A Phase 1, Open-label Study to Assess Copper Balance in Healthy Participants Following Administration of ALXN1840
Phase: PHASE1
Conditions: Healthy
Sponsor: Alexion Pharmaceuticals, Inc.

A Phase 1, Open-label Study to Assess Copper Balance in 
Healthy Participants Following Administration of 
ALXN1840 
 
Unique Protocol ID: 
ALXN1840-HV-108 
NCT Number: 
NCT04594252 
EudraCT Number:  
2019-003010-14 
Date of Protocol:  
29 May 2020 
 

PPD
PPD

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 2 of 71 
Alexion Confidential 
INVESTIGATOR’S AGREEMENT 
I have read the study protocol amendment 2 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 2, 29 May 2020 
ALXN1840-HV-108 
Page 3 of 71 
Alexion Confidential 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
10 Mar 2020 
Amendment 1 
07 Apr 2020 
Amendment 2 
29 May 2020 
Amendment 2 (29 May 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The main reason for preparation of this amendment was to remove contradictory text on the 
assessment of intensity of serious adverse events and to include language on the collection of 
pregnancy information. Additional changes are included in the table below. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or Clarifications 
Title Page 
Change of Sponsor signatory 
To reflect a change in Alexion Medical 
Monitor 
Section 5.1 Inclusion Criteria 
Edits to text in inclusion 
criterion 7 regarding 
requirements for contraception 
To improve the flow of text and 
remove duplicate text that is also 
present in Section 10.4 of the protocol 
Section 6.1 Study Intervention 
Administration 
Text in Table 5 edited with 
respect to labeling of study 
intervention. 
Wording regarding labeling amended to 
reflect that the study is planned to be 
conducted in the UK 
Section 10.3.3 Recording and 
Follow-Up of AE and/or SAE 
Removal of contradictory text on 
the assessment of intensity of 
AEs and /or SAEs 
Assessment of the intensity of AEs 
and/or SAEs and assignment to a 
category should be performed 
according to the National Cancer 
Institute Common Terminology 
Criteria for Adverse Events (CTCAE) 
v5.0, published 27 Nov 2017. The 
section has been revised to remove 
unnecessary duplication in assessment  
Section 10.4 Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Addition of language on 
collection of pregnancy 
information 
Reporting procedures were added in 
order to collect pregnancy information 
as well as information regarding 
exposure of infants to ALXN1840 
during breastfeeding 
Section 2 Introduction 
Section 2.2 Background 
Section 2.3.2 Overall Benefit: Risk 
Conclusion 
Section 10.5 Appendix 5: 
Abbreviations 
Removal of text relating to 
primary biliary cholangitis 
To reflect that development of 
ALXN1840 is for Wilson disease 
Appendix 10.6 Appendix 6: 
Protocol Amendment History 
Addition of details of the 
previous amendment to the 
protocol 
To include details of the changes that 
were made in the previous amendment, 
Amendment 1 
All 
Minor editorial changes 
For consistency and to correct minor 
typographical errors 

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 4 of 71 
Alexion Confidential 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
1. 
PROTOCOL SUMMARY ............................................................................................8 
1.1. 
Synopsis ........................................................................................................................8 
1.2. 
Schema ........................................................................................................................11 
1.3. 
Schedule of Activities (SoA) ......................................................................................13 
2. 
INTRODUCTION ......................................................................................................17 
2.1. 
Study Rationale ...........................................................................................................17 
2.2. 
Background .................................................................................................................18 
2.3. 
Benefit/Risk Assessment ............................................................................................19 
2.3.1. 
Benefit Assessment .....................................................................................................20 
2.3.2. 
Overall Benefit: Risk Conclusion ...............................................................................21 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................22 
4. 
STUDY DESIGN .......................................................................................................24 
4.1. 
Overall Design ............................................................................................................24 
4.2. 
Scientific Rationale for Study Design ........................................................................25 
4.2.1. 
Participant Input into Design ......................................................................................26 
4.3. 
Justification for Dose ..................................................................................................26 
4.4. 
End of Study Definition ..............................................................................................27 
5. 
STUDY POPULATION .............................................................................................28 
5.1. 
Inclusion Criteria ........................................................................................................28 
5.2. 
Exclusion Criteria .......................................................................................................29 
5.3. 
Lifestyle Considerations .............................................................................................32 
5.4. 
Screen Failures ............................................................................................................33 
6. 
STUDY INTERVENTION ........................................................................................35 
6.1. 
Study Intervention Administered ................................................................................35 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................36 
6.4. 
Study Intervention Compliance ..................................................................................36 
6.5. 
Concomitant Therapy .................................................................................................36 

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 5 of 71 
Alexion Confidential 
6.5.1. 
Allowed Medicine and Therapy .................................................................................36 
6.5.2. 
Disallowed Medicine and Therapy .............................................................................37 
6.6. 
Dose Modification ......................................................................................................37 
6.6.1. 
Adverse Reaction Rules ..............................................................................................37 
6.6.1.1. 
General Adverse Reaction Rules ................................................................................38 
6.6.1.2. 
Individual Adverse Reaction Rules ............................................................................38 
6.6.1.3. 
Group Adverse Reaction Rules ..................................................................................38 
6.6.1.4. 
Special individual Adverse Reaction Rules ................................................................38 
6.6.1.5. 
Special group Adverse Reaction Rules .......................................................................39 
6.6.1.6. 
Safety Oversight and Implementation Stopping Rules ...............................................39 
6.7. 
Intervention After the End of the Study .....................................................................40 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................41 
7.1. 
Discontinuation of Study Intervention ........................................................................41 
7.2. 
Participant Discontinuation/Withdrawal From the Study ...........................................41 
7.3. 
Lost to Follow-up .......................................................................................................42 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................43 
8.1. 
Efficacy Assessments .................................................................................................43 
8.2. 
Safety Assessments .....................................................................................................43 
8.2.1. 
Physical Examinations ................................................................................................43 
8.2.2. 
Vital Signs ..................................................................................................................43 
8.2.3. 
Electrocardiograms .....................................................................................................44 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................44 
8.2.4.1. 
Bowel and Urine Monitoring ......................................................................................45 
8.2.4.2. 
Intake monitoring ........................................................................................................45 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................45 
8.2.6. 
Pregnancy ...................................................................................................................45 
8.3. 
Adverse Events and Serious Adverse Events .............................................................45 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................46 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................46 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................46 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................46 
8.3.5. 
Adverse Events of Special Interest .............................................................................47 

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 6 of 71 
Alexion Confidential 
8.3.6. 
Retained and Biobanked Sample ................................................................................47 
8.4. 
Treatment of Overdose ...............................................................................................47 
8.5. 
Pharmacokinetics ........................................................................................................47 
8.6. 
Pharmacodynamics .....................................................................................................48 
8.7. 
Copper and Molybdenum Balance Measurements .....................................................48 
8.7.1. 
Food and fluid collection for Cu and Mo concentrations ...........................................48 
8.7.2. 
Urine Collection for Measurement of Copper and Molybdenum content ..................48 
Fecal Collection for Measurement of Copper and Molybdenum content ......................................49 
8.8. 
Genetics ......................................................................................................................49 
8.9. 
Biomarkers ..................................................................................................................49 
8.10. 
Immunogenicity Assessments ....................................................................................49 
8.11. 
Health Economics Data and/or Medical Resource Utilization ...................................49 
9. 
STATISTICAL CONSIDERATIONS .......................................................................50 
9.1. 
Statistical Hypotheses .................................................................................................50 
9.1.1. 
Primary Hypothesis ....................................................................................................50 
9.2. 
Sample Size Determination ........................................................................................50 
9.3. 
Populations for Analyses ............................................................................................50 
9.4. 
Statistical Analyses .....................................................................................................50 
9.4.1. 
Efficacy Analyses .......................................................................................................50 
9.4.1.1. 
Analyses of Primary Endpoint ....................................................................................51 
9.4.1.2. 
Analyses of Secondary Efficacy Endpoint(s) .............................................................52 
9.4.1.3. 
Analyses of Exploratory Endpoint(s) .........................................................................52 
9.4.2. 
Safety Analyses ..........................................................................................................52 
9.4.3. 
PK/PD Analyses .........................................................................................................53 
9.5. 
Interim Analyses .........................................................................................................53 
9.6. 
Data Monitoring Committee .......................................................................................53 
9.7. 
Safety Review Committee ..........................................................................................53 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................54 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................54 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................54 
10.1.2. 
Financial Disclosure ...................................................................................................54 
10.1.3. 
Informed Consent Process ..........................................................................................55 

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 7 of 71 
Alexion Confidential 
10.1.4. 
Data Protection ...........................................................................................................55 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................56 
10.1.6. 
Data Quality Assurance ..............................................................................................56 
10.1.7. 
Source Documents ......................................................................................................56 
10.1.8. 
Study and Site Start and Closure ................................................................................56 
10.1.9. 
Publication Policy .......................................................................................................57 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................59 
10.3. 
Appendix 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 .......................................................................................................61 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................62 
10.3.4. 
Reporting of SAEs ......................................................................................................64 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................65 
10.5. 
Appendix 5: Abbreviations .........................................................................................67 
10.6. 
Appendix 6: Protocol Amendment History ................................................................69 
11. 
REFERENCES ...........................................................................................................70 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................13 
Table 2: 
Schedule of Pharmacokinetic/Pharmacodynamic and Safety Assessments on 
Day 1 and Day 15 .......................................................................................................16 
Table 3: 
Potential Risks and Mitigation Strategy .....................................................................20 
Table 4: 
Healthy Participant Lifestyle Considerations .............................................................32 
Table 5: 
Details of Study Intervention Administered ...............................................................35 
Table 6: 
Populations for Analyses ............................................................................................50 
Table 7: 
Protocol-Required Safety Laboratory Assessments ...................................................59 
Table 8: 
List of Abbreviations and Definitions of Terms .........................................................67 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................11 
 

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 8 of 71 
Alexion Confidential 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, Open-label Study to Assess Copper Balance in Healthy Participants 
Following Administration of ALXN1840 
Short Title: Copper Balance in Healthy Participants Administered ALXN1840 
Rationale: 
The principal aim of this study is to assess the change from baseline in mean daily copper (Cu) 
balance in healthy participants with repeat-dose administrations of ALXN1840 over 2 weeks to 
demonstrate that ALXN1840 promotes a net negative Cu balance through enhanced fecal 
elimination of Cu. If observed, these data will support the ALXN1840 decoppering mechanism 
of action ie, liver decoppering with subsequent biliary excretion and fecal elimination. A 
secondary aim of this study is to characterize the steady state absorption, distribution, 
metabolism, and excretion (ADME) (mass balance) of total molybdenum (Mo), which is a 
surrogate measure of ALXN1840 disposition. 
ALXN1840 contains the active anion tetrathiomolybdate (TTM) and has been shown to cause 
negative Cu balance when administered to healthy animals as well as decopper the liver in 
animal models of Wilson Disease (WD) (Mills, 1981; Czachor, 2002). In Study WTX101-201, 
which assessed the safety and efficacy of ALXN1840 in patients with WD, ALXN1840 
demonstrated enhanced Cu control as measured by reduced plasma non-ceruloplasmin bound Cu 
(NCC) corrected for the stable tetrathiomolybdate-Cu-albumin complex (tripartite complex; 
TPC) (NCCcorrected) (Weiss, 2017).  
Depletion of Cu by ALXN1840 has been shown to occur primarily through fecal elimination in 
both healthy and WD animal models. In contrast, Cu chelators (current standard of care [SoC] 
such as trientine and penicillamine) enhance urinary Cu output and penicillamine has been 
shown to drive a net negative Cu balance in most patients with WD and in healthy participants 
(Strickland, 1971; Walshe, 1973).  
Published literature support that a Cu balance study may be conducted in healthy participants to 
investigate the mechanism of action of decoppering agents such as ALXN1840. Copper balance 
is assessed through measurement of all Cu intake (food and drink) and measurement of all Cu 
output (urine and feces) and is classically considered the most objective measure of decoppering 
ability with a decoppering agent able to drive a net negative Cu balance (Hill, 1986; Strickland, 
1971; Walshe, 1973). Because participants may have different baseline Cu balance values and 
may include values that are both mildly positive or negative, the primary objective of the study 
will be to assess the change from baseline in Cu balance in healthy participants treated with 
ALXN1840. This approach will allow an assessment of change in Cu balance due to ALXN1840 
treatment. Secondarily, the study will also assess whether a mean net negative Cu balance is 
achieved following ALXN1840 treatment. Taken together, these 2 complementary Cu balance 
endpoints will allow an assessment of the role of ALXN1840 on Cu balance and study its 
mechanism of action of decoppering, mostly of liver, through urine and fecal excretions.  
As part of the secondary objective, the study has been designed to descriptively assess the total 
Mo mass balance (as a measure of ALXN1840 balance). A Mo mass balance study in healthy 

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 9 of 71 
Alexion Confidential 
participants is sufficient to characterize the ADME profile for ALXN1840 and for comparisons 
to the results from Long-Evans Agouti (LEA; normal Wistar) and Long-Evans Cinnamon (LEC; 
Wilson disease model) rats. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Assess change from baseline in copper (Cu) 
balance over 2 weeks of repeated daily 
ALXN1840 dosing 
Change in mean daily Cu balance from 
pretreatment baseline period to ALXN1840 
treatment period, as measured by the 
calculated difference between Cu intake (in 
food and drink), and Cu output (in feces and 
urine) 
Secondary  
Assess net Cu balance over 2 weeks of 
repeated daily ALXN1840 dosing 
Mean daily Cu balance during ALXN1840 
treatment period where Cu balance is 
measured by the calculated difference 
between Cu intake (in food and drink), and 
Cu output (in feces and urine) 
Assess steady-state molybdenum (Mo) 
balance after 2 weeks of repeated daily 
ALXN1840 dosing 
Mean daily Mo balance at ALXN1840 
pharmacokinetic (PK) steady state, as 
demonstrated through measurement of Mo 
intake (in food, drink, and ALXN1840), and 
Mo output (in feces and urine) 
Assess extent of Mo excretion in urine and 
feces 
Quantify total Mo excretion in urine and feces 
following ALXN1840 treatment compared 
with baseline 
Determine the steady-state plasma PK of 
ALXN1840 after 2 weeks of repeated daily 
ALXN1840 dosing 
PK parameters for plasma total Mo and 
plasma ultrafiltrate (PUF) Mo including 
terminal elimination for Mo after steady-state 
dosing 
Investigate the effect of ALXN1840 on the 
disposition of Cu after 2 weeks of repeated 
daily ALXN1840 dosing at steady state 
Cu quantified in food, feces, and urine over 
2 weeks of ALXN1840 dosing including 
plasma total and labile bound Cu (LBC) at 
steady state 
Investigate the effect of ALXN1840 on the 
disposition of Cu over 2 weeks of repeated 
daily ALXN1840 dosing and through the 
post-treatment period 
Cu quantified in food, drink, feces, and urine  
Investigate the effect of ALXN1840 on the 
disposition of Mo over 2 weeks of repeated 
daily ALXN1840 dosing and through the 
post-treatment period 
Mo quantified in ALXN1840 doses given and 
in food, drink, feces, and urine 
Safety 
Evaluate the safety and tolerability of 
repeated dose administration of ALXN1840 
Safety parameters:  
Treatment-emergent adverse events 
(TEAEs)/serious adverse events (SAEs) 

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 10 of 71 
Alexion Confidential 
Clinical laboratory assessments (serum 
chemistry, hematology, coagulation, and 
urinalysis) 
Physical examinations 
Heart rate, intervals (PR, QRS, QT and QTc), 
and clinically significant ECG findings as 
determined by triplicate 12-lead ECG 
Vital sign assessments (blood pressure and 
heart rate) 
Exploratory 
Assess the effects of ALXN1840 on 
ceruloplasmin, ceruloplasmin-bound Cu, and 
LBC profiles in plasma 
Absolute and percent changes in 
ceruloplasmin, ceruloplasmin-bound Cu, 
ceruloplasmin-bound Cu:ceruloplasmin ratio, 
and LBC during treatment period and post-
treatment compared with predose baseline 
Assess the effects of repeated daily 
ALXN1840 dosing on Cu:Mo ratio in plasma 
at steady state 
Measure plasma Cu:Mo ratios during 
treatment period and post-treatment compared 
with predose baseline 
Assess the effects of ALXN1840 on Cu:Mo 
ratio in urine and feces 
Measure the average daily Cu:Mo ratio in 
urine and feces during treatment and post-
treatment compared with predose 
Assess the effects of ALXN1840 on the time 
course of Cu balance over 2 weeks 
Evaluate the effect of time on change in 
average daily Cu balance  
Overall Design 
This is a single-arm, open-label, repeat-dose (30 mg/day) study designed to assess the effects of 
ALXN1840 administration on Cu balance in healthy participants. The safety and tolerability of 
ALXN1840 in healthy participants will also be assessed. ALXN1840 pharmacokinetics (PK) in 
plasma as measured via total Mo and plasma ultrafiltrate (PUF) Mo will be determined after 
single and repeated dosing along with total Mo mass balance at steady state. 
Disclosure Statement: This is an open-label, 2-period study with 1 arm. 
Number of Participants: 
Approximately 17 enrolled participants will receive study intervention to ensure 13 participants 
complete the study.   
This study will be conducted in a minimum of 2 groups. The first group will consist of 
approximately 6 participants and no more than 8 participants. The second group may be initiated 
after the Safety Review Committee (SRC) reviews safety information (all adverse events [AEs], 
safety laboratory data, and vital signs) through Day 18 and agrees that it is safe to continue 
enrollment to complete the study. If ceruloplasmin concentrations or AE findings are suggestive 
of Cu depletion, the SRC may propose a dose reduction to 15 mg/day for the remainder of the 
study population. 
Note: “Enrolled” means all participants who sign the ICF, are eligible for the study, and are 
registered on Day -7 when participants are assigned a subject number. 

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 11 of 71 
Alexion Confidential 
Intervention Groups and Duration: 
This is a single arm 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 
Cu and Mo balance (Day -4 through Day -1). Following the Run-in Period, participants will be 
administered ALXN1840 at 30 mg/day for 15 days (Day 1 through Day 15). ALXN1840 will be 
administered orally after an overnight fast and participants will remain fasted for a minimum of 
2 hours following each dose administration. Following completion of the 15-day dosing period, 
participants will remain in the clinical research unit (CRU) for an additional 16 days until 
discharge on Day 31. 
Total intake and output will be measured continuously from Day -4 through Day 30 with Day 1 
through Day 15 representing the ALXN1840 treatment period and Day 16 through Day 30 
representing the post-treatment period. The collection period will support assessment of Cu and 
Mo mass balance including assessment of steady state and terminal elimination.   
Participants will return to the CRU for a final study visit on Day 43 ± 2 days, approximately 
28 days after the final dose of ALXN1840, to conclude the safety follow up period. 
If participants withdraw from the study early, they will be seen and assessed by the Investigator 
or study physician and whenever possible, will undergo the procedures associated with the end 
of study (EOS) Visit. Participants may be replaced at the discretion of Alexion. 
Safety Review Committee: 
An SRC, composed of a minimum of the Investigator and Alexion’s medical monitor, will 
review safety information from the first group (approximately 6-8 participants) through Day 18 
including all AEs, safety laboratory data, and vital sign assessment and agree that it is safe to 
continue enrollment to complete the study. If ceruloplasmin concentrations or AEs findings are 
suggestive of Cu depletion, the SRC may propose a dose reduction to 15 mg/day for the rest of 
the enrolled study participants.   
1.2. 
Schema 
The study design is presented in Figure 1. 
 
Figure 1: 
Study Design Schematic 
 
Run-in Period
Day -7
Day -4 
-
Baseline I/O
Days -4 through -1 
Day 4
ALXN1840 30 mg/day Treatment Period 
Treatment I/O
Days 1 through 30
Day 7
Day 30
EOS 
Admit to 
CRU Day -8
Discharge from
CRU Day 31
Day 15
Day 43
Enrollment
Day -1 Day 1
Days -35 to -9
Screening
Day 16

Protocol Amendment 2, 29 May 2020 
ALXN1840-HV-108 
Page 12 of 71 
Alexion Confidential 
Participants will be admitted to the CRU on Day -8 and discharged on Day 31.  
Participants eligible for the study will be enrolled (assigned a subject number) on Day -7. A Cu- and Mo-controlled 
diet will be initiated on Day -7 and will be continued through Day 30. 
Participants will be administered ALXN1840 at a dose of 30 mg/day on Day 1 through Day 15, with post-treatment 
period starting at Day 16.  
Total intake and total output (I/O) samples for measurement of Cu and Mo will be collected during the baseline 
(Day -4 through Day -1), treatment (Day 1 through Day 15), and post-treatment periods (Day 16 through Day 31). 
I/O defines the period in which all intake (food and drink) and all output (urine and feces) will be collected for the 
measurement of Cu and Mo. 
Intensive PK/PD sampling will occur on Day 1 and Day 15. Pre-dose PK/PD samples will be collected on Days 2 
(Day 1, Hour 24), 3, 5, 8, 11, and 14. During the post-treatment period, PK/PD samples will be collected on Days 
16, 18, 21, 24, 27, and 30. 
Abbreviations: CRU = clinical research unit; EOS = end of study; I/O = input/output. 
 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 13 of 71 
Alexion Confidential 
1.3. 
Schedule of Activities (SoA) 
Table 1: 
Schedule of Activities 
Study Procedures 
Scree
ninga 
Check
-inb 
 
 
EOS or 
ETc 
 
Days -35 
to -9 
-8 
-7  -6 to 
-5 
-4 to 
-1 
1 
2 
3 
4  
5 
6-7 
8 
9-10 11 
12-
13 
14 
15 
16-17 
18 
19-
20 21-29 30 31 
EOS Day 
43 ± 2 
Eligibility 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to unit 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from unit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
Inclusion/exclusion  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discuss/document 
contraception 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Follicle stimulating 
hormone (post-
menopausal females) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Administration 
Medical 
history/demographicse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Heightg, weight, and BMI 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
Enrollment (prior to 
administration of study 
intervention) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of Study Intervention 
ALXN1840h 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
PK Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALXN1840 (total Mo) and 
PUF Mo PKi 
 
 
 
 
 
Xj 
Xk 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
Xj 
Xk 
Xk 
 
Xk,n 
Xk 
 
 
Safety Assessments/Laboratory Analyses 
Chemistryl, Hematology, 
Coagulation 
X 
X 
 
 
Xm 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Xn 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 14 of 71 
Alexion Confidential 
Study Procedures 
Scree
ninga 
Check
-inb 
 
 
EOS or 
ETc 
 
Days -35 
to -9 
-8 
-7  -6 to 
-5 
-4 to 
-1 
1 
2 
3 
4  
5 
6-7 
8 
9-10 11 
12-
13 
14 
15 
16-17 
18 
19-
20 21-29 30 31 
EOS Day 
43 ± 2 
Pregnancy testo 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum ceruloplasmin and 
Cu 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Retained sample (safety)p 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals sign measurementsq  X 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
12-lead ECG (triplicate)q 
X 
 
X 
 
 
Xj 
X 
 
 
X 
 
X 
 
X 
 
X 
Xj 
 
 
 
 
 
 
X 
AE monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Balance assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cu/Mo controlled mealsr 
 
 
X 
X 
X 
X 
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 
X 
X 
 
 
Urination and bowel 
movement monitoring, 
menstruation checko  
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
24-hour urine for Cu and 
Mos 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Feces for Cu and Mot 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Plasma total Cu, PUF Cu 
ceruloplasmin, 
ceruloplasmin-bound Cu, 
and LBC 
 
 
 
 
 
Xj 
Xk 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
Xj 
Xk 
Xk  
 
Xk,n Xk 
 
X 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Within 35 days of ALXN1840 administration (or within approximately 28 days of enrollment) 
b Participants will be admitted to the CRU at least 10 hours prior to enrollment and initiation of Cu- and Mo-controlled diet 
c Participants are required to return to the CRU approximately 28 days (±2 days) after final ALXN1840 dose administration. In the event of early termination, 
the procedures listed at the end of the study are performed prior to participant discharge. Additional follow-up for participants who undergo early termination 
are allowed per the Investigator’s discretion. 
d Discharge from the CRU may occur after completion of all procedures on Day 31 and after investigator has reviewed all safety assessment (including safety 
labs) and confirmed that participant is appropriate for discharge. 
e Parameters include age and sex. Race and ethnicity will be collected where permitted by local regulations. 
f A full physical examination will be performed at screening, at check-in for the study, and at the end of the study or upon early termination. A physical 
examination should also be performed on any participant with ongoing AEs prior to discharge from the unit. Otherwise, a symptom-driven physical 
examination may be performed at other times, at the Investigator’s discretion. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 15 of 71 
Alexion Confidential 
g Height at screening only. 
h Study intervention will be administered after an overnight fast (ie, at least 10 hours) at the same time every morning; ALXN1840 is to be administered with 
240 mL of water. Participants will remain fasted for a minimum of 2 hours following each dose administration. 
i Blood samples will be collected pre-dose on dosing days for PK. On Days 1 and 15, intensive blood sampling for PK/PD will occur at the timepoints described 
in Table 2. Blood samples for PK/PD on Days 16 (Day 15 24-hour time point), 18, 21, 24, 27, and 30 (non-dosing days) will be collected at approximately 
0800 and before breakfast. 
j See Table 2 for PK/PD blood sampling and ECG schedules on Days 1 and 15. 
k Procedures will occur pre-dose on Day 1 through Day 15; starting on Day 16, procedure will occur at approximately 0800 and before breakfast 
l Samples for serum chemistry will be obtained following a fast of at least 8 hours at screening, and of at least 6 hours at check-in. In case of dropouts, rechecks, 
and postdose serum chemistry, participants may not have fasted for 6 or 8 hours before the serum chemistry sample is taken. 
m Day -1 only. 
n Laboratory assessment including chemistry, hematology, and coagulation parameters should be performed on Days 21, 24, and 27; blood sampling for plasma 
PK (total and PUF Mo) and PD (total and PUF Cu, ceruloplasmin, ceruloplasmin-bound Cu, and LBC) should occur at approximately 0800 or before breakfast 
on Days 21, 24, and 27. 
o 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 IRBs/IEC 
(Section 10.2). 
p 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 
q 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. 
r Cu and Mo controlled meals will be initiated after enrollment (Day -7 breakfast) and continued through Day 30; during this time participants will be strongly 
encouraged to complete all meals. If a participant is unable to eat 100% of the food, the remaining food will be weighed and reported in the CRF to support 
Cu/Mo determination as a fraction of total meal (Table 4). 
s For each intake/output balance period, 24-hour urine samples are to be collected for measurement of Cu and Mo. 24-hour collection volumes will be recorded 
in the CRF. The 24-hour collection period is defined as relative to the first ALXN1840 dose administration.  
t 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; CRF = case report form; CRU = clinical research unit; Cu = copper; EOS/ET = End of Study or 
Early Termination; HR = heart rate; Mo = molybdenum; PK = pharmacokinetics; PUF = plasma ultrafiltrate; LBC = labile bound copper. 
Note: 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 
 

Protocol Amendment 2, 14 May 2020 
 
ALXN1840-HV-108 
Page 16 of 71 
Alexion Confidential 
Table 2: 
Schedule of Pharmacokinetic/Pharmacodynamic and Safety Assessments on 
Day 1 and Day 15 
Time point (h)a  
Predoseb 
0 
1 
2 
3 
4 
5 
6 
8 
12 
24 
ALXN1840 (total Mo) and PUF 
Mo PK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma total Cu, ceruloplasmin, 
ceruloplasmin-bound Cu, and 
LBC  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (triplicate) 
X 
 
 
 
 
X 
 
 
 
 
 
a Time points are relative to dosing (0 hours) on Day 1 and Day 15. 
b Pre-dose should be collected within 1 hour prior to dosing. 
Note 1: Windows for PK/PD time points will be defined as ± 10% of the nominal time point. 
Note 2: The 24-hour PK/PD samples after Day 1 and Day 15 dosing are to be collected at pre-dose on Day 2 and at 
approximately 0800 am on Day 16. 
Note 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. 
Abbreviations: Cu = copper; LBC = labile-bound copper; Mo = molybdenum; PK = pharmacokinetic; PUF = plasma 
ultrafiltrate. 

Protocol Amendment 2, 14 May 2020 
 
ALXN1840-HV-108 
Page 17 of 71 
Alexion Confidential 
2. 
INTRODUCTION 
ALXN1840 (bis-choline tetrathiomolybdate; formerly known as WTX101) is a novel, 
first-in-class, copper (Cu)-protein binding agent in development for the treatment of Wilson 
disease (WD). 
2.1. 
Study Rationale 
The principal aim of this study is to assess the change from baseline in mean daily copper (Cu) 
balance in healthy participants with repeat-dose administrations of ALXN1840 over 2 weeks to 
demonstrate that ALXN1840 promotes a net negative Cu balance through enhanced fecal 
elimination of Cu. If observed, these data will support the ALXN1840 decoppering mechanism 
of action ie, liver decoppering with subsequent biliary excretion and fecal elimination. A 
secondary aim of this study is to characterize the steady state absorption, distribution, 
metabolism, and excretion (ADME) (mass balance) of total molybdenum (Mo), which is a 
surrogate measure of ALXN1840 disposition. 
ALXN1840, which contains the active anion tetrathiomolybdate (TTM) and has been shown to 
cause Cu depletion 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 patients with WD, ALXN1840 demonstrated enhanced Cu control 
as measured by reduced plasma non-ceruloplasmin-bound Cu (NCC) corrected for the stable 
tetrathiomolybdate -Cu-albumin complex (tripartite complex; TPC) (NCCcorrected) (Weiss, 2017).  
Studies in both healthy and WD animal models showed that treatment with tetrathiomolybdate 
results in removal of Cu from the liver. Tetrathiomolybdate administered to healthy mice by 
intraperitoneal injection resulted in a dose-dependent reduction in liver Cu 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 Cu 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 Long-Evans Cinnamon (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 Cu concentration. 
Mechanistic work in vitro and in vivo has shown that tetrathiomolybdate is capable of removing 
Cu directly from metallothionein (MT), which may enhance its ability to decopper the liver 
compared with other decoppering agents (Suzuki, 1995). The Cu removed from the liver is 
believed to be excreted into the blood or bile as a soluble tetrathiomolybdate -Cu-albumin 
complex or TPC (Komatsu, 2000). 
Depletion of Cu 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 Cu 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, LEC rats were injected intra-peritoneally with a saline 
solution of tetrathiomolybdate at a dose of 10 mg/kg body weight daily for 8 consecutive days 
(Ogra, 2000). The amounts of both Cu and Mo excreted into the feces increased significantly 

Protocol Amendment 2, 14 May 2020 
 
ALXN1840-HV-108 
Page 18 of 71 
Alexion Confidential 
during treatment with tetrathiomolybdate, which suggest that Cu is excreted in complex with 
tetrathiomolybdate into the feces. While fecal Cu increased with tetrathiomolybdate 
administration, the amount of Cu excreted into the urine decreased and that of Mo increased 
significantly during treatment with tetrathiomolybdate. Mo in the urine does not bind to Cu (data 
on file). These findings are in-line with other studies showing enhanced biliary and/or fecal 
excretion of Cu and Mo upon administration of tetrathiomolybdate in rats and sheep (Komatsu, 
2000; Ogra, 1995; Mason, 1988). In contrast, Cu chelators (current standard of care [SoC] for 
WD such as trientine and penicillamine) enhance urinary Cu output, and have been shown to 
drive a net negative Cu balance in most patients with WD and in healthy participants (Strickland, 
1971; Brewer, 1995; Walshe, 1973). These data support that a Cu balance study may be 
conducted in healthy participants to investigate the mechanism of action of decoppering agents 
such as ALXN1840. 
As both healthy and WD animal models have supported the characterization of 
tetrathiomolybdate’s mechanism of action, namely liver Cu depletion through mobilization of Cu 
into plasma and bile and excretion into feces, healthy participants are adequate for assessing the 
mechanism of action of ALXN1840 on Cu balance, which is the primary objective of this study. 
Copper balance is assessed through measurement of all Cu intake (food and drink) and 
measurement of all output (urine and feces) and is classically considered the most objective 
measure of decoppering ability with a decoppering agent able to drive a net negative Cu balance 
(Hill, 1986; Strickland, 1971; Walshe, 1973). Because participants may have different baseline 
Cu balance values and may include values that are both mildly positive and/or negative, the 
primary objective of the study will be to evaluate the change from baseline in Cu balance in 
healthy participants treated with ALXN1840. This approach will allow an assessment of change 
in Cu balance due to ALXN1840 treatment.  Secondarily, the study will also assess whether a net 
negative Cu balance is achieved following ALXN1840 treatment. Taken together, these 
2 complementary Cu balance endpoints will allow an assessment of the role of ALXN1840 on 
Cu balance or its mechanism of action.  
As part of the secondary objective, the study has been designed to descriptively assess the total 
Mo balance (as a surrogate measure of ALXN1840 balance). A dedicated, single-dose study of 
ALXN1840 was performed in normal (Long Evans Agouti [LEA]) rats and LEC WD model rats 
(Plitz, 2018). The rats were treated with 1.5 mg/kg intravenous tetrathiomolybdate single 
injection and placed in a metabolic cage to support collection of urine and feces over 7 days. 
During the 7-day (168 hours) collection period in LEA rats, approximately 87% of the dose was 
accounted for with approximately 79% total Mo dose (as a measure of ALXN1840) excreted in 
the urine and approximately 7% in the feces. Conversely, in the LEC rats, less than half the 
1.5 mg/kg dose was excreted in the 7-day (168 hours) period with approximately 30% remaining 
in the liver and 5-10% in the kidney. A Mo mass balance in healthy participants is sufficient to 
characterize the ADME profile for ALXN1840 and for comparisons to the results from LEA and 
LEC rats. 
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 patients with WD and 

Protocol Amendment 2, 14 May 2020 
 
ALXN1840-HV-108 
Page 19 of 71 
Alexion Confidential 
other indications. Ammonium tetrathiomolybdate as well as bis-choline tetrathiomolybdate 
non-clinical and clinical data reported to date support the efficacy and safety of ALXN1840. 
ALXN1840 rapidly forms irreversible tetrathiomolybdate -Cu-albumin tripartite complexes 
(TPC), which stabilize free Cu leading to a reduction in the NCC concentrations after correction 
for free Cu bound to TPC (NCCcorrected). 
In the Phase 2 proof of concept Study WTX101-201 in patients with WD, ALXN1840 
demonstrated a sustained control of free Cu as measured by NCCcorrected. Importantly, 
ALXN1840 treatment resulted in improvements in disability and neurologic symptoms as 
measured by the Unified Wilson’s 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 patient titration of dose based on safety, NCCcorrected, and symptoms.  
ALXN1840 is currently being evaluated in a Phase 3 multicenter, randomized study to assess the 
efficacy of ALXN1840 compared with SoC on plasma toxic Cu control as measured by 
NCCcorrected. Toxic Cu in this study can be measured via PUF and/or LBC or assessed via 
NCC/NCCcorrected methods. 
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 may be found in the IB. Information about the known or 
potential risks and benefits are detailed in the sections following. 
 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 20 of 71 
Alexion Confidential 
Table 3: 
Potential Risks and Mitigation Strategy 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cu = copper; 
IB = Investigator’s Brochure; PK = pharmacokinetics; WD = Wilson Disease. 
 
2.3.1. 
Benefit Assessment 
This is a healthy participant study, and there is no direct benefit to study participants.  
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 patients with 
WD; see the IB 
Regular monitoring of liver 
function tests.  
Dose modification or 
discontinuation (Section 6.6) 
Anemia 
Anemia has been observed in 
patients with WD, attributed to 
overtreatment and resultant Cu 
depletion, see the IB 
Monitoring complete blood count. 
Dose modification or 
discontinuation (Section 6.6) 
Low white blood cell count 
(leukopenia, bone marrow toxicity)  
Leukopenia and bone marrow 
toxicity (myelosuppression) have 
been observed in patients with 
WD, attributed to overtreatment 
and resultant Cu depletion. 
Results obtained from studies of 
ALXN1840 and ammonium  
tetrathiomolybdate  in patients with 
WD; see the IB 
Monitoring of complete blood 
count.  Dose modification or 
discontinuation (Section 6.6) 
Neurological dysfunction 
Neurological worsening may 
occur due to Cu mobilization. 
Peripheral neuropathy may be 
seen with over-decoppering; 
however, symptoms such as 
myelosuppression is typically 
seen earlier 
Neurologic dysfunction is not 
anticipated in HV population.  
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 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 21 of 71 
Alexion Confidential 
2.3.2. 
Overall Benefit: Risk Conclusion 
Taking into account the measures implemented to minimize risk to participants participating in 
this study, the potential risks identified in association with ALXN1840 are justified by the 
anticipated benefits that may be afforded to patients with WD. 
 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 22 of 71 
Alexion Confidential 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Assess change from baseline in copper (Cu) 
balance over 2 weeks of repeated daily 
ALXN1840 dosing 
Change in mean daily Cu balance from 
pretreatment baseline period to ALXN1840 
treatment period, as measured by the 
calculated difference between Cu intake (in 
food and drink), and Cu output (in feces and 
urine) 
Secondary  
Assess net Cu balance over 2 weeks of 
repeated daily ALXN1840 dosing 
Mean daily Cu balance during ALXN1840 
treatment period where Cu balance is 
measured by the calculated difference 
between Cu intake (in food and drink), and 
Cu output (in feces and urine) 
Assess steady-state molybdenum (Mo) 
balance after 2 weeks of repeated daily 
ALXN1840 dosing 
Mean daily Mo balance at ALXN1840 
pharmacokinetic (PK) steady state, as 
demonstrated through measurement of Mo 
intake (in food, drink, and ALXN1840), and 
Mo output (in feces and urine) 
Assess extent of Mo excretion in urine and 
feces 
Quantify total Mo excretion in urine and feces 
following ALXN1840 treatment compared 
with baseline 
Determine the steady-state plasma PK of 
ALXN1840 after 2 weeks of repeated daily 
ALXN1840 dosing 
PK parameters for plasma total Mo and 
plasma ultrafiltrate (PUF) Mo including 
terminal elimination for Mo after steady-state 
dosing 
Investigate the effect of ALXN1840 on the 
disposition of Cu after 2 weeks of repeated 
daily ALXN1840 dosing at steady state 
Cu quantified in food, feces, and urine over 
2 weeks of ALXN1840 dosing including 
plasma total and labile bound Cu (LBC) at 
steady state 
Investigate the effect of ALXN1840 on the 
disposition of Cu over 2 weeks of repeated 
daily ALXN1840 dosing and through the 
post-treatment period 
Cu quantified in food, drink, feces, and urine  
Investigate the effect of ALXN1840 on the 
disposition of Mo over 2 weeks of repeated 
daily ALXN1840 dosing and through the 
post-treatment period 
Mo quantified in ALXN1840 doses given and 
in food, drink, feces, and urine 
Safety 
Evaluate the safety and tolerability of 
repeated dose administration of ALXN1840 
Safety parameters:  
Treatment-emergent adverse events 
(TEAEs)/serious adverse events (SAEs) 
Clinical laboratory assessments (serum 
chemistry, hematology, coagulation, and 
urinalysis) 
Physical examinations 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 23 of 71 
Alexion Confidential 
Heart rate, intervals (PR, QRS, QT and QTc), 
and clinically significant ECG findings as 
determined by triplicate 12-lead ECG 
Vital sign assessments (blood pressure and 
heart rate) 
Exploratory 
Assess the effects of ALXN1840 on 
ceruloplasmin, ceruloplasmin-bound Cu, and 
LBC profiles in plasma 
Absolute and percent changes in 
ceruloplasmin, ceruloplasmin-bound Cu, 
ceruloplasmin-bound Cu:ceruloplasmin ratio, 
and LBC during treatment period and post-
treatment compared with predose baseline 
Assess the effects of repeated daily 
ALXN1840 dosing on Cu:Mo ratio in plasma 
at steady state 
Measure plasma Cu:Mo ratios during 
treatment period and post-treatment compared 
with predose baseline 
Assess the effects of ALXN1840 on Cu:Mo 
ratio in urine and feces 
Measure the average daily Cu:Mo ratio in 
urine and feces during treatment and post-
treatment compared with predose 
Assess the effects of ALXN1840 on the time 
course of Cu balance over 2 weeks 
Evaluate the effect of time on change in 
average daily Cu balance  
 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 24 of 71 
Alexion Confidential 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a single-arm, open-label, repeat-dose (30 mg/day) study designed to assess the effects of 
ALXN1840 administration on Cu balance in healthy participants. 
This study will be conducted in a minimum of 2 groups. The first group will consist of 
approximately 6 participants and no more than 8 participants. The second group may only be 
initiated after the Safety Review Committee (SRC; defined in Section  9.7) reviews safety 
information (all AEs, safety laboratory data, and vital signs) through Day 18 and agrees that it is 
safe to continue enrollment to complete the study. If ceruloplasmin concentrations or AE 
findings are suggestive of over-depletion of Cu, the SRC may propose a dose reduction to 
15 mg/day for remainder of the study population. 
This is a single arm study. Following screening and enrollment, participants will have a Run-in 
Period to support diet equilibration (Day -7 through Day -5) and measure of pretreatment Cu and 
Mo balance (Day -4 through Day -1). Following the Run-in Period, participants will be 
administered ALXN1840 at 30 mg/day for 15 days (Day 1 through Day 15). ALXN1840 will be 
administered orally after an overnight fast, and participants will remain fasted for a minimum of 
2 hours following each dose administration. Following completion of the 15 days dosing period, 
participants will remain the clinical research unit (CRU) for an additional 16 days until discharge 
on Day 31.   
Total intake and output will be measured continuously from Day -4 through Day 30 with Day 1 
through Day 15 representing the ALXN1840 treatment period and Day 16 through Day 30 
representing the post-treatment period. The collection period will support assessment of Cu 
balance and Mo mass balance including assessment at steady state and terminal elimination.    
Participants will return to the CRU for a final study visit on Day 43 ± 2 days, approximately 
28 days after the final dose of ALXN1840, to conclude the safety follow-up period. 
Participants meeting all study entry criteria prior to Cu/Mo controlled diet initiation are eligible 
for enrollment.  At the time of enrollment, participants will be assigned a subject number for the 
study.   
Throughout the period in the CRU, participants will remain on a Cu- and Mo-controlled diet with 
a limited selection of meals utilized for breakfast, lunch and dinner throughout the study to 
ensure Cu/Mo control (Table 4). During the intake and output collection periods, daily urine will 
be pooled (24-hour collection) with volumes recorded for each 24-hour period. Fecal samples 
will be individually collected; each sample will include a collection date, time, and weight. To 
support accurate determination of daily Cu/Mo content for each 24-hour period, participants 
should be encouraged to provide urine and fecal sample (if appropriate) prior to 0800 or the 
dosing time each morning. To support assessment of daily Cu/Mo balance, on Days -4 through 
Day 30, at every mealtime, an additional meal will be prepared from the same batch as the meals 
being given to the study participants and will be analyzed for Cu and Mo content. A minimum of 
3 complete meals from each prepared batch will be sent for analysis. 
Copper balance is defined as the difference between the measured Cu input in food and drink, 
and the measured Cu elimination in urine and feces, and will be calculated as the average daily 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 25 of 71 
Alexion Confidential 
Cu balance over the collection period. For assessment of ALXN1840 effect on Cu 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; Weaver, 1984). 
Collection over the entire 15 days of ALXN8140 treatment allows a robust average assessment 
of Cu balance and ensures a complete assessment of Mo ADME.  The study assumes insensible 
loss due to sweat does not change significantly with ALXN1840 treatment and is therefore not 
measured.  While menstruation is not anticipated to significantly impact Cu/Mo balance, it may 
have minor impact on interpretation of the urine data.  Dates of menstruation should be collected 
to help support data interpretation.  
Mo mass balance, as a measure of ALXN1840 ADME, will be calculated in an analogous 
fashion to Cu balance; however, the Mo balance will also include the Mo content in ALXN1840 
as part of the Mo intake in the calculation. Following the final ALXN1840 dose administration 
on Day 15, intake and output collection will continue through Day 30 to characterize the extent 
of Mo and Cu elimination, which may allow for better understanding of Mo and Cu elimination 
after dose discontinuation.  
Intensive blood sampling for PK/PD will occur over the 24-hour dosing periods on Day 1 and 
Day 15. Additional PK/PD sampling will occur as noted in the Schedule of Activities (Table 1).  
4.2. 
Scientific Rationale for Study Design 
As both healthy and WD animal models have supported the characterization of 
tetrathiomolybdate’s (ALXN1840) mechanism of action, namely liver Cu depletion through 
mobilization of Cu into plasma and bile and excretion into feces, healthy participants are 
adequate for assessing the mechanism of action of ALXN1840 on Cu balance, which is the 
primary objective of this study. The inclusion and exclusion criteria for this study are consistent 
with typical Phase 1 clinical pharmacology studies for assessing the medication of interest. To 
limit the risk of Cu depletion in healthy participants (or the risk of recruiting participants with 
abnormal Cu metabolism), only participants with serum Cu and ceruloplasmin above the lower 
limit of normal will be included.   
The 15-day duration for ALXN1840 dosing is supported by both preclinical and clinical data. 
Preclinical models suggest that Cu excretion in feces may be increased or at least sustained with 
repeated-dose administration over 5-8 days. With gastrointestinal transit in humans being 
somewhat longer than most animal models (Mason, 1988; Ogra, 2000), a 15-day repeat dose is 
considered reasonable. Based on studies in oncology patients, a dose of 30 mg/day for 28 days 
resulted in a substantive reduction in ceruloplasmin (Lin, 2013). Copper-containing 
ceruloplasmin, known has holo-ceruloplasmin, has a half-life of approximately 5 days, and 
serum ceruloplasmin concentrations (largely determined by holo-ceruloplasmin) are indicative of 
reduction in total body Cu load (Harris, 1997; Sternlieb, 1961). Taken together, a dose of 
30 mg/day for 15 days is expected to result in a net negative Cu balance in healthy participants 
with an acceptable safety profile. 
Following ALXN1840 administration, the active drug moiety tetrathiomolybdate rapidly binds 
Cu to form TPC 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 Mo, and is excreted in the urine. Total Mo 
concentration has been measured as a surrogate of ALXN1840 PK; however, total Mo 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 26 of 71 
Alexion Confidential 
concentration cannot distinguish whether the Mo is complexed with Cu and albumin (as in TPC), 
free active ALXN1840 drug, intermediate hydrolysis products, or molybdate which may be from 
ALXN1840 hydrolysis.  To better characterize the amount of non-TPC bound ALXN1840 and 
its degradation products, plasma ultrafiltrate Mo (PUF Mo), which represents the free parent 
drug (ALXN1840), short-lived intermediate hydrolysis products, and molybdate, will be 
measured. Total Mo and PUF Mo concentrations also include physiologic molybdate 
concentrations from dietary micronutrient molybdate intake. While it is not feasible to separate 
and quantify ALXN1840 directly in the plasma, total Mo PK and PUF Mo PK provide surrogate 
measures to characterize ALXN1840 exposure. To better characterize the ADME of ALXN1840, 
the PK of both total Mo and PUF Mo will be characterized and described.  
Single dose administration of the enterically-coated ALXN1840 under fasted conditions in 
healthy participants resulted in a peak total Mo concentration, as stable TPC, at approximately 
4.54 hours with a half-life of approximately 51 hours. In Study WTX101-HV-106, a 60-mg dose 
demonstrated a total Mo time to maximum concentration (Tmax) of approximately 6 hours with 
up to 14% of the total Mo represented as PUF Mo, which also peaked at approximately 6 hours 
post dose. By 24 hours, PUF Mo had declined to approximately 3-5% of the total Mo.  These 
findings are consistent with results from the Phase 2 Study WTX101-201 in patients with WD. 
Given the much longer half-life of total Mo, a repeat dose study of 15 days duration will support 
steady state assessment of ALXN1840 ADME (as measured by total Mo and PUF Mo). In 
addition, complete collection of Mo over the ALXN1840 treatment period as well as the 15-day 
terminal elimination period may support a complete assessment of Mo balance for the study. 
As this study represents the first repeat dose study in healthy participants, dosing duration will be 
limited to 15 days.  Safety laboratory tests will be monitored at least every 3 days with individual 
and cohort stopping criteria in place if significant safety risks are identified. In addition, if 
findings of Cu depletion or toxicity are identified in the initial study group by Day 18, the dose 
of ALXN1840 may be reduced to 15 mg/day for the remainder of the enrolled participants. 
4.2.1. 
Participant Input into Design 
Not applicable as this is a study in healthy participants. 
4.3. 
Justification for Dose 
The 30-mg dose selected for this study in healthy participants is within the 15 to 60 mg daily 
dose range that has demonstrated an acceptable safety profile in healthy volunteers and patients 
with WD in Phase 1 to Phase 3 clinical studies. 
Repeated doses between 15 and 60 mg/day have been tested in the Phase 2 Study WTX101-201 
and are being tested in the ongoing Phase 3 Study WTX101-301. A single oral dose of 60 mg has 
been tested in healthy volunteers in Phase 1 Studies WTX101-101, WTX101-102, and 
WTX101‑HV-106, and has been well tolerated.  
While most studies used high doses (120-300 mg/day or greater) of tetrathiomolybdate to rapidly 
deplete total body Cu as measured by ceruloplasmin, Lin et al reported use of bis-choline 
tetrathiomolybdate (ALXN1840) at a more modest dose of 30 mg/day in prostatic malignancy 
administered in 28‑day cycles (Lin, 2013). At this dose, only a moderate reduction in 
ceruloplasmin was reported with the median value remaining just above 20 mg/dL (reference 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 27 of 71 
Alexion Confidential 
range: 20‑35 mg/dL). Only one Grade 3 hematologic finding of leukopenia was reported at this 
dose (during the study, which included up to four 28‑day cycles of ALXN1840). The proposed 
dosing period for this study is half that of a single 28-day cycle, for which reports indicate that 
the safety risk is acceptable with adequate monitoring and management (Lin, 2013). 
In addition to its use in both patients with WD and healthy volunteers, tetrathiomolybdate, the 
active anion in ALXN1840, has been used in a substantive number of oncology programs, and 
based on published data, bis-choline tetrathiomolybdate (ALXN1840) has been well tolerated up 
to a maximum tolerated repeated dose of 300 mg/day (Lowndes, 2008). Early oncology 
programs employed an induction approach with the use of high doses of tetrathiomolybdate 
followed by lower maintenance doses and used serum ceruloplasmin as a marker for depletion of 
total body Cu, with a target ceruloplasmin concentration between 5 and 15 mg/dL (Lowndes, 
2008; Brewer, 2000; Lin, 2013; Pass, 2008; Henry, 2006). The most commonly reported AEs in 
oncology programs include fatigue, dizziness, myelosuppression (anemia, leukopenia, 
neutropenia, lymphocytopenia and/or thrombocytopenia), and gastrointestinal complaints 
(nausea, vomiting, diarrhea, constipation, flatulence, sulfur burps, anorexia). With the exception 
of the gastrointestinal complaints, reported AEs have largely been associated with over-
decoppering. Myelosuppression is monitorable and has been shown to be reversible with 
correction of Cu deficiency. Occasional reports of liver function test abnormalities were also 
noted (Lin, 2013; Lowndes, 2008).  
Based on the above safety and ceruloplasmin data, a dose of 30 mg/day for 15 days has been 
chosen for this study. The dose of 30 mg/day is 1/10th of the MTD identified in oncology 
patients. In addition, the reduction in ceruloplasmin concentration, which is considered a 
measure of total body Cu, suggests that a 30 mg/day dose may be sufficient to drive a net 
negative Cu balance during the treatment period. 
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 (Table 1). 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 28 of 71 
Alexion Confidential 
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 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Participants must be 18 to 45 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Participants who are healthy as determined by medical evaluation with no clinically 
significant or relevant abnormalities as determined by medical history, physical 
examination, vital signs, 12-lead ECG, and clinical laboratory evaluation (hematology, 
biochemistry, coagulation, and urinalysis) that are reasonably likely to interfere with the 
participant's participation in or ability to complete the study, or to potentially confound 
interpretation of study results, as assessed by the Investigator. 
3. Have regular bowel movements (at least once per day) 
4. Adequate venous access in the left or right arm to allow collection of study-required 
blood samples.  
5. Willing and able to adhere to all dietary requirements of the study. 
Weight 
6. Body weight between 50 to 70 kg (inclusive) for female participants, and 65 to 85 kg 
(inclusive) for male participants, and body mass index (BMI) within the range 
18 – 25 kg/m2 (inclusive). 
Sex 
7. 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 (ie, 3 months 
after the EOS Visit).  Male participants must not donate sperm for at least 3 months 
after the end of systemic exposure of the study intervention (ie, 3 months after the 
EOS Visit).  
• 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 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 29 of 71 
Alexion Confidential 
partner’s systemic exposure to the study intervention (ie, 3 months after the EOS 
Visit).  
• Barrier contraception 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 barrier 
method (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 (ie, 3 months after the EOS Visit). 
Female participants must not donate ova for at least 3 months after the EOS (ie. 3 
months after the EOS Visit). 
• 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 
8. Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions  
1. History or presence of/significant history of or current cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological 
disorders, or psychiatric disorder. Any surgical or medical history which may 
significantly alter the absorption, metabolism, or elimination of drugs or constitute a risk 
when taking the study intervention; or interfering with the interpretation of data (eg, 
gastric bypass, cyclical vomiting, etc). 
2. History or presence of gastrointestinal conditions including chronic constipation and 
irritable bowel syndrome 
3. Supine blood pressure ≤ 90/60 mmHg or > 140/90 mmHg at Screening and on vital signs 
assessed prior to enrollment (Day -7); systolic or diastolic components outside of range 
should result in exclusion. Supine blood pressure should be taken after a minimum of 5 
minutes in supine position. If vital signs are abnormal, two additional readings will be 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 30 of 71 
Alexion Confidential 
taken. The mean of the 3 replicates will be recorded in the case report form (CRF) and 
used to determine inclusion.   
4. Lymphoma, leukemia, or any malignancy except for basal cell or squamous epithelial 
carcinomas of the skin that have been resected with no evidence of metastatic disease for 
3 years. 
5. Breast cancer within the past 10 years 
6. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin 
> upper limit of normal (ULN) of laboratory reference range at screening and at check-in 
(Day -8). At the discretion of the Investigator, a single repeat analysis may be performed 
per time point to assess eligibility. ALT, AST, and total bilirubin values on Day -1 must 
not exceed 1.3 x ULN to initiate ALXN1840 dosing on Day 1. 
7. Serum Cu or serum ceruloplasmin below lower limit of normal on laboratory reference 
range at Screening 
8. History of anemia or hemoglobin < 130 g/L for men and hemoglobin < 115 g/L for 
women at screening and at check-in (Day -8). At the discretion of the Investigator, a 
single repeat analysis may be performed per time point to assess eligibility. 
9. History of benign ethnic neutropenia or absolute neutrophil count < 1500/uL; lymphocyte 
count below 1000/uL at check-in (Day -8). At the discretion of the Investigator, a single 
repeat analysis may be performed per time point to assess eligibility. 
10. Blood donation or blood loss in excess of 500 mL in the 60 days prior to screening  
11. ECG showing 120 ms > PR > 240 ms, QRS> 110 ms, and QTcF> 450 ms for men and 
QTcF> 480 ms for women at Screening and on Day -7 prior to enrollment. As with vital 
signs, if ECG interval measurements are abnormal, an additional 2 replicate measures 
will be performed with the mean of the 3 measured interval values used to confirm 
eligibility and recorded in the CRF.  
12. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(except for asymptomatic gallstones). Participants with elevated total bilirubin or history 
of Gilbert’s will be excluded from the study. 
13. Any other significant disease or disorder which, in the opinion of the Investigator, may 
put the participant at risk or confound the interpretation of the results.  
14. History of hypersensitivity to ALXN1840 or its excipients or any significant allergic 
reaction (eg, anaphylaxis or angioedema) to any product (eg, food, pharmaceutical).  
Prior/Concomitant Therapy 
15. Use or intended use of prescription medications (excluding oral contraceptives) within 
14 days or 5 half-lives of the drug (whichever is longer) prior to Day -7, and/or intended 
use at any point over the duration of the study except with prior approval of Alexion.  
16. Use of nonprescription/ over-the-counter medications, including herbal remedies and 
supplements, within 7 days or 5 half-lives of the drug (whichever is longer) prior to 
Day -7 and/or intended use at any point over the duration of the study.  

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 31 of 71 
Alexion Confidential 
Prior/Concurrent Clinical Study Experience 
17. Exposure to more than 4 new chemical entities within 12 months prior to dosing 
18. Current enrollment or past participation, within the last 90 days, before signing of 
consent in this or any other clinical study involving an investigational study intervention 
or any other type of medical research. Participants, involved in intervention studies using 
investigation or non-investigational drug with prolonged half-lives, are not eligible unless 
the time since last treatment has exceeded 90 days or 5 half-lives of the study 
intervention, whichever is longer. Those who participated in the non-interventional 
Cu/Mo balance test study C19029 conducted by Richmond Pharmacology Limited 
(RPL), London, the United Kingdom between 17 Oct 2019 and 27 Oct 2019 are eligible 
to participate in this study. 
Diagnostic Assessments 
19. Presence of hepatitis B surface antigen or positive hepatitis C antibody or RNA test result 
at screening or within 3 months prior to first dose of the study intervention. 
NOTE: Patients with positive Hepatitis C antibody due to prior resolved disease can be 
enrolled if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test result is 
obtained. NOTE: The RNA test is optional and patients with negative Hepatitis C 
antibody test are not required to also undergo Hepatitis C RNA testing 
20. Positive human immunodeficiency virus (HIV) antibody test 
Other Exclusions 
21. Female participants who are pregnant, as evidenced by a positive serum pregnancy test 
result at screening, or breastfeeding. 
22. Prior exposure to ALXN1840. 
23. Major surgery or hospitalization within 90 days prior to dosing on Day 1.  
24. Use of tobacco in any form (eg, smoking, chewing or vaping), other nicotine-containing 
products in any form (eg, gum, patch, electronic cigarettes, or vapes), or any recreational 
inhalational product within 6 months prior to the planned first day of dosing.   
25. Use of known drugs of abuse within 6 months prior to the planned first day of dosing. 
26. 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 NHS alcohol tracker 
http://www.nhs.uk/Tools/Pages/drinks-tracker.aspx.  
27. Positive urine drug toxicology screen at Screening or on Day -8.   
28. Alcohol consumption within 24 hours prior to study intervention administration or 
positive alcohol breath test at screening or on Day -8. 
29. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or Medical Monitor, contraindicates 
participation in the study. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 32 of 71 
Alexion Confidential 
5.3. 
Lifestyle Considerations 
Participants must be able and willing to adhere to the lifestyle restrictions detailed in Table 4. 
Table 4: 
Healthy Participant Lifestyle Considerations 
Restrictions 
Timeframe restriction 
applies 
Restrictions end 
Food 
Participants will remain on a Cu/Mo controlled diet. 
Standardized Cu- and Mo-controlled meals will be 
provided as described in the SoA (Table 1). 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 
Cu/Mo determination as a fraction of the total meal.  
Participants will be expected to fast overnight. During 
the dosing period (Day 1 through Day 15), 
participants will be administered ALXN1840 with 
240 mL of water each morning; participants must 
remain fasted for a least 2 hours after dose 
administration. 
 
Participants must allow for collection of all stool and 
urine from Day -4 through Day 30) 
Dietary restrictions will 
remain in place from Day -7 
through Day 30 
 
 
Participants may return 
to routine diet after 
completion of Day 30. 
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 from Day -7 
through Day 30 
Participants may return 
to routine fluid intake 
after completion of Day 
30.   
Tobacco in any form (eg, smoking or chewing), other 
nicotine-containing products in any form (eg, gum, 
patch, electronic cigarettes), or any recreational 
inhalational product.  
From Screening to EOS 
visit. 
Restrictions ends after 
completion of EOS visit. 
Not consume any other substances known to be potent 
inhibitors or inducers of CYP450s. This includes food 
or drink products containing cranberry, pomegranate, 
star fruit, grapefruit, pomelos, exotic citrus fruits or 
Seville oranges (including marmalade and juices 
made from these fruits). Red wine should also not be 
consumed. 
Within 7 days before check-
in to the CRU (Day -8) until 
discharge on Day 31. 
After discharge from the 
CRU. 
Caffeine-containing or xanthine-containing products 
(eg, tea, coffee, cola drinks, and chocolate).  
During each dosing period, 
24 hours before check-in to 
the CRU (Day -8) through 
Day 30. 
After collection of the 
final PK sample for the 
study (Day 30). 
Energy drinks or drinks containing taurine, 
glucuronolactone (eg, Red Bull).  
48 hours before check-in to 
the CRU (Day -8) through 
EOS visit. 
Restrictions ends after 
completion of EOS visit. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 33 of 71 
Alexion Confidential 
Restrictions 
Timeframe restriction 
applies 
Restrictions end 
Alcohol 
48 hours before check-in to 
the CRU (Day -8) and until 
discharge (Day 31), and 48 
hours before each study 
outpatient/Follow-up Visit.  
Discharge from the 
clinical research unit 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 four 
24 hour prior to each for the duration of the study.   
48 hours prior to check-in to 
the CRU (Day -8) and until 
discharge (Day 31). 
 
Restrictions ends after 
completion of EOS visit. 
Any prescription medication. Concomitant 
prescription medications may be used during the 
study to treat adverse events as deemed medically 
indicated by the investigator.  The investigator or 
delegate will notify the Sponsor of any adverse events 
requiring administration of prescription medication(s) 
while on study. 
Note: Investigator in consultation with the Sponsor 
should determine participant’s continued suitability to 
remain in the study.   
14 days or 5 half-lives 
(whichever is longer) prior 
to Day -7 through EOS visit. 
 
Restrictions ends after 
completion of EOS visit. 
Any nonprescription/over-the-counter medication, 
including herbal remedies and supplements. For 
details, Section 6.5.1.  
Nonprescription/over-the-
counter medications may be 
used for adverse events 
under the direction and at 
the discretion of the 
investigator including up to 
1000 mg/day of 
paracetamol/acetaminophen. 
After the EOS visit. 
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 inclusion criteria #7). 
See Section 10.4. 
Abbreviations: CRF = case report form; CRU = clinical research unit; Cu = copper; CYP450 = cytochrome 
CYP450; EOS = end of study; Mo = molybdenum; PK = pharmacokinetic. 
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 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 34 of 71 
Alexion Confidential 
(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. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 35 of 71 
Alexion Confidential 
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 Administered 
Details of ALXN1840 administered in the study are provided in Table 5. 
Table 5: 
Details of Study Intervention Administered 
Arm Name 
Study Intervention 
Intervention 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 dose 30 mg administered as 2 × 15 mg ALXN1840 tablets for 15 days 
Route of Administration 
Oral 
Use 
experimental/study intervention  
IMP and NIMP 
IMP  
Sourcing 
Provided centrally by Alexion 
Packaging and Labeling 
The labeling of study intervention will be in compliance with Good 
Manufacturing Practice specifications, as described in the Rules Governing 
Medicinal Products in the European Union, Volume 4, annex 13, Investigational 
Medicinal Products, and any other or local applicable regulations.  
Sample labels will be submitted to the UK health authorities according to the 
submission requirements. 
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. 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 
PPD

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 36 of 71 
Alexion Confidential 
related to the identity, quality, durability, reliability, usability, safety, effectiveness, or 
performance of a product or clinical trial 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. 
4. 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 the same dose of ALXN1840. 
6.4. 
Study Intervention Compliance 
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 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. Study 
site personnel will examine each participant’s mouth to ensure that the study intervention was 
ingested. 
For additional information on study intervention compliance and management, refer to the 
Pharmacy Manual. 
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 end of study visit must be 
recorded along with: 
• Reason for use 
• 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 
and/or prior therapy. 
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 
co-administration 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 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 37 of 71 
Alexion Confidential 
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 designee.  
• 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 
Asymptomatic elevations of hepatic transaminases and gamma glutamyltransferase have been 
reported in patients with WD treated with ALXN1840 and have occasionally been seen in 
ALXN1840 single dose studies in healthy volunteers, and in published data from oncology 
studies. Liver enzymes will be monitored a minimum of every 3 days throughout the study. In 
addition, chronic treatment with ALXN1840 may result in anemia, leukopenia or 
thrombocytopenia due to over-decoppering. As this is the first repeat-dose study to be conducted 
in healthy participants, complete blood count with platelets will also be monitored a minimum of 
every 3 days. Ceruloplasmin concentrations will be measured and may be used as appropriate to 
guide group dosing decisions. 
If laboratory tests result in abnormal values, it will be expected that the tests are repeated to 
confirm those results. Depending on the severity of the abnormal values, laboratory tests may be 
checked as frequently as daily; it is at the discretion of the Investigator to track abnormal values.  
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, ECG abnormality or AE 
that are considered of clinical concern by the Investigator. Investigators must notify Alexion 
immediately of drug discontinuation.  The decision to discontinue drug should not be delayed for 
causality assessment. 
Following dosing of the first group of approximately 6-8 participants, if ceruloplasmin 
concentrations or AE findings are suggestive of Cu depletion, the SRC (Section 9.7) may reduce 
the dose to 15 mg/day for the remainder of the study population. 
Dose modification guidelines will be specified as follows. 
6.6.1. 
Adverse Reaction Rules 
An adverse reaction is any treatment emergent adverse event (TEAE) that is considered related 
to the study medication (for a full definition of related TEAEs, see Section 10.3.3). When a 
TEAE occurs, timely determination of relatedness is not always feasible. In such cases, the 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 38 of 71 
Alexion Confidential 
Investigator and Alexion should use judgment in protecting the individual patient and study 
population. 
6.6.1.1. 
General Adverse Reaction Rules 
The general adverse reaction rules refer to all adverse reactions, excluding those relating to the 
liver and hematology and QT interval prolongation. The Common Terminology Criteria for 
Adverse Events (CTCAE) may not give clear enough guidance, and grading may not be 
appropriate for this study in healthy volunteers; therefore, special study-specific rules have been 
created. 
6.6.1.2. 
Individual Adverse Reaction Rules 
An individual participant will not receive any further dose(s) of ALXN1840, if either of the 
following occurs: 
• Participant experiences any CTCAE Grade 3 (or higher) adverse reaction, or a serious 
adverse reaction, irrespective of severity/CTCAE grade. 
• Participant experiences any CTCAE Grade 1 or 2 adverse reaction considered to be 
related to ALXN1840 and considered a safety concern by the SRC. 
6.6.1.3. 
Group Adverse Reaction Rules 
Dosing will be suspended for all participants or potentially only in an affected dose group (in the 
event a dose reduction is employed for the second group), if either of the following occurs: 
• One participant experiences a non-serious, severe (CTCAE Grade 3) adverse reaction. 
• One participant experiences a serious adverse reaction, irrespective of 
severity/CTCAE grade. 
• One participant experiences a Grade 2 or higher adverse reaction which is considered 
by the SRC of significant medical consequence to the remaining group to require 
discontinuation of dosing to the remainder of the group 
In the event of suspension of dosing, continuation of the study will require a protocol amendment 
that has been approved by the MHRA and ethics committee. 
6.6.1.4. 
Special individual Adverse Reaction Rules 
Dosing in an individual participant will be suspended if they experience any of the following: 
• Liver function test elevation 
− ALT or AST value > 3 × ULN in the presence or absence of symptoms. Grade 2 
or higher by NCI CTCAE v 5.0. 
− Any possible Hy’s law case will be considered a serious adverse event defined as 
ALT ≥ 3 × ULN AND total bilirubin ≥ 2 x ULN (or 35% increase in direct bilirubin) 
or INR > 1.5 (if measured) 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 39 of 71 
Alexion Confidential 
− Any ALT or AST or other liver function test elevation or trend in elevation that in 
the opinion of the Investigator and/or Alexion may place the participant at risk if 
dosing is continued 
• Hematology 
− Hemoglobin reduction to an absolute value of 9.5 g/dL (95 g/L) or lower. Because 
of the repeated blood draws in the study, an addition 0.5 g/dL (5 g/L) over the 
Grade 2 CTCAE v 5.0 value may be tolerated at the investigator discretion and 
based on clinical judgment. 
− Platelet count reduction to an absolute value < 75,000/mm3, defined as Grade 2 or 
higher by NCI CTCAE v 5.0 
− Any hematologic abnormality that in the opinion of the investigator and Alexion 
may place the participant at risk if dosing is continued 
• QT interval prolongation 
− A prolongation of the QTcF interval of > 500 ms (using consistent, technically 
valid triplicate ECG)  
6.6.1.5. 
Special group Adverse Reaction Rules 
• For special group adverse reaction stopping rules (ie transaminase elevation, 
hematologic abnormalities and QT prolongation), dosing will be suspended for all 
participants or to the dosing group if any of the following occurs: 
− One or more participants experience a non-serious, severe (NCI CTCAE Grade 3) 
or higher adverse reaction. 
− One or more participants experience a serious adverse reaction, irrespective of 
severity/CTCAE grade 
− One or more participants experience a Grade 2 or higher adverse reaction that is 
considered by the SRC of significant medical consequence to the remaining group 
to require discontinuation of dosing to the remainder of the group 
6.6.1.6. 
Safety Oversight and Implementation Stopping Rules  
• If one or more participants fulfills criteria from either the individual adverse reaction 
rules (outlined in Section 6.6.1.2 and/or Section 6.6.1.4) or for group adverse reaction 
rules (outlined in Section 6.6.1.3 and/or Section 6.6.1.5), a SRC meeting will be 
arranged. At this meeting, a decision will be made regarding the 
continuation/discontinuation of dosing for the remaining participants as well as need 
for dose modification. Based on the severity and medical risk to other participants and 
on request of either the Investigator or Alexion, dosing for all participants will be 
temporarily suspended until the SRC meets.  
• The SRC will meet following completion of Day 18 of Group 1 to confirm adequate 
safety to complete dosing at 30 mg/day. Dose reduction to 15 mg/day may be made 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 40 of 71 
Alexion Confidential 
following review of Group 1 data if there is evidence of over-decoppering as 
determined by AEs and/or ceruloplasmin concentration.   
• The SRC will be comprised of, at minimum, the Investigator and Alexion’s Medical 
Monitor. Additional site staff and Alexion personnel may also be included and will be 
responsible for reviewing all safety data and making determination around dosing. 
• In the event of suspension of dosing, continuation of the study will require a protocol 
amendment that has been approved by the MHRA and ethics committee. 
6.7. 
Intervention After the End of the Study 
This is a healthy participant study and no follow-up intervention is planned. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 41 of 71 
Alexion Confidential 
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 SoA 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 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. This is expected to be uncommon. 
• At the time of discontinuation from the study, participants will be seen and assessed 
by the Investigator or study physician and whenever possible, will undergo the 
procedures associated with the early termination visit. as shown in the SoA. See the 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 42 of 71 
Alexion Confidential 
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. 
• 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. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 43 of 71 
Alexion Confidential 
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. 
8.1. 
Efficacy Assessments 
No efficacy assessments will be obtained during this study. 
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.  
PK 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. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 44 of 71 
Alexion Confidential 
• 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 semi-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 patient 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 2 replicate 
measures will be performed with the mean of the 3 measured interval values used to 
confirm eligibility 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 test results with values considered abnormal and clinically significant 
during participation in the study 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. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 45 of 71 
Alexion Confidential 
8.2.4.1. 
Bowel and Urine Monitoring 
Participants’ bowel movements and urination will be monitored by the clinical staff. The clinical 
staff will record each time a fecal and urine sample is collected in the CRF. All urine and feces 
must be collected from Day -4 through Day 30. Day -4 through Day -1 will represent the 
pretreatment baseline, Day 1-15 will represent the treatment period and Day 16-30 will represent 
the post-treatment period. 
8.2.4.2. 
Intake monitoring 
To support accurate quantification of Cu/Mo 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 Cu/Mo 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  
Not applicable to this study.  
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 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-up with for 
3 months postpartum. Exposure of an infant to an Alexion product during breastfeeding 
must also be reported (see Section 10.3 for contact information). 
• 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. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 46 of 71 
Alexion Confidential 
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 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 towards 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, IRBs/ IECs, and Investigators. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 47 of 71 
Alexion Confidential 
• 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. 
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 or 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 Mo and PUF Mo as specified in the SoA (Table 1) via inductively coupled 
plasma mass spectrometry (ICP-MS).  
• 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. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 48 of 71 
Alexion Confidential 
• Samples 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 8.7 for details of Mo measured in food, drinks, urine, and feces. 
8.6. 
Pharmacodynamics 
Plasma total Cu, ceruloplasmin, ceruloplasmin-bound Cu, 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. The isolated plasma will be stored at -20°C before analysis. Plasma samples 
will be used for ICP-MS measurement of total Cu, ceruloplasmin, ceruloplasmin-bound Cu, and 
toxic copper as measured by LBC and/or NCC at the time points indicated in the SoA (Table 1). 
8.7. 
Copper and Molybdenum Balance Measurements 
Copper and Mo 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 Cu and 
Mo concentration of each sample will be determined by ICP-MS. Cu and Mo 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. 
8.7.1. 
Food and fluid collection for Cu and Mo concentrations 
Samples of all meal and fluid batches will be collected and analyzed for measurement of Cu and 
Mo 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 Cu and Mo content.   
Samples will be collected, stored and shipped as detailed in the Laboratory Manual. All sample 
handling procedures, including the time of each sample collection, the time of placement into 
frozen storage, and the date of transfer or shipment of the samples to the responsible analyst will 
be documented in detail in the Laboratory Manual. Copper and Mo concentration of each food 
sample (ng/g) and each fluid sample (ng/ml) sample will be determined by ICP-MS. 
8.7.2. 
Urine Collection for Measurement of Copper and Molybdenum content 
Urine samples to measure Cu and Mo content will be taken on Day -4 through Day 30, 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, including the time of each sample 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 49 of 71 
Alexion Confidential 
collection, the time of placement into frozen storage, and the date of transfer or shipment of the 
samples to the responsible analyst will be documented in detail as described in the Laboratory 
Manual. Copper and Mo concentration (ng/mL) of each 24-hour urine sample will be determined 
by ICP-MS. 
Fecal Collection for Measurement of Copper and Molybdenum content 
Fecal samples to measure Cu and Mo content will be taken on Day -4 through Day 30 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, 
including the time of each sample collection, the time of placement into frozen storage, and the 
date of transfer or shipment of the samples to the responsible analyst will be documented in 
detail in the Laboratory Manual. Copper and Mo concentration (ng/g) of each stool sample will 
be determined by ICP-MS; each sample will be analyzed using a minimum of technical 
triplicates.  
8.8. 
Genetics 
Genetics are not evaluated in this study. 
8.9. 
Biomarkers 
Please see Section 8.6 for details of total Cu, ceruloplasmin, ceruloplasmin-bound Cu, and toxic 
copper as measured by LBC and/or NCC, and Section 8.7 for details of Cu measured in food, 
drink, urine, and feces. 
8.10. 
Immunogenicity Assessments 
Not applicable. 
8.11. 
Health Economics Data and/or Medical Resource Utilization 
Health economic and medical resource utilization parameters are not evaluated in this study. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 50 of 71 
Alexion Confidential 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary Hypothesis 
Not applicable. 
9.2. 
Sample Size Determination 
The study sample size is not based on null hypothesis significance testing. A sample size of 
13  participants has been selected based on convention for this type of study (Strickland, 1971). 
To accommodate a 25% dropout rate, approximately 17 participants will be enrolled to achieve 
13 evaluable participants. 
9.3. 
Populations for Analyses 
The population sets used for analysis sets are defined in Table 6. 
Table 6: 
Populations for Analyses 
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 
Safety Set  
All participants who receive at least 1 dose of ALXN1840  
Full Analysis Set  
All participants who receive at least 1 dose of ALXN1840   
Per Protocol Set 
All participants who receive at least 1 dose of ALXN1840 and have both 
baseline and Day 15 values. Participants with major protocol deviations 
that are likely to impact the primary efficacy endpoint analysis will be 
excluded from the Per Protocol Set. Major protocol deviations, and the Per 
Protocol Set, will be defined, documented, and agreed within Alexion prior 
to database lock. 
Pharmacokinetic/Pharmacodynamic 
Analysis Set 
All participants who have sufficient samples to enable the calculation of 
PK parameters and provide PK/PD profiles 
Abbreviations: ICF = informed consent form; PK = pharmacokinetics 
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 day and period 
(predose baseline, treatment, steady state, and post-treatment) where applicable. Descriptive 
statistics for continuous variables will minimally include the number of participants, mean, SD, 
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. 
Efficacy Analyses 
No efficacy endpoints are included as part of this study, therefore there is no analysis of efficacy.   

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 51 of 71 
Alexion Confidential 
9.4.1.1. 
Analyses of Primary Endpoint 
The primary objective of this study is to assess the change from baseline in average daily Cu 
balance after 2 weeks of ALXN1840 treatment at 30 mg/day in healthy participants. Secondarily, 
the study will also assess whether a net negative Cu balance is achieved following ALXN1840 
treatment. The study will also assess Mo balance at ALXN1840 PK steady state. 
The primary analysis will be performed using the Full Analysis Set. Change from baseline in 
average daily Cu balance over Days 4 to 15 will be summarized using descriptive statistics based 
on data as observed. The 95% confidence limits for the mean change from baseline will be 
provided. 
Copper balance is defined by the difference in Cu input and Cu output. A negative Cu balance 
will indicate greater Cu output than Cu intake. Copper input is defined as the sum of all Cu input 
as measured in all food and fluids over the specified period. Copper output will be defined as the 
sum of all Cu output as measured in urine and feces over the specified collection period.  Daily 
balance values may also be calculated.  The study assumes insensible Cu/Mo loss due in sweat 
does not change significantly with ALXN1840 treatment and is therefore not measured.  While 
menstruation is not anticipated to significantly impact Cu/Mo balance, it may have minor impact 
on interpretation of the urine data.  Dates of menstruation should be collected to help support 
data interpretation. 
Mo mass balance is defined as the difference in Mo input and Mo output. It will be calculated in 
an analogous manner as Cu balance and includes the additional Mo intake from ALXN1840. Mo 
mass balance will be calculated at steady state (Day 12 through Day 15) and over the entire 
treatment period (Day 1 through Day 30).   
The average daily Cu and Mo balance, and/or change from baseline in average daily Cu and Mo 
balance will be calculated using data from the following periods: 
• Day -4 through Day -1 representing the pre-dose baseline period (Cu/Mo balance) 
• Days 4 through Day 15 representing the 30 mg/day treatment period (Cu balance for 
primary and secondary endpoints) 
• Day 1 through Day 15 ALXN1840 treatment period (Mo mass balance and Cu as 
exploratory analyses) 
• Days 12 through Day 15 representing steady state treatment period (steady state 
Mo/Cu balance) 
• Days 1 through Day 30 representing the entire treatment and post-treatment period 
(total Mo and Cu balance) 
As ALXN1840 is expected to increase Cu removal through fecal excretion, Cu in stool will be 
critical for determining Cu balance. Because stools can be irregular, assessment of Cu and Mo 
balance will only include data up to the day of the final bowel movement. For example, if for the 
Day 1 through Day 15 collection period, the final bowel movement occurs on Day 14, average 
daily Cu balance for the Day 1 through Day 15 period will only include data averaged from 
Day 1 through Day 14 (and Day 15 data will be omitted). In the case of the primary endpoints, 
calculations will be based on data starting on Day 4. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 52 of 71 
Alexion Confidential 
To improve understanding of the effects of ALXN1840 treatment duration, individual periods 
may be sub-segmented. For example, Day 1 through Day 15 may be divided into Day 1 through 
Day 5, Day 6 through Day 10, and Day 11 through 15 to assess copper output early following 
treatment, in the middle of treatment period and at the end of treatment period.   
In the case of the 30 mg/day steady state period for Mo balance, fecal data collected on Days 16 
and 17 may be used if needed to support assessments for the 30 mg/day Mo steady balance. Use 
of this fecal data (as needed) is consistent with an approximately 2-day gastrointestinal transit 
time. 
In the case of bowel movement irregularity and to support assessment of Cu output over time, 
bowel movement Cu and Mo outputs may be averaged over the days between bowel movements 
(or start of study) to ensure an approximate value for each 24-hour period as needed for 
calculations. The 24-hour collection period is defined as relative to the first ALXN1840 dose 
administration. 
Additional details will be provided in the SAP. 
9.4.1.2. 
Analyses of Secondary Efficacy Endpoint(s) 
Secondary analyses will be performed using the Full Analysis Set. The secondary continuous 
endpoints (Cu balance, Mo balance, urinary excretion, etc.) will be analyzed using the same 
methods described for the primary analysis. 
9.4.1.3. 
Analyses of Exploratory Endpoint(s) 
Details of the analysis of exploratory endpoints will be provided in the SAP. 
9.4.2. 
Safety Analyses 
All safety analyses will be made on the Safety 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, 
blood cell count with differential, and urinalysis) will be summarized by treatment. Laboratory 
parameter values will be graded according to the National Cancer Institute CTCAE. Shift tables 
by treatment will be produced for these laboratory 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.  
ECG 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 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 53 of 71 
Alexion Confidential 
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. 
9.4.3. 
PK/PD Analyses 
For PK endpoints, analyses will be performed using the PK Analysis Set. Individual plasma total 
Mo and PUF Mo (as surrogate measures of ALXN1840) concentration-time data will be listed 
and plotted. The following total Mo (ALXN1840) PK parameters will be derived for individual 
participants and summarized with descriptive statistics. Analyses of PUF Mo may also be 
conducted: 
• Maximum observed concentration (Cmax), time to maximum concentration (tmax), AUC 
from time 0 to the time of last measurable concentration (AUCt), AUC from time 0 to 
infinity (AUC∞), apparent terminal-phase elimination rate constant (λz), t½, clearance 
bioavailability (CL/F), and apparent volume of distribution (Vd/F). 
For exploratory endpoints such as plasma total Cu, ceruloplasmin, ceruloplasmin-bound Cu, and 
toxic copper as measured by LBC and/or NCC, a 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  
No interim analysis is planned. 
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 
An SRC, composed of a minimum of the Investigator and Alexion’s medical monitor, will 
review safety information from the first group (approximately 6-8 participants) through Day 18 
including all AEs, safety laboratory data, and vital sign assessment and agree that it is safe to 
continue enrollment to complete the study. If ceruloplasmin concentrations or AEs findings are 
suggestive of Cu depletion, the SRC may propose a dose reduction to 15 mg/day for the 
remainder of the study population   

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 54 of 71 
Alexion Confidential 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, 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 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 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 55 of 71 
Alexion Confidential 
10.1.3. 
Informed Consent Process 
• It is the responsibility of the Investigator to obtain signed (written or electronic 
signature) ICF 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(s).  
• Participants must be reconsented to the most current version of the ICF(s) 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. 
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 
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, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 56 of 71 
Alexion Confidential 
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 
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. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 57 of 71 
Alexion Confidential 
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 
• Where possible, primary manuscripts reporting results of the primary efficacy 
endpoint or the final results will be submitted for publication within 12 to 18 months 
of the primary evaluation date or end of study, whichever is earlier.  
• Investigators who participate as authors in manuscripts derived from 
Alexion-sponsored studies will agree to the prerequisites as outlined in the Alexion 
author engagement agreement prior to engaging in manuscript development.  
• The Investigator agrees to submit proposals for new manuscripts (whether or not the 
proposed analyses are derived from protocol-specified endpoints) to Alexion for 
review and consideration. All manuscripts or abstracts emanating from approved 
proposals are to be submitted to Alexion for review before submission to the 
journal/society. This allows Alexion to protect proprietary information and to provide 
comments.  
− The proprietary nature of some development work may preclude publication. In 
some cases, it may be necessary to delay a publication to allow Alexion to ensure 
protection of intellectual property.  
• In general, primary publications, including congress and journal publications, 
containing the protocol-specified results of a study should occur prior to the 
publication of individual study site results or case reports. Alexion’s policy prohibits 
duplicate publication, whereby the same results must not be published in multiple 
peer-reviewed journal manuscripts.  

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 58 of 71 
Alexion Confidential 
− Encore congress publications may be appropriate to allow communication of 
research findings to relevant audience and geographical regions. 
• Alexion will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, Alexion will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a Coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements and per the Alexion 
Publication Policy. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 59 of 71 
Alexion Confidential 
10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 7 will be performed by the local laboratory or central 
laboratories as appropriate.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.   
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. Investigators must 
document their review of each laboratory safety report and indicate whether out of 
range results are clinically significant or not clinically significant. 
• 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 
IRBs/IECs and should be performed per the time points specified in the SoA 
(Section 1.3). Screening pregnancy criteria are detailed in Section 5.1. 
Table 7: 
Protocol-Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Clinical Chemistry 
Blood urea nitrogen 
Potassium 
Creatinine 
Creatine kinase 
Sodium 
Chloride 
Potassium 
Glucose 
HbA1c 
Bicarbonate  
Aspartate aminotransferase 
Gamma glutamyltransferase 
Alanine aminotransferase 
Alkaline phosphatase 
Urea 
Magnesium 
Total and direct bilirubin 
Total protein 
Albumin 
Calcium 
Phosphate 
Hematology 
Platelets 
White blood cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
Mean cell hemoglobin 
Neutrophils 
Monocytes 
Basophils 
Hemoglobin 
Mean corpuscular volume 
Mean cell hemoglobin concentration 
Lymphocytes 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 60 of 71 
Alexion Confidential 
Eosinophils 
Coagulation 
Prothrombin time - International Normalized Ratio 
Partial Thromboplastin Time  
Urinalysis 
Bilirubin 
Glucose 
Leukocytes 
Nitrite 
Protein 
Urobilinogen 
Blood 
Ketones 
Microscopy, if required 
pH 
Specific gravity 
Red blood cells 
Other Tests 
Human immune deficiency virus (HIV)-1 and HIV-2 antibodies, HBsAg, anti-HBC 
IgG + IgM (if IgG positive), and anti-hepatitis C virus (HCV) with confirmation by 
HCV ribonucleic acid (RNA) 
Ceruloplasmin (serum) (safety) 
Serum Cu (safety) 
Ceruloplasmin (plasma) 
Ceruloplasmin-bound Cu 
Pooled 24-hour urine Cu and Mo 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential) 
Alcohol breath and urine drug screen (to include at minimum: amphetamines, 
barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, methamphetamine, 
3,4-methylenedioxy-methamphetamine, methadone, and tetrahydrocannabinol 
[cannabinoids])a 
Total Cu and total Mo 
PUF Mo and Cu 
LBC and/or NCC 
Follicle-stimulating hormone (FSH) (postmenopausal females only) 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 6.6.1.5. All events of ALT ≥ 3 × 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: Cu = copper; LBC = labile bound Cu ; NCC = non-ceruloplasmin bound Cu ; Mo = molybdenum; 
PUF = plasma ultrafiltrate 
Investigators must document their review of each laboratory safety report. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 61 of 71 
Alexion Confidential 
10.3. 
Appendix 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. 
• 
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.  
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
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). 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 62 of 71 
Alexion Confidential 
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. 
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. 
• 
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 subject number, will be redacted on the copies of 
the medical records before submission to Alexion. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to one of the following categories from National Cancer Institute CTCAE v 5.0, 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 
 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 63 of 71 
Alexion Confidential 
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. 
• 
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. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 64 of 71 
Alexion Confidential 
10.3.4. 
Reporting of SAEs  
 
SAE Reporting to GDS via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours 
awareness. 
• 
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. 
PPD
PPD

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 65 of 71 
Alexion Confidential 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
• 
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 Cu-containing IUD are excluded from study 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
o 
(Vasectomized partner 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 
ovulationc 
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.) 
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. 
 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea 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) 
Female participants of non-childbearing potential are exempt from contraception requirements. Non-
childbearing potential for female patients is defined as any of the following: 
• 
Prior to first menses 
• 
Postmenopausal, as documented by amenorrhea for at least 1 year prior to the Day 1 visit and 
follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status 
• 
Permanent sterilization at least 6 weeks prior to the Day 1 visit: 
− 
Hysteroscopic sterilization 
− 
Bilateral tubal ligation or bilateral salpingectomy 
− 
Hysterectomy 
− 
Bilateral oophorectomy 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 66 of 71 
Alexion Confidential 
• 
Collection of pregnancy information 
o If a female participant or a male participant’s female spouse/partner becomes pregnant during the 
conduct of this study, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and 
Outcome Form" to Alexion 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. Further details are provided in Section 8.2.6. 
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). 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 67 of 71 
Alexion Confidential 
10.5. 
Appendix 5: Abbreviations 
A list of abbreviations and terms are used in this study protocol is provided in Table 8. 
Table 8: 
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  
BMI 
body mass index 
BSA 
body surface area 
CYP 
cytochrome P450  
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CL/F 
clearance bioavailability 
Cmax 
maximum observed concentration  
CONSORT 
Consolidated Standards of Reporting Trials  
CRF 
case report form  
CRU 
clinical research unit  
CTCAE 
Common Terminology Criteria for Adverse Events 
Cu 
Copper 
EDC 
electronic data capture 
EOS 
End of Study  
ET 
Early Termination 
FSH 
follicle-stimulating hormone  
GCP  
Good Clinical Practice   
GDPR 
General Data Protection Regulation 
GDS 
Global Drug Safety  
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus  
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  

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 68 of 71 
Alexion Confidential 
 
IEC 
Independent Ethics Committee  
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
LEA 
Long-Evans Agouti (normal Wistar rats) 
LBC 
labile bound copper 
LEC 
Long-Evans Cinnamon (Wilson disease model rats) 
Mo 
molybdenum  
MT 
metallothionein 
NCC 
non-ceruloplasmin-bound copper  
NCCcorrected 
corrected NCC 
NIMP 
noninvestigational medicinal product 
PK 
pharmacokinetic(s)  
PUF 
plasma ultrafiltrate  
QT 
interval between the start of the Q wave and the end of the T wave in an ECG  
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula  
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan  
SoA 
Schedule of Activities 
SoC 
standard of care 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event  
t½ 
terminal elimination half-life  
tmax 
time to maximum concentration  
TPC 
Cu-tetrathiomolybdate-albumin tripartite complex formed after ALXN1840 
administration 
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 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 69 of 71 
Alexion Confidential 
10.6. 
Appendix 6: 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 
Overall Rationale for the Amendment 
Original protocol 
10 Mar 2020 
Not applicable 
Amendment 1 
07 Apr 2020 
To clarify text regarding temporary suspension of dosing if one or 
more participants fulfils criteria from the adverse reaction rules. 
 
Amendment 1 (07 Apr 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
This amendment has been prepared to clarify text regarding temporary suspension of dosing if 
one or more participants fulfills criteria from the adverse reactions rules.  
Change to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or Clarifications 
Section 6.6.1.6 Safety Oversight 
and Implementation Stopping 
Rules 
The word “may” has been replaced 
with “will” in the following 
sentence: 
• Based on the severity and 
medical risk to other 
participants and on request of 
either the Investigator or 
Alexion, dosing for all 
participants may will be 
temporarily suspended until 
the SRC meets.  
 
The change was made in response to 
the request by MHRA to clarify that if 
one or more participants fulfills criteria 
from the adverse reactions rules, dosing 
will be temporarily suspended for all 
participants until the Safety Review 
Committee meets. 
 
 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 70 of 71 
Alexion Confidential 
11. 
REFERENCES 
Brewer GJ. Practical Recommendations and New Therapies for Wilson’s Disease. Drugs. 
1995;50(2):240-249. 
Brewer GJ, Dick RD, Grover DK, et al. Treatment of metastatic cancer with tetrathiomolybdate, 
an anticopper, antiangiogenic agent: Phase I study. Clin Cancer Res. 2000;6(1):1-10. 
Camilleri M, Brown ML, Malagelada JR. Relationship between impaired gastric emptying and 
abnormal gastrointestinal motility. Gastroenterology. 1986;91(1):94-99. 
Czachor JD, Cherian MG, Koropatnick J. Reduction of copper and metallothionein in toxic milk 
mice by tetrathiomolybdate, but not deferiprone. J Inorg Biochem. 2002;88(2):213-222. 
Harris ZL, Morita H, Gitlin JD. The biology of human ceruloplasmin. In: Messerschmidt A, 
editor. Multi-Copper Oxidases Singapore: World Scientific Pub Co; 1997. 
Henry NL, Dunn R, Merjaver S, et al. Phase II trial of copper depletion with tetrathiomolybdate 
as an antiangiogenesis strategy in patients with hormone-refractory prostate cancer. Oncology. 
2006;71(3-4):168-175. 
Hill GM, Brewer GJ, Juni JE, Prasad AS, Dick RD. Treatment of Wilson's disease with zinc. II. 
Validation of oral 64copper with copper balance. Am J Med Sci. 1986;292(6):344-349. 
Komatsu Y, Sadakata I, Ogra Y, Suzuki KT. Excretion of copper complexed with thiomolybdate 
into the bile and blood in LEC rats. Chem Biol Interact. 2000;124(3):217-231. 
Lin J, Zahurak M, Beer TM, et al. A non-comparative randomized phase II study of 2 doses of 
ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent 
hormone-naive prostate cancer. Urol Oncol. 2013;31(5):581-588. 
Lowndes SA, Adams A, Timms A, et al. Phase I study of copper-binding agent ATN-224 in 
patients with advanced solid tumors. Clin Cancer Res. 2008;14(22):7526-7534. 
Mason J, Lamand M, Tressol JC, Mulryan G. Studies of the changes in systemic copper 
metabolism and excretion produced by the intravenous administration of trithiomolybdate in 
sheep. Br J Nutr. 1988;59(2):289-300. 
Metcalf AM, Phillips SF, Zinsmeister AR, MacCarty RL, Beart RW, Wolff BG. Simplified 
assessment of segmental colonic transit. Gastroenterology. 1987;92Mills CF, Elgallad TT, 
Bremner I. Effects of molybdate, sulfide, and tetrathiomolybdate on copper-metabolism in rats. J 
Inorg Biochem. 1981;14(3):189-207. 
Ogra Y, Ohmichi M, Suzuki KT. Systemic dispositions of molybdenum and copper after 
tetrathiomolybdate injection in LEC rats. J Trace Elem Med Biol. 1995;9(3):165-169. 
Ogra Y, Chikusa H, Suzuki KT. Metabolic fate of the insoluble copper/tetrathiomolybdate 
complex formed in the liver of LEC rats with excess tetrathiomolybdate. J Inorg Biochem. 
2000;78(2):123-128. 
Pass HI, Brewer GJ, Dick R, Carbone M, Merajver S. A phase II trial of tetrathiomolybdate after 
surgery for malignant mesothelioma: final results. Ann Thorac Surg. 2008;86(2):383-389; 
discussion 390. 

Protocol Amendment 2, 29 May 2020 
 
ALXN1840-HV-108 
Page 71 of 71 
Alexion Confidential 
Plitz T, Boyling L. Metabolic disposition of WTX101 (bis-choline tetrathiomolybdate) in a rat 
model of Wilson disease. Xenobiotica. 2018:1-7. 
Sternlieb I, Morell AG, Tucker WD, Greene MW, Scheinberg IH. The incorporation of copper 
into ceruloplasmin in vivo: studies with copper64 and copper67. J Clin Invest. 1961;40:1834-
1840. 
Strickland GT, Blackwell RQ, Watten RH. Evaluation of Efficacy of Chelation Therapy in 
Respect to Copper Balance. Metabolic Studies in Wilson’s Disease. AmJ Medicine. 1971;51:31-
40. 
Suzuki KT, Ogra Y, Ohmichi M. Molybdenum and copper kinetics after tetrathiomolybdate 
injection in LEC rats: specific role of serum albumin. J Trace Elem Med Biol. 1995;9(3):170-
175. 
Walshe JM. Copper chelation in patients with Wilson's disease. A comparison of penicillamine 
and triethylene tetramine dihydrochloride. Q J Med. 1973;42(167):441-452. 
Weaver LT, Steiner H. The bowel habit of young children. Arch Dis Child. 1984;59(7):649-652. 
Weiss K, Askari F, Czlonkowska A, et al. Bis-choline tetrathiomolybdate in patients with 
Wilson's disease: an open-label, multicentre, phase 2 study. Lancet Gastroenterol Hepatol. 
2017;12:869-876.