 
baseline 
Platelets below 
reference range 
at baseline 
Reduce dose to previous dose level 
if up-titration has occurred or reduce 
dose to 15 mg QOD if on 15 mg 
QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
Neutrophils 
< 1.0 × 
10
3/µL 
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when neutrophils 
and other hematology parameters 

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Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety Monitoringa 
Rechallengeb,c,d 
(hemoglobin and platelets) are at 
baseline concentration. 
> 30% ↓ 
from 
baseline 
Neutrophils 
below reference 
range at 
baseline 
Reduce dose to previous dose level 
if up-titration has occurred or reduce 
dose to 15 mg QOD if on 15 mg 
QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
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. 
Rechallenge under these conditions 
requires approval of the Alexion 
Medical Monitor. 
Neurological 
assessment 
Evidence of neurologic 
worsening by AEs or by 
neurologic physical exam 
assessment  
Investigator and Alexion 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. 
All neurologic worsening should 
be documented as AEs and 
followed up until study 
completion or resolution of 
symptoms. 
Discuss with the Alexion Medical 
Monitor. 
Psychiatric 
assessment 
Evidence of clinically 
significant acute psychiatric 
worsening which may include 
but not limited to suicidality, 
acute depression, or 
psychosis. 
Investigator and Alexion 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. 
Worsening psychiatric 
symptoms will be documented 
as adverse events in the eCRF 
and will be followed until 
completion of the study or 
resolution of symptoms. 
Discuss with the Alexion 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 rechallenges will be allowed. 
c For rechallenges, participants who were on 15 mg QOD should be rechallenged at the 15 mg QOD dose. 
d The Investigator, in consultation with the Medical Monitor, may change dose and dose frequency in participants who require rechallenge. 
Abbreviations: AEs = adverse event; ALT = alanine aminotransferase; eCRF = electronic case report form; QD = once daily; QOD = every other day; ULN = 
upper limit of normal. 

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6.7. 
Intervention After the End of the Study 
Following completion of both inpatient periods of the study (ie, Day 40), participants will either: 
• transition to therapy that was discontinued before enrollment, or 
• transition to other standard of care therapy as directed by the treating physician, or 
• at the discretion of the treating physician, consider and request continuation of 
ALXN1840 treatment permissible under local regulations for preapproval access. 
All participants should return to the CRU for the EOS Visit on Day 54 (+/- 2 days). 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) the study intervention. If the study intervention is definitively discontinued, the 
participant should remain in the study to be evaluated for safety follow-up. See the Schedule of 
Activities (SoA, Section 1.3) for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in the Dose Modification 
criteria (Section 6.6) or if the Investigator believes that it is in best interest of the participant. 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the Investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
Participants must be considered for discontinuation from study intervention if any of the 
following occur during the study: 
• Serious hypersensitivity reaction; 
• Severe uncontrolled infection; 
• Use of disallowed medication; 
• Pregnancy or planned pregnancy (see Section 8.2.6); or 
• Alexion or the Investigator deems it is necessary for the participant. 
See the SoA (Table 1) for samples and data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal From the Study 
• All efforts should be made to ensure participants are willing to comply with study 
participation prior to conducting the screening procedures. The study staff should 
notify Alexion and their site monitor of all study withdrawals as soon as possible. The 
reason for participant discontinuation must be recorded in the source documents and 
CRF. 
• A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons.  
• At the time of discontinuation from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 

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• The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
• If the participant withdraws consent for disclosure of future information, Alexion may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site 
study records. 
7.3. 
Lost to Follow-up 
A participant 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 participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 
 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
• The following only applies to sites in the US. 
− In the US only, it is permissible for study visits for individual participants to 
occur at more than 1 site. Some sites may perform screening procedures only and 
not any of the remaining study procedures. These sites will be known as 
“screening sites”. The procedures performed at screening sites are defined in the 
Screening column (Study Days -42 to -9 and -21) of the SoA (Section 1.3). 
Following the completion of screening procedures at a screening site, eligible 
participants will be transferred to the CRU, where the remaining study procedures 
and visits will occur. Site-to-site transfer of the participant will be documented 
accordingly.  
8.1. 
Efficacy Assessments 
8.1.1. 
Copper and Molybdenum Balance Measurements 
Copper and molybdenum balance measurements will be made on all intake (ie, investigational 
agent, food and fluids) and all output (urine and feces) from participants as indicated in the SoA. 
The copper and molybdenum concentration of each sample will be determined by inductively 
coupled plasma mass spectrometry (ICP-MS). Copper and molybdenum content of all intake and 
output will be calculated based on the volume or weight of intake and output and the 
concentration of representative samples. 
8.1.1.1. 
Food and Fluid Collection for Copper and Molybdenum Concentrations 
Samples of all meal and fluid batches will be collected and analyzed for measurement of copper 
and molybdenum content. A minimum of 3 complete portions/meals from each food and liquid 
batch will be sent for analysis. All participants will drink water from the same large water bottle 
dispenser. Samples of water from this dispenser will be collected and analyzed for copper and 
molybdenum content. 
Samples will be collected, stored and shipped as detailed in the Laboratory Manual. All sample 
handling procedures will be documented in detail in the Laboratory Manual. Copper and 

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molybdenum concentration of each food sample (ng/g) and each fluid sample (ng/mL) sample 
will be determined by ICP-MS. 
8.1.1.2. 
Urine Collection for Measurement of Copper and Molybdenum content 
Urine samples to measure copper and molybdenum content will be collected periodically as 
described in the SoA (Table 1). Samples will be collected, stored and shipped as detailed in the 
Laboratory Manual. For each 24-hour collection period, urine will be pooled for analysis and 
volumes will be recorded. All sample handling procedures will be documented in detail as 
described in the Laboratory Manual. Copper and molybdenum concentration (ng/mL) of each 
24-hour urine sample will be determined by ICP-MS. 
8.1.1.3. 
Fecal Collection for Measurement of Copper and Molybdenum Content 
Fecal samples to measure copper and molybdenum content will be collected periodically as 
described in the SoA (Table 1). Samples will be collected, stored, and shipped as detailed in the 
Laboratory Manual. Fecal samples will be individually collected, weighed, and stored. The 
weight and time of each bowel movement will be recorded. All sample handling procedures will 
be documented in detail in the Laboratory Manual. Copper and molybdenum concentration 
(ng/g) of each stool sample will be determined by ICP-MS; each sample will be analyzed using a 
minimum of technical triplicates. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
When multiple procedures are scheduled to occur at the same time, the following order of events 
should be strictly adhered to whenever possible: ECG, vital signs, blood sampling, study 
intervention administration, and meal. 
Pharmacokinetic collection should occur as close as possible to the scheduled time. 
All routine safety laboratory samples should be drawn following a minimum of 8 hours fasting.  
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height (at 
Screening only) and weight (as per the SoA for physical examinations) will also be 
measured and recorded. A symptom-driven physical examination may be performed at 
other times, at the Principal Investigator’s discretion.  
8.2.2. 
Vital Signs 
• Body temperature, heart rate, respiratory rate, and systolic and diastolic blood pressure 
(mm Hg) will be assessed using consistent methods and equipment to allow 
comparability and reproducibility throughout the study.  
• Blood pressure and heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 

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• Blood pressure and heart rate measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, cell phones). 
Ideally, the same arm for each participant should be used for measurements. 
• Vital signs will be measured in a supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, and heart rate. Vital signs will consist 
of a single pulse and blood pressure measurement. If vital signs are abnormal as defined 
by inclusion/ exclusion criteria, 2 additional vital signs measurements will be made. The 
average of the 3 vital signs measurements will be recorded in the CRF and used to 
determine participant eligibility. The average of the blood pressure readings will be 
recorded in the CRF.   
8.2.3. 
Electrocardiograms 
• Triplicate 12-lead ECGs will be conducted as outlined in the SoA (see Section 1.3) to 
obtain heart rate, PR, QRS, QT, and QTc intervals. Refer to Section 7 for QTc 
withdrawal criteria and any additional QTc readings that may be necessary. As with vital 
signs, if ECG interval measurements are abnormal, an additional triplicate will be 
performed and recorded in the CRF.  
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
laboratory values are those deemed by the Investigator to be clinically significant 
resulting in further evaluation or treatment or those associated with an AE or clinical 
signs or symptoms.  
• All laboratory tests with values considered abnormal and clinically significant during 
participation in the study or after the last dose of study intervention should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator or Medical Monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and Alexion 
notified. 
− All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 
− All laboratory values from non-protocol-specified laboratory assessments must 
also be recorded in the CRF. 

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8.2.4.1. 
Bowel and Urine Monitoring 
Participant’s bowel movements and urination will be monitored by the clinical staff. The clinical 
staff will record in the CRF each time a fecal and urine sample is collected. All urine and feces 
must be collected from Day -4 through Day -1, Day 1 through Day 8, Day 25 through Day 39. 
8.2.4.2. 
Intake Monitoring 
To support accurate quantification of copper/molybdenum intake, each participant’s intake 
including both food and fluids will be monitored and recorded. Following each standardized 
meal, the clinical staff will record 100% completion of each meal including all liquids. If a 
participant is unable to eat 100% of the food for a given meal, the remaining food will be 
weighed and reported in the CRF to support accurate determination of copper/molybdenum as a 
fraction of the total meal. Similarly, if participants do not complete 100% of non-water fluids 
with meal, the remaining volume will be measured and recorded in the CRF. In the case of water 
intake, the staff will record daily water volume intake in the CRF.   
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring  
Suicidal ideation and behavioral changes will be recorded as adverse events and may, at the 
discretion of the Investigator, result in withdrawal of the participation from the study and urgent 
referral for psychiatric treatment. 
8.2.6. 
Pregnancy 
• Pregnancy data from female participants and female spouses/partners of male participants 
will be collected from the signing of the ICF and at the time points specified in the SoA. 
Any female participant who becomes pregnant while participating in the study will be 
discontinued from the study intervention. If a pregnancy is reported, the Investigator must 
immediately inform Alexion within 24 hours of awareness of the pregnancy and follow 
the procedures outlined in Section 10.4. 
• For all Alexion products, both in development or post approval, 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 participant discontinues the study intervention or 
withdraws from the study. The corresponding infant must be followed for 3 months 
postpartum. 
• Pregnancy is not considered as an AE (Section 10.4) 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, ectopic pregnancy, spontaneous 
abortion, intrauterine fetal demise, neonatal death, or congenital anomaly) (Section 8.3). 
Elective abortions without complications should not be reported as AEs. 
8.3. 
Adverse Events and Serious Adverse Events  
The definitions of AEs and SAEs can be found in Section 10.3. 

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All AEs will be reported to the Investigator or qualified designee by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’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 participant to discontinue the study intervention (see Section 7). 
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in 
Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the EOS Visit.  
All SAEs will be recorded and reported to Alexion or the designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The Investigator will 
submit any updated SAE data to Alexion within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE data after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify 
Alexion. 
8.3.2. 
Method of Detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant 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 up on each 
participant at subsequent visits/contacts. All SAEs will be followed up until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs  
• Prompt notification of an SAE by the Investigator to Alexion is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
• Alexion 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. Alexion will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/ Independent Ethics Committees (IECs), and Investigators. 

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• Suspected unexpected serious adverse reactions (SUSARs) must be reported 
according to local regulatory requirements and Alexion policy and forwarded to 
Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from Alexion will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Adverse Events of Special Interest  
There are no adverse events of special interest for this study.  
8.3.6. 
Retained and Biobanked Sample 
A single biobanked serum sample will be collected predose from each participant to serve as a 
retained sample during the study. Samples will remain on site and will be discarded following 
the completion of the clinical study report. The sample will not be used for genetic testing (see 
Section 8.7).   
8.4. 
Treatment of Overdose 
For this study, any dose of ALXN1840 greater than that specified in the protocol will be 
considered an overdose. 
Alexion does not recommend specific treatment for an overdose. 
Overdoses are medication errors that are not considered AEs unless there is an untoward medical 
occurrence resulting from the overdose. 
In the event of an overdose or suspected overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE.  
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
• Whole blood samples will be collected for the measurement of plasma concentrations 
of total molybdenum and PUF-molybdenum as specified in the SoA (Table 1) via 
ICP-MS. Samples collected within ± 10% or 30 min, whichever is less, of the 
scheduled time will not be considered a protocol deviation. 

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• Instructions for the collection and handling of biological samples will be provided by 
Alexion. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• Total molybdenum and PUF-molybdenum are surrogate measures of ALXN1840 and 
concentrations will be used to evaluate the PK of ALXN1840. Samples collected for 
analyses of plasma concentrations may also be used to evaluate safety aspects related 
to concerns arising during or after the study. 
• Excess/additional samples may be stored for up to 5 years and used for PD and/or 
diagnostic biomarker development and research to understand the pathways 
associated with the mechanism of action of ALXN1840. These samples will not be 
used for genetic analyses (ie, RNA or DNA analyses). 
• Genetic analyses will not be performed on these whole blood samples. Participant 
confidentiality will be maintained.  
• See also Section 8.1.1 for details of molybdenum measured in food, drinks, urine, and 
feces. 
8.6. 
Pharmacodynamics 
Plasma total and PUF-copper, ceruloplasmin, ceruloplasmin-bound copper, and LBC will be 
assessed during the study.  
Blood samples will be collected as described in the SoA (Table 1) for plasma isolation as per the 
Laboratory Manual. Plasma samples will be used for ICP-MS measurement of total copper and 
PUF-copper, ceruloplasmin, ceruloplasmin-bound copper, and non-ceruloplasmin-bound copper 
measured via PUF-copper, and/or LBC, or assessed via NCC/NCCcorrected methods at the time 
points indicated in the SoA (Table 1). 
8.7. 
Genetics 
Genetics will not be evaluated in this study. 
8.8. 
Biomarkers 
Please see Section 8.6 for details of total copper and PUF-copper, ceruloplasmin, 
ceruloplasmin-bound copper, and non-ceruloplasmin-bound copper as measured via PUF-copper, 
and/or LBC, or assessed via NCC/NCCcorrected methods, and Section 8.1.1 for details of copper 
measured in food, drink, urine, and feces. 
8.9. 
Immunogenicity Assessments 
Not applicable. 
8.10. 
Health Economics Data and/or Medical Resource Utilization 
Health economic and medical resource utilization parameters are not evaluated in this study. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary Hypothesis 
As this study is an exploratory study, no formal hypothesis testing is being conducted. Study 
results will be summarized using descriptive statistics. 
9.2. 
Sample Size Determination 
The sample size will be approximately 10 participants which will allow a general 
characterization of copper balance in response to ALXN1840. 
9.3. 
Populations for Analyses 
The population sets used for analysis are defined Table 8. 
Table 8: 
Populations for Analysis 
Population 
Description 
Screened 
All participants who sign the ICF. 
Enrolled 
All participants who sign the ICF, are eligible for the study, and are 
registered on Day -7 when participants are assigned a participant number. 
Safety Analysis Set  
All participants who receive at least 1 dose of ALXN1840 treatment.  
Full Analysis Set  
All participants who receive at least 1 dose of ALXN1840 treatment.  
Per Protocol Set 
All participants who received at least 1 dose of ALXN1840, had Baseline 
and all post Baseline values of copper intake (in food and drink) and 
copper output (in feces and urine), and were 100% compliant with study 
drug dosing. Participants with major protocol deviations that are likely to 
impact the primary endpoint analysis will be excluded from the Per 
Protocol (PP) Set. Major protocol deviations, and the PP Set, will be 
defined, documented, and agreed within Alexion prior to database lock. 
Pharmacokinetic/Pharmacodynamic 
Analysis Set 
All participants who have sufficient plasma samples to enable the 
calculation of PK parameters and provide PK/PD profiles. 
Abbreviations: ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic. 
9.4. 
Statistical Analyses 
Statistical methods described in this section will be further elaborated in a separate Statistical 
Analysis Plan (SAP). Summary statistics will be computed and displayed by visit where 
applicable and will be presented by cohort (treatment experienced/treatment naïve), and overall 
Descriptive statistics for continuous variables will minimally include the number of participants, 
mean, standard deviation, minimum, median, and maximum. For categorical variables, 
frequencies, and percentages will be presented. Graphical displays will be provided as 
appropriate. 
Analyses will be performed using the SAS® software Version 9.4 or higher. 
9.4.1. 
Primary Analysis 
The primary objective of this study is to demonstrate a net negative copper balance with daily 
repeat-dose ALXN1840 treatment (15 mg and 30 mg) in participants with WD. 

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The primary analysis will be performed using the Full Analysis Set. Average daily copper 
balance and molybdenum balance will be calculated over the following periods: 
1. 
Day -4 through Day -1 representing predose baseline  
2. 
Days 1 through 8 representing the ALXN1840 15 mg/day accumulation period 
3. 
Days 25 through 28 representing the ALXN1840 15 mg/day steady-state period 
4. 
Days 31 through 35, representing the ALXN1840 30 mg/day accumulation period 
5. 
Days 36 through 39 representing the ALXN1840 30 mg/day steady-state period 
As ALXN1840 is expected to increase copper excretion through fecal excretion, copper in stool 
will be critical for determining copper balance. Because stools can be irregular, assessment of 
copper and molybdenum balance will only include data up to the day of the final bowel 
movement. For example, for the period Day 1 through Day 8, if the final bowel movement 
occurs on Day 7, average daily copper balance for the Day 1 through Day 8 period will only 
include data from Day 1 through Day 7. 
In the case of the 15 mg/day steady-state period (ie, Day 25 through Day 28), stool data collected 
on Days 29 - 30 samples may be used if needed to support assessments for the 15 mg/day dose. 
Use of these stool data (as needed) are consistent with an approximately 2-day gastrointestinal 
transit time. 
In the case of stool irregularity, and to support assessment of copper output over time, bowel 
movement copper and molybdenum outputs may be averaged over the days between bowel 
movement (or start of study) to ensure an approximate value for each 24-hour period. 
9.4.2. 
Secondary Analyses 
Secondary analyses will be performed using the Full Analysis Set. The secondary continuous 
endpoints (including copper balance, molybdenum balance, and 24-hour urine excretion of 
copper and molybdenum) will be analyzed using the same methods described for the primary 
analysis. 
9.4.3. 
Safety Analysis 
Safety analyses will be performed using the Safety Analysis Set. 
Safety analyses will include all AEs, ECGs, clinical laboratory data, physical examinations, and 
vital sign measurements using descriptive statistics. 
No inferential statistical analyses are planned for the safety parameters of this study. The 
incidence of AEs and SAEs will be summarized by System Organ Class and Preferred Term for 
each treatment and overall, and by relationship to study intervention. Adverse events will also be 
summarized by treatment and overall by severity. Serious AEs and AEs resulting in withdrawal 
from the study will be listed. Participants having multiple AEs within a category (eg, overall, 
System Organ Class, Preferred Term) will be counted once in that category. For severity tables, a 
participant’s most severe event within a category will be counted.  
Changes from baseline in vital sign measurements and laboratory assessments (eg, chemistry, 
hematology, coagulation, and urinalysis) will be summarized by treatment. Laboratory parameter 
values will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE). Shift tables by treatment will be produced for these laboratory 

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parameters. These tables will summarize the number of participants with each baseline grade 
relative to the reference ranges and changes to the worst highest grade assessed post dose during 
the study. 
Electrocardiogram parameters will be measured at the specified time points as per the SoA 
(Table 1), including heart rate, PR, RR, QRS, QT, and QTcF intervals. The average of the 
triplicate ECG readings at the time points collected will be calculated, and changes from 
pretreatment baseline values will be assessed by each treatment. 
All concomitant medications will be coded and summarized using the World Health 
Organization (WHO) Drug Dictionary. 
9.4.4. 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
For PK, PD, and biomarker endpoints, analyses will be performed using the PK/PD Analysis Set. 
The following plasma PK parameters will be calculated for total molybdenum and PUF 
molybdenum (as surrogate measures of ALXN1840 PK) using noncompartmental methods with 
Phoenix® WinNonlin® (Certara USA Inc., Princeton, New Jersey) Version 8.0 or higher or SAS 
Version 9.3 or higher (SAS Institute Inc., Cary, North Carolina), as applicable. Calculations will 
be based on the actual sampling times recorded during the study. 
• Time delay between the time of dosing and time of appearance of molybdenum 
concentration (Tlag) in plasma 
• Maximum observed concentration (Cmax) 
• Time to maximum concentration (tmax) 
• Trough (predose) concentration observed at the start of the dosing interval (Ctrough) 
• Area under the plasma concentration versus time curve (AUC) from time 0 to the last 
quantifiable concentration (AUCt) 
• AUC over the dosing interval (AUCtau) 
• Accumulation ratio (AR) calculated as: 
For 15 mg/day:  
− Cmax,Day25/Cmax,Day1 
− Ctrough,Day26/Ctrough,Day2 
− AUCtau,Day25/AUC tau,Day1  
For 30 mg/day:  
− Cmax,Day39/Cmax,Day29,adjusted 
− Ctrough,Day40/Ctrough,Day30,adjusted 
− AUCtau,Day39/AUCtau,Day29,adjusted  
Note: total molybdenum and PUF molybdenum concentration-time profiles on Day 28 
after the last 15 mg ALXN1840 dose will be extrapolated to Day 29 (0-24 hr) and 
subtracted from the observed Day 29 concentration-time profiles after the first 30 mg 

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ALXN1840 dose for the estimation of the Cmax,Day29,adjusted, Ctrough,Day30,adjusted, and 
AUCtau,Day29,adjusted. 
• Apparent terminal phase elimination rate constant (λz) 
• Terminal elimination half-life (t½) 
• Apparent total body clearance (CL/F) of ALXN1840 from plasma 
• Apparent volume of distribution (Vd/F). 
Additional plasma PK parameters may be calculated if deemed appropriate. 
Plasma concentrations of total molybdenum and PUF molybdenum vs. time data will be 
presented in a data listing by participant. Plasma concentration data will be summarized 
separately by analyte and time point for each treatment by day using the following descriptive 
statistics: number of participants, arithmetic mean, geometric mean (GM), SD, coefficient of 
variation (CV), GMCV, median, minimum, and maximum. Mean plasma concentration versus 
scheduled time profiles will be presented in figures on both linear and semilogarithmic scales. 
Individual plasma concentration versus actual time profiles will be presented similarly. 
Pharmacokinetic parameters derived from plasma concentrations of total molybdenum and PUF 
molybdenum will be presented in data listings and summarized separately using the following 
descriptive statistics: number of participants, arithmetic mean, GM, SD, arithmetic CV, GMCV, 
median, minimum, and maximum. Geometric mean and geometric CV will be presented for Cmax 
and AUCs only.  
For PD (total and PUF copper and LBC) and biomarker endpoints (ceruloplasmin, 
ceruloplasmin-bound copper), concentration-time data will be listed and summarized with 
descriptive statistics and plotted. The same analyses will be conducted on the absolute and 
percent changes from baseline of these concentration-time data. 
9.5. 
Interim Analyses  
Marketing Authorisation Application(s) may be submitted before all patients complete the 
Treatment Periods; therefore, interim analyses of safety and efficacy data may be performed to 
support these submissions. These analyses will be descriptive only; they will not include formal 
hypothesis testing and will not be used to adapt the study. Full details will be provided in the 
SAP. 
9.6. 
Data Monitoring Committee 
There will not be a Data Monitoring Committee, but provision is included for an SRC 
(Section 9.7). 
9.7. 
Safety Review Committee (SRC) 
A SRC, composed of a minimum of the Investigator, Alexion Medical Monitor, and Alexion 
Safety Physician, will meet at the end of 15 mg/day dosing to confirm proceeding to 30 mg/day 
and as necessary based on any emerging safety concerns as described in Section 6.6.  

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
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 International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol substantial amendments, ICF, IB, 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 approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• The Investigator will notify the IRB/IEC of deviations from the study protocol or 
GCP as defined by UK legislation as a serious breach or as required by IRB/IEC 
procedures. 
• 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 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, Directive 2001/20/EC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and Subinvestigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 

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10.1.3. 
Informed Consent Process 
• It is the responsibility of the Investigator to obtain signed (written or electronic 
signature) informed consent from all study participants prior to any study-related 
procedures including screening assessments. 
• The Investigator or his/her representative will explain the nature of the study 
(including but not limited to the objectives, potential benefits and risks, 
inconveniences, and the participant’s rights and responsibilities) to the participant or 
his/her legally authorized representative, defined according to local and country 
regulations where the study is taking place, and answer all questions regarding the 
study. 
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent or a certified translation if applicable, that meets the requirements of 
21 CFR 50, local regulations, EU General Data Protection Regulation (GDPR), ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that signed (written or electronic) 
informed consent was obtained before the participant was screened in the study and 
the date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF/ICFs. 
• Participants must be reconsented to the most current version of the ICF/ICFs during 
their participation in the study. 
• A copy of the signed (written or electronic) informed consent documentation (ie, a 
complete set of participant information sheets and fully executed signature pages) 
must be provided to the participant or the participant’s legally authorized 
representative, as applicable. This document may require translation into the local 
language. Signed (written or electronic) consent [or assent] forms must remain in 
each participant’s study file and must be available for verification at any time. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
participant or their legally authorized representative the objectives of the exploratory research. If 
sharing exploratory research results with the Investigator is not planned, the ICF should mention 
it. Participants or their legally authorized representative will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a participant’s agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to participate 
in this optional research will not provide this separate signature. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by Alexion. Any participant records 
or datasets that are transferred to Alexion will contain the identifier only; participant 

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names or any information which would make the participant identifiable will not be 
transferred. 
• Participants must be informed that their personal study-related data will be used by 
Alexion in accordance with local data protection law. The level of disclosure must 
also be explained to the participants who will be required to give consent for their 
data to be used as described in the informed consent.  
• Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Alexion, 
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, www.clinicaltrials.gov or www.clinicaltrialsregister.eu), as appropriate, and in 
accordance with national, regional, and local regulations. 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to Alexion or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Alexion or designee is responsible for the data management of this study including 
quality checking of the data. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for a minimum of 25 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 Alexion. No records may be transferred to another location or party 
without written notification to Alexion. 
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The Investigator or designee will prepare and maintain adequate 

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and accurate source documents (eg, medical records, ECGs, AE and concomitant medication 
reporting, raw data collection forms) designed to record all observations and other pertinent data 
for each participant. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. Source documents are filed at the Investigator’s site. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is consented. 
Alexion reserves the right to close the study site or terminate the study at any time for any reason 
at the sole discretion of Alexion. Study sites will be closed after the study is completed or 
following the decision to close or terminate the study. A study site is considered closed when all 
participants have completed the end of study or early discontinuation visit, all data have been 
collected and entered into electronic data capture (EDC) system, all required documents and 
study supplies have been collected, and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Alexion or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Alexion’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
10.1.9. 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 

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10.2. 
Clinical Laboratory Tests 
• The tests detailed in Table 9 will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• Pregnancy testing: Women of childbearing potential should only be enrolled after a 
negative serum pregnancy test result at Screening. Additional urine pregnancy testing 
will be standard for the protocol unless serum testing is required by site policies, local 
regulation, or IRB/IEC and should be performed per the time points specified in the 
SoA (Section 1.3). Screening pregnancy criteria are detailed in Section 5.1. 
 
 
 

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Table 9: 
Protocol-Required Safety Laboratory Assessments 
Clinical Chemistry 
Blood urea nitrogen (BUN) 
Alanine aminotransferase 
Potassium 
Alkaline phosphatase 
Creatinine 
Urea 
Creatine kinase 
Magnesium 
Sodium 
Iron 
Chloride 
Zinc 
Potassium 
Total and direct bilirubin 
Glucose 
Total protein 
Total carbon dioxide 
Albumin 
Aspartate aminotransferase 
Calcium 
Gamma glutamyltransferase 
Phosphate 
Hematology 
Hematocrit 
Red blood cell counta 
Platelets 
Mean corpuscular volume 
White blood cell count 
Mean cell hemoglobin concentration 
Mean cell hemoglobin 
Lymphocytes 
Neutrophils 
Eosinophils 
Monocytes 
Prothrombin time 
Basophils 
International normalized ratio 
Hemoglobin 
Partial thromboplastin time 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes 
Microscopy 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Red blood cells 
Bacteria 
 
Other Tests 
HIV, hepatitis B, and hepatitis C screen 
Total copper and total molybdenum 
Ceruloplasmin (serum and plasma) 
PUF-molybdenum and PUF-copper 
Ceruloplasmin-bound copper 
Labile bound copper 
24-hour urine copper and molybdenum 
Serum and urine pregnancy test 
Urine drug screen 
 
a Including nucleated red blood cells. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 6.6. All events of alanine aminotransferase (ALT) ≥ 3 × upper limit of 
normal (ULN) and bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT ≥ 3 × ULN and international normalized 
ratio (INR) > 1.5, if INR measured which may indicate severe liver injury (possible Hy’s Law), must be reported 
as an SAE (excluding studies of hepatic impairment or cirrhosis). 
Abbreviations: HIV= human immunodeficiency virus; PUF = plasma ultrafiltrate; SAE = serious adverse event. 
Investigators must document their review of each laboratory safety report. 
 

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10.3. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study 
intervention, whether or not considered related to the study intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 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. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.  
 
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.  
• 
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 study intervention are to be reported 
within 24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will be collected for 
regulatory reporting and safety evaluation. 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than expected for 
the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the participant’s condition. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 

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10.3.2. 
Definition of SAE 
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). 
An 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 participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it 
was more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant 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 participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually be considered serious. 
• 
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. 
 
A suspected unexpected serious adverse reaction (SUSAR) is defined as: 
A serious event that is not listed in the Reference Safety Information of the Investigator’s Brochure and that the 
Investigator or Sponsor identifies as related to investigational product or procedure. United States Title 21 CFR 
312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national 
regulatory requirements in participating countries require the reporting of SUSARs. 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 guidances. Suspected unexpected serious adverse reactions will be reported to the 
national competent authority and IRBs/IECs where applicable. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
Recording of AE and/or SAE 
• 
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 participant’s medical records to Alexion 
in lieu of completion of the AE/SAE CRF page. 

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Recording of AE and/or SAE 
• 
There may be instances when copies of medical records for certain cases are requested by Alexion. In this 
case, all participant identifiers, with the exception of the participant number, will be redacted on the copies 
of the medical records before submission to Alexion. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Severity 
The Investigator will make an assessment of severity for each AE and SAE reported during the study and assign 
it to one of the following categories from National Cancer Institute CTCAE v5.0, published 27 Nov 2017:  
• 
Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
• 
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Grade 3: Severe (incapacitating, with inability to perform normal activities) 
• 
Grade 4: Life-threatening 
• 
Grade 5: Fatal 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the study intervention and each occurrence of 
each AE or SAE. An Investigator causality assessment must be provided for all AEs (both nonserious and 
serious). This assessment must be recorded in the CRF and on any additional forms, as appropriate. The 
definitions for the causality assessments are as follows: 
− 
Not related: There is no reasonable possibility the study intervention caused the AE. 
• 
The AE has a more likely alternative etiology; it may be due to underlying or 
concurrent illness, complications, concurrent treatments, or effects of another 
concurrent drug. 
• 
The event does not follow a reasonable temporal relationship to administration of the 
study intervention. 
− 
Related: There is a reasonable possibility the study intervention caused the AE. 
• 
The AE has a temporal relationship to the administration of the study intervention. 
• 
The event does not have a likely alternative etiology. 
• 
The event corresponds with the known pharmaceutical profile of the study 
intervention. 
• 
There is improvement on discontinuation and/or reappearance on rechallenge. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed products, in his/her 
assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to 
include in the initial report to Alexion. However, it is very important that the Investigator always make an 
assessment of causality for every event before the initial transmission of the SAE data to Alexion. 

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Assessment of Causality 
• 
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 to elucidate the nature and/or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, the Investigator 
will provide Alexion with a copy of any post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of the information. 
10.3.4. 
Reporting of SAEs  
SAE Reporting to Alexion via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours awareness. 
• 
All SAEs will be reported using the Safety Reporting Form and submitted to Alexion GDS. The Investigator 
must complete, sign, and date the SAE pages, verify the accuracy of the information recorded on the SAE 
pages with the corresponding source documents, and send a copy via email or facsimile to the contact 
information provided below: 
− 
Email:
or Fax: 
 
• 
Additional follow-up information, if required or available, should be entered into the CRF and sent to 
Alexion GDS within 24 hours of the Investigator or study site staff becoming aware of this additional 
information via the reporting process outlined above.  
• 
For all SAEs, the Investigator must provide the following: 
− 
Appropriate and requested follow-up information in the time frame detailed above 
− 
Causality of the SAE(s) 
− 
Treatment of/intervention for the SAE(s) 
− 
Outcome of the SAE(s) 
− 
Medical records and laboratory/diagnostic information 
• 
All paper forms and follow-up information submitted to Alexion GDS 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. 
Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1. 
Definitions and Contraceptive Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD): female participants with a copper-containing IUD are excluded from study 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
o 
Vasectomy is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days. 
Highly Effective Methodsb That Are User Dependent 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 
o 
Oral 
o 
Injectable 
o 
Intravaginal 
o 
Transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
Oral 
o 
Injectable 
• 
Sexual abstinence 
o 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
Female participants of non-childbearing potential are exempt from contraception requirements. 
Non-childbearing potential for female participants 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 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 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction). 
a  Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b  Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
 

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10.4.2. 
Collection of Pregnancy Information 
If a female participant or a male participant’s female spouse/partner becomes pregnant after the 
first dose of ALXN1840 through 3 months after the end of systemic exposure of the study 
intervention, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and Outcome 
Form” to Alexion Global Drug Safety (GDS) via fax or email (see Section 10.3 for contact 
information). 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 (see Section 10.3 for 
contact information). 
 

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10.5. 
COVID-19 Vaccine Risk Assessment 
To date, following a review of the limited available COVID-19 vaccine data (eg, 
Pfizer/BioNTech, Moderna, AstraZeneca), it is unlikely that the immune response to a 
COVID-19 vaccine will be diminished with concomitant ALXN1840 administration, based on 
ALXN1840’s mechanism of action. There is currently no information available evaluating the 
safety or efficacy of COVID-19 vaccines in participants treated with ALXN1840.  
Local and national guidelines should be consulted for recommendations related to COVID-19 
vaccination. Alexion suggests that participants complete vaccination series before study 
participation, if feasible. The decision to allow COVID-19 vaccinated participants to continue in 
the study should be made by the investigator on a participant-by-participant basis. 
The potential risks identified and mitigation measures put in place in light of the COVID-19 
vaccination rollout are provided in Table 10. 
Table 10: 
Potential Risks and Mitigation Measures due to COVID-19 Vaccine 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Data quality and 
integrity 
Missing data due to appointments for COVID-19 
vaccination or side effects of COVID-19 vaccine 
may impact study visit schedules and increase 
missed visits and/or participant study 
discontinuations, inadvertently resulting in 
missing data (eg, for protocol-specified 
procedures).  
It will be important to capture 
specific information in the eCRF 
that explains the reason the data is 
missing (eg, missed study visits 
due to appointments for 
COVID-19 vaccination or side 
effects of COVID-19 vaccine). 
Abbreviation: COVID-19 = coronavirus disease 2019. 
 

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10.6. 
Abbreviations 
A list of abbreviations and terms used in this study protocol is provided in Table 11. 
Table 11: 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
λz 
apparent terminal-phase elimination rate constant 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event  
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
AUC 
area under the plasma concentration versus time curve 
AUCt 
area under the plasma concentration versus time curve from time 0 to the last 
quantifiable concentration  
AUC∞ 
area under the plasma concentration versus time curve from zero to infinity  
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
chronic kidney disease 
CL/F 
 apparent total body clearance 
Cmax 
maximum observed concentration  
CONSORT 
Consolidated Standards of Reporting Trials  
COVID-19 
Coronavirus disease 
CRF 
case report form  
CRU 
clinical research unit  
CTCAE 
Common Terminology Criteria for Adverse Events  
CYP 
cytochrome P450  
CYP2C9/2B6 
cytochromes 2C9 and 2B6 
EDC 
electronic data capture 
EOS 
End of Study  
GCP  
Good Clinical Practice  
GDPR 
General Data Protection Regulation 
GDS 
Global Drug Safety  
HED 
human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure  
ICH 
International Council for Harmonisation 
ICF 
informed consent form  
ICP-MS 
inductively coupled plasma mass spectrometry 
IEC 
Independent Ethics Committee  
IRB 
Institutional Review Board 

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IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
LBC 
labile bound copper 
LEC 
Long-Evans Cinnamon 
MELD 
model for end-stage liver disease 
MT 
metallothionein 
NCC 
non-ceruloplasmin-bound copper  
NCCcorrected 
corrected NCC 
NHS 
National Health Service 
PD 
pharmacodynamic 
PK 
pharmacokinetic(s)  
PUF 
plasma ultrafiltrate  
QTcF 
QT interval corrected for heart rate using Fridericia’s formula  
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan  
SoA 
Schedule of Activities 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event  
t½ 
terminal elimination half-life  
Tlag 
time delay between the time of dosing and time of appearance of molybdenum 
concentration 
tmax 
time to maximum concentration  
TPC 
tripartite complex 
TTM 
tetrathiomolybdate 
ULN 
upper limit of normal 
UWDRS 
Unified Wilson Disease Rating Scale 
Vd/F 
apparent volume of distribution  
WD 
Wilson disease  
WHO 
World Health Organization 

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10.7. 
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 Protocol 
12 May 2020 
Amendment 1 
18 Aug 2020 
Amendment 2 
19 Mar 2021 
Amendment 3 
31 Aug 2021 
Amendment 3.1 (US) 
18 Mar 2022 
Amendment 1 (18 Aug 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 
The main reason for preparation of this amendment was to update procedures outlined in the 
Schedule of Activities, remove contradictory text on the reporting of serious adverse events, and 
add details of an interim analysis. Additional, minor changes are included in the table below. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or Clarifications 
Section 1.3, Schedule of Activities, 
Section 4.1, Overall Design, 
Section 6.4, Study Intervention 
Compliance 
Procedures updated include 
Wilson disease history and 
treatment; study intervention 
compliance during outpatient 
period captured with study 
dosing diary; light exercise.  
Data collected for analysis of patient 
population and study intervention 
compliance, and to compare endpoints 
with other ALXN1840 studies. 
Section 2, Introduction 
Section 2.2, Background 
Removal of text relating to 
primary biliary cholangitis. 
To reflect that development of 
ALXN1840 is for Wilson disease. 
Section 6.7, Intervention After the 
End of Study 
Text updated regarding access to 
study intervention after the end 
of study. 
To clarify the option for study 
intervention access at the end of study. 
Section 9.3, Populations for 
Analysis 
Definition of the Per Protocol set 
was updated. 
To align the definition with the 
Statistical Analysis Plan. 
Section 9.5, Interim Analyses 
Text pertaining to an interim 
analysis was added. 
Interim data may support Marketing 
Authorisation Application(s). 
Section 10.3.2, Definition of SAE 
Definition of SUSAR was 
added. 
To align with current Alexion approved 
language 
Section 10.3.4, Reporting of SAEs 
Removal of contradictory text on 
SAE reporting via an electronic 
data collection tool. 
SAE reporting will be via a paper 
safety reporting form.  
All 
Minor editorial updates and 
corrections 
For clarification, and to ensure 
accuracy and consistency throughout 
the protocol 
 

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Amendment 2 (19 Mar 2021) 
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 main reason for preparation of this amendment was to revise the exclusion criterion for a 
urine drug screen. Changes implemented via Administrative Letter 1 and Administrative Letter 
2, as well as COVID vaccination guidance, have also been incorporated. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or Clarifications 
Section 1.1, Synopsis; 
Section 9.2, Sample Size 
Determination 
The number of participants 
changed from “up to 10” to 
“approximately 10”. 
Clarification of sample size. 
Section 1.1, Synopsis; 
Section 1.2, Schema;  
Section 1.3, Schedule of 
Activities; Section 4.1, 
Overall Design; 
Section 6.4, Study 
Intervention Compliance 
SMS text messaging will replace 
the dosing diary as the method of 
confirming treatment compliance 
during the outpatient period. 
 
Site processes does not allow 
use of paper diary. 
Section 2.3.1.1, Coronavirus 
Disease 2019; 
Section 10.5, COVID-19 
Vaccine Risk Assessment 
COVID-19 vaccination guidance 
added. 
To provide guidance on potential risks 
identified and mitigation measures put in 
place regarding the COVID-19 vaccination 
rollout. 
Section 5.1, Inclusion 
criteria 
Inclusion criterion for confirmation 
of diagnosis of WD changed to 
Leipzig score ≥ 4 and expanded to 
include historical test results. 
To 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 WD 
Clinical Practice Guidelines. 
Section 5.2, Exclusion 
criteria 
Exclusion criterion for drug screen 
revised to state that cannabinoids 
will not be tested. 
• 
To align with other ALXN1840 Phase 
2 and Phase 3 study protocols which 
did not reference this criterion 
• 
Recreational use of cannabis use is 
being decriminalized in many countries 
• 
Medicinal use of cannabis would 
potentially relieve symptoms of WD 
• 
Recent use of cannabis is not expected 
to alter copper or molybdenum balance 
Section 5.2, Exclusion 
criteria 
Exclusion criterion 11 revised to 
“The use of an experimental or 
unapproved/unlicensed therapy at 
the same time or within 90 days or 
5 half-lives, whichever is longer, 
prior to the Screening Visit.” 
For consistency across all ALXN1840 
protocols.  
Section 10.1.1, Regulatory 
and Ethical Considerations 
Added: “The Investigator will 
notify the IRB/IEC of deviations 
from the study protocol or GCP as 
defined by UK legislation as a 
serious breach or as required by 
IRB/IEC procedures.” 
To align with UK legislation 
All sections 
Minor editorial updates and 
corrections 
For clarification, and to ensure accuracy 
and consistency throughout the protocol 

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Amendment 3 (31 Aug 2021) 
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, 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 preparation of this amendment was to update the washout period for zinc. 
Additional changes are listed below. 
Changes to the Protocol 
Section # and Name 
Description of Change 
 Brief Rationale and/or 
Clarifications 
Section 1.3, Schedule of 
Activities; Section 4.2, Scientific 
Rationale for Study Design; 
Section 5.2, Exclusion Criteria 
Previous treatment with zinc changed to 21 
days prior to Day 1. 
To align with feasibility of 
study participation. 
Section 4.1, Overall Design, 
Table 4  
Deleted the Adaptive Protocol Feature 1 
that allowed enrollment of participants who 
had completed other ALXN1840 studies.  
To remove contradiction of 
the exclusion for previous 
treatment with ALXN1840. 
Section 6.7 Intervention after the 
End of Study 
Updated the options for intervention after 
study completion to include both therapy 
that was discontinued before enrollment and 
other standard of care therapy. 
To clarify treatment options at 
end of study. 
 

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11. 
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