A Phase 1, Open-label, Dose-escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ALXN1850 in Adults With Hypophosphatasia
Phase: PHASE1
Conditions: Hypophosphatasia
Sponsor: Alexion Pharmaceuticals, Inc.

Protocol Amendment 5 
ALXN1850-HPP-101
10 Mar 2022
TITLE PAGE
Protocol Title:
A Phase 1, Open-label, Dose-escalating Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ALXN1850 in Adults with Hypophosphatasia
Protocol Number: ALXN1850-HPP-101
Amendment Number: 5
Compound: ALXN1850
Study Phase: Phase 1
Short Title: Safety and Tolerability, Pharmacokinetic, and Pharmacodynamic Study of 
ALXN1850 in Participants with Hypophosphatasia (HPP)
Sponsor Name: Alexion Pharmaceuticals, Inc.
Legal Registered Address: 
121 Seaport Boulevard
Boston MA 02210
USA
Regulatory Agency Identifier Number(s)
NCT: NCT04980248
Approval Date: 
Amendment 5
10 Mar 2022
Amendment 4
27 Oct 2021
Amendment 3
14 May 2021
Amendment 2
31 Mar 2021
Amendment 1
02 Feb 2021
Original protocol
12 Nov 2020
Sponsor Signatory: 
Date
Medical Monitor Name and Contact Information will be provided separately.
11-Mar-2022 | 14:46:44 EST
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NCT #: NCT04980248

Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
INVESTIGATOR’S AGREEMENT 
I have read the study Protocol Amendment 5 and agree to conduct the study in accordance with 
this protocol, all applicable government regulations, the principles of the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 
Guideline 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 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 5 (10 Mar 2022) 
This amendment is considered substantial according to 21 CFR part 312.30(b) and any 
applicable local regulations. 
Overall Rationale for the Amendment 
The protocol has been amended to address the recommendation from the FDA to clarify that if 
the initial triplicate ECG results are abnormal (Exclusion Criterion 5; both additional ECG 
triplicates must be normal for a participant to be enrolled in the study). Clarifications have also 
been added regarding the urine pregnancy test, physical examinations, exclusion criteria relating 
to GFR and eGRF, classification of infusion site reactions, and to the Schedules of Activities.  
In addition, changes made in Administrative Change Letter 4 (dated 17 Nov 2021) have been 
incorporated into this amendment. 
Changes to the protocol in Amendment 5 are detailed below. 
Section 
Description of Change 
Brief Rationale and/or Clarification 
Section 1.1 Synopsis, 
Intervention Groups and 
Duration 
Revised the Screening duration from 6 to 8 
weeks, bringing the total study duration for 
each participant to 22.5 22.1 weeks. 
To enable sufficient time for all screening 
procedures to be performed. The current 
health crisis sometime leads to delays in 
assays and tests, an extra 2 weeks are 
necessary to ensure enrollment and timely 
Screening 
Section 1.1 Synopsis, 
Overall Design 
Section 4.1 Overall Design 
Section 6.6 Dose 
Modification 
Deleted the “4” so that the sentence reads 
“remaining number of participants” 
The 4 was removed, because there may be 
more than 4 remaining participants in a 
cohort. 
Section 1.1 Synopsis, 
Number of Participants 
Added “approximately” to the number of 
participants per cohort 
To reflect that approximately 5 participants 
will be enrolled in each cohort. 
Section 1.2 Schema 
Revised the schema to reflect that 
Screening starts on Day -56. 
To correct the start of Screening from 
Day -42 to Day -56. 
Section 1.3 Schedule of 
Activities, Table 1 and 
Table 2 
Revised the SoA tables to reflect that a 
urine pregnancy test is required on Day -1. 
To enable a pre-dosing urine pregnancy 
test to be performed closer to dosing, 
rather than just during Screening. This 
change is also consistent with the urine 
pregnancy test performed on other pre-
dosing days. 
Revised the SoA tables to reflect that urine 
PEA is optional. Optional collections were 
added to Screening and End of Treatment 
Visit (Day 65 for first participant in a 
cohort, Day 57 for all others). 
Although PEA is a substrate of TNSALP, 
it is still an exploratory endpoint, because 
it is not known if it is correlated with 
clinical safety or efficacy. Due to logistical 
challenges at different sites in obtaining 
results for these samples, this assessment 
was changed to optional. Two additional 
collections were added to increase the 
sampling at sites.   
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or Clarification 
Added visits for the abbreviated physical 
examination and added a footnote to clarify 
that the predose and postdose abbreviated 
physical examinations are allowed at the 
predose or dosing day, and on the day after 
dosing or 2 days after dosing, depending on 
when the participant is admitted and 
discharged.  
To align with the site’s requirement to 
perform a physical examination when 
participants are admitted and discharged 
for each of the inpatient periods of the 
study.  
Added the visit window of ±1 day for the 
first participant’s Day 36 visit and 
subsequent participants’ Day 29 visit. 
The window was mistakenly removed in 
Protocol Amendment 4.  
In the footnote for ophthalmological and 
renal assessments, the timeframe during 
which, if a potential participant is 
rescreened, ophthalmological and renal 
assessments do not need to be performed 
again, changed from 6 months to 12 
months between each test and enrollment. 
In clinical practice these tests are only 
done once per year. Since there will not be 
any IP exposure for the participant since 
the initial screening, the tests can still be 
considered baseline for re-screens. 
Changed “PCP result” to drug screen. 
Removed “3-5 days” from the footnote for 
drug screening. 
A negative PCP result drug screen at 
Screening is required for participant 
enrollment. 
Table 1 only text:  Drug screens collected 
at timepoints prior to dosing (Days -1, 14, 
21, 28) are not required to confirm a 
negative drug screen prior to dosing. The 
PCP drug screen results are received 3-5 
days after sampling will be noted, and if 
positive, the participant will be 
discontinued from the study.  
Table 2 only text: :  Drug screens collected 
at timepoints prior to dosing (Days -1, 7, 
14, 21) are not required to confirm a 
negative drug screen prior to dosing. The 
PCP drug screen results are received 3-5 
days after sampling will be noted, and if 
positive, the participant will be 
discontinued from the study. 
The drug screen test panel includes 
additional screening for other drugs 
besides PCP. Also removed the duration 
for receipt of drug screen results, because 
the turnaround time for results is variable. 
Updated the numbering of footnotes. 
Footnotes renumbered to take into account 
addition and deletion of footnotes. 
Section 1.3 Schedule of 
Activities, Table 1 and 
Table 2 
Section 8.2.2 Vital Signs 
Deleted text relating to assessment of 
orthostatic hypotension. 
Criterion relating to orthostatic 
hypotension was removed in Protocol 
Amendment 4; therefore, text relating to 
assessment of orthostatic hypotension 
should also have been removed. 
Section 1.3 Schedule of 
Activities, Table 3 
Revised footnote “c” to state that at least 
the last of the 3 predose triplicate 12-lead 
ECGs will be performed within half an 
hour prior to dosing. 
To clarify that at least the last of the 3 
predose triplicate ECGs will be performed 
within half an hour prior to dosing, rather 
than exactly at 30 minutes prior to dosing.  
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or Clarification 
Section 4.3 Justification for 
Dose, Table 5 
Revised N from 4 to 5. 
To correct the N from 4 to 5. 
Section 5.1 Inclusion 
Criteria 
Revised inclusion criterion 2b to add “at 
Screening” so that it reads as follows: 
Serum ALP level below the laboratory age- 
and sex-adjusted normal range at 
Screening. 
To clarify that the value for serum ALP is 
the value at Screening, rather than 
historical ALP values. 
Section 5.2 Exclusion 
Criteria 
Revised Exclusion Criterion 5 to clarify 
that if the results of the first triplicate ECG 
are abnormal, both subsequent ECG 
triplicates must be normal. In addition, 
reference to vital signs has been removed.  
Revised as per a request by the US FDA 
for clarification. Removal of the reference 
to vital signs was because the vital signs 
criterion was removed in Protocol 
Amendment 4. 
Revised Exclusion Criterion 13 to clarify 
that this criterion is only required for 
patients with a history of asfotase alfa use. 
Revised for clarity and alignment with 
SoA. 
Revised exclusion criterion 18 to state 
eGFR instead of GFR and removal of the 
term “renal insufficiency”. 
Based on the following FDA guidance, this 
study will utilize the eGFR for evaluation 
of renal function: “There are different 
ways to assess renal function. 
Measurement of the GFR provides a more 
accurate assessment of renal function than 
estimating equations. However, these 
methods are not routinely used in clinical 
practice and estimation of renal function 
using a widely accepted serum creatinine-
based equation is usually sufficient for PK 
studies.” 
Deleted exclusion criterion 19. 
Removed as exclusion criterion 18 relates 
to eGFR. It is not necessary to have both 
GFR and eGFR tests because they measure 
the same parameter. eGFR is an estimate 
of the GFR and requires only a blood 
sample to perform. 
Deleted “or > 1.5 × ULN of the reference 
range of the testing laboratory on Day -1” 
from Exclusion Criterion 21 (formerly 
Exclusion Criterion 22):  
x 
Alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) 
> ULN of the reference range of the
testing laboratory at Screening or
> 1.5 × ULN of the reference range
of the testing laboratory on Day -1”
The value required to pass Screening is 
more stringent, so the Day -1 assessment is 
not needed. 
Section 5.4 Screen Fails 
Removed the restriction of one-time 
rescreening. 
Removed restriction on one-time 
rescreening to allow participants to be 
enrolled if the eligibility criteria are met as 
described in this amendment of the 
protocol. 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or Clarification 
Section 7.2 Participant 
Discontinuation/ 
Withdrawal from the Study 
Removal of “or completes it out of 
window” from the following: 
x 
If a participant misses a dosing visit or 
completes it out-of-window, they do 
not need to be withdrawn or 
discontinued from treatment or the 
study; however, they will not be 
considered “completed” even if they 
continue on to complete the end-of-
treatment assessments. These 
participants should be replaced unless 
at least 3 participants in their cohort 
have already “completed” or are on 
track to “complete. 
Removed because participants cannot 
make up a missed dose. Therefore, dosing 
visits should not be conducted out of 
window. 
Section 8.2.3.1 Safety 
Review of 12-lead 
Electrocardiograms 
Removed of reference to Holter 
Holter was removed in Protocol 
Amendment 4.  
Section 8.3.6.1 
Injection/Infusion Site 
Reactions  
Removed Infusion site reactions from 
section. Added/deleted text as follows:  
Deleted text in strikethrough, new text in 
bold. 
Antibodies have been associated with 
injection/infusion reactions, with onset 
typically during or shortly after completion 
of the injection/infusion. For this reason, 
participants will be carefully observed 
during each injection/infusion. 
Injection/infusion site reactions are defined 
as AEs localized to the site of IV or SC 
route of study drug administration, 
occurring at any time during study 
participation that are assessed by the 
Investigator to be related to study drug. 
Injection site reactions (ISRs) are 
defined as AEs localized to the site of 
study drug administration that occur at 
any time during study participation that 
are assessed by the Investigator as 
possibly, probably, or definitely related 
to study drug. AE intensity reporting 
procedures are outlined in Section 
10.3.4.  
Injection site reactions may occur at any 
timepoint after study drug 
administration. There is no additional 
laboratory testing required for ISRs.  
The Investigator is responsible for 
monitoring for ISRs in patients 
throughout the duration of the study. As 
part of the study-required physical 
examinations, Investigators should 
evaluate injection sites for signs of 
reaction(s). 
To clarify descriptions of and symptoms 
associated with the severity of injection 
site reactions and to provide cross 
reference to section of protocol describing 
reporting of AEs and SAEs. 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or Clarification 
Section 8.3.6.2 
Injection/Infusion-
associated Reactions 
Removed Infusion site reactions from 
section.  Removed reference to IV 
administration. 
Added following sentence as final sentence 
in the section: AE intensity reporting 
procedures are outlined in Section 
10.3.4. 
To clarify for this study, as drug will be 
administered SC only, and to provide cross 
reference to section of protocol describing 
reporting of AEs and SAEs.  
Section 8.6 
Pharmacodynamics 
Whole blood samples will be collected for 
measurement of PLP/PL, PA, and PPi. 
Addition of PA to PLP/PL and PPi 
Section 10.2 Clinical 
Laboratory Tests 
Calcium, calcium/creatinine have been 
removed from routine urinanalysis 
Calcium and calcium/creatinine are not 
part of a routine urinalysis.  However, they 
assessed via a separate collection, and the 
table has been updated for clarity. 
All 
Minor edits to wording. 
For clarification and consistency. 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; CTCAE = Common Terminology Criteria for 
Adverse Events; electrocardiogram ECG = electrocardiogram; (e)GFR = (estimated) glomerular filtration rate; FDA 
= Food and Drug Administration; ISR = injection site reaction; IV = intravenous;  PA = pyridoxic acid; 
PCP = phencyclidine PD = pharmacodynamics(s); PEA = phosphoethanolamine; PK = pharmacokinetic(s); 
PL = pyridoxal; PLP = pyridoxal-5’-phosphate; PPi = inorganic pyrophosphate;  SAE = serious adverse event; 
SoA = Schedule of Assessments; SC = subcutaneous; TNSALP = tissue non-specific isoenzyme of alkaline 
phosphatase; ULN = upper limit of normal  
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................. 1 
INVESTIGATOR’S AGREEMENT ........................................................................................... 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ....................................................... 3 
1.
PROTOCOL SUMMARY ...................................................................................... 13 
1.1. 
Synopsis ................................................................................................................. 13 
1.2. 
Schema ................................................................................................................... 16 
1.3. 
Schedule of Activities ............................................................................................. 17 
2.
INTRODUCTION .................................................................................................. 29 
2.1. 
Study Rationale ...................................................................................................... 29 
2.2. 
Background ............................................................................................................ 30 
2.2.1. 
Hypophosphatasia ................................................................................................... 30 
2.2.2. 
ALXN1850 ............................................................................................................. 30 
2.2.2.1. 
Chemistry ............................................................................................................... 30 
2.2.2.2. 
Pharmacology ......................................................................................................... 31 
2.2.2.3. 
Toxicology ............................................................................................................. 31 
2.3. 
Benefit/Risk Assessment ........................................................................................ 33 
2.3.1. 
Risk Assessment ..................................................................................................... 33 
2.3.1.1. 
Coronavirus Disease 2019 ...................................................................................... 33 
2.3.2. 
Benefit Assessment................................................................................................. 33 
2.3.3. 
Overall Benefit Risk Conclusion ............................................................................. 33 
3.
OBJECTIVES AND ENDPOINTS ......................................................................... 35 
4.
STUDY DESIGN ................................................................................................... 36 
4.1. 
Overall Design ........................................................................................................ 36 
4.2. 
Scientific Rationale for Study Design ..................................................................... 36 
4.3. 
Justification for Dose .............................................................................................. 37 
4.4. 
End of Study Definition .......................................................................................... 38 
5.
STUDY POPULATION ......................................................................................... 39 
5.1. 
Inclusion Criteria .................................................................................................... 39 
5.2. 
Exclusion Criteria ................................................................................................... 39 
5.3. 
Lifestyle Considerations ......................................................................................... 41 
5.3.1. 
Meals and Dietary Restrictions ............................................................................... 41 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
5.3.2. 
Alcohol, and Tobacco ............................................................................................. 41 
5.3.3. 
Activity .................................................................................................................. 41 
5.4. 
Screen Failures ....................................................................................................... 42 
6.
STUDY INTERVENTION ..................................................................................... 43 
6.1. 
Study Interventions Administered ........................................................................... 43 
6.2. 
Preparation/Handling/Storage/Accountability ......................................................... 43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ...................................... 44 
6.4. 
Study Intervention Compliance ............................................................................... 44 
6.5. 
Concomitant Therapy ............................................................................................. 44 
6.5.1. 
Allowed Medicine and Therapy .............................................................................. 45 
6.5.2. 
Disallowed Medicine and Therapy .......................................................................... 45 
6.6. 
Dose Modification .................................................................................................. 45 
6.6.1. 
Dose Escalation ...................................................................................................... 46 
6.7. 
Intervention After the End of the Study................................................................... 46 
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL ...................................... 47 
7.1. 
Discontinuation of Study Intervention..................................................................... 47 
7.1.1. 
Cohort Stopping Rules ............................................................................................ 47 
7.1.2. 
Individual Participant Stopping Rules ..................................................................... 47 
7.2. 
Participant Discontinuation/Withdrawal from the Study.......................................... 48 
7.3. 
Lost to Follow-up ................................................................................................... 49 
8.
STUDY ASSESSMENTS AND PROCEDURES ................................................... 50 
8.1. 
Efficacy Assessments ............................................................................................. 50 
8.2. 
Safety Assessments................................................................................................. 50 
8.2.1. 
Physical Examinations ............................................................................................ 50 
8.2.2. 
Vital Signs .............................................................................................................. 51 
8.2.3. 
Electrocardiograms ................................................................................................. 51 
8.2.3.1. 
Safety Review of 12-lead Electrocardiograms ......................................................... 51 
8.2.4. 
Clinical Safety Laboratory Assessments ................................................................. 51 
8.2.5. 
Drug and Alcohol Screen ........................................................................................ 52 
8.2.6. 
Pregnancy ............................................................................................................... 52 
8.2.7. 
Injection or Infusion Site Evaluation ....................................................................... 52 
8.2.8. 
Ophthalmological Examination ............................................................................... 52 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
8.2.9. 
Renal Ultrasound .................................................................................................... 53 
8.3. 
Adverse Events and Serious Adverse Events........................................................... 53 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE ......................................... 53 
8.3.2. 
Method of Detecting AEs and SAEs ....................................................................... 53 
8.3.3. 
Follow-up of AEs and SAEs ................................................................................... 53 
8.3.4. 
Regulatory Reporting Requirements for SAEs ........................................................ 54 
8.3.5. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs .......................................................................................................... 54 
8.3.6. 
Adverse Events of Special Interest .......................................................................... 54 
8.3.6.1. 
Injection Site Reactions .......................................................................................... 54 
8.3.6.2. 
Injection-associated Reactions ................................................................................ 54 
8.4. 
Treatment of Overdose ........................................................................................... 55 
8.5. 
Pharmacokinetics .................................................................................................... 55 
8.6. 
Pharmacodynamics ................................................................................................. 55 
8.7. 
Genetics.................................................................................................................. 56 
8.8. 
Biomarkers ............................................................................................................. 56 
8.9. 
Immunogenicity Assessments ................................................................................. 56 
8.10. 
Health Economics Data and Medical Resource Utilization ...................................... 57 
9.
STATISTICAL CONSIDERATIONS .................................................................... 58 
9.1. 
Statistical Hypotheses ............................................................................................. 58 
9.2. 
Sample Size Determination ..................................................................................... 58 
9.3. 
Populations for Analyses ........................................................................................ 58 
9.4. 
Statistical Analyses ................................................................................................. 58 
9.4.1. 
Efficacy Analyses ................................................................................................... 58 
9.4.2. 
Safety Analyses ...................................................................................................... 59 
9.4.3. 
Other Analyses ....................................................................................................... 60 
9.4.3.1. 
Pharmacokinetic Analyses ...................................................................................... 60 
9.4.3.2. 
Pharmacodynamic Analyses ................................................................................... 60 
9.4.3.3. 
Immunogenicity Analysis ....................................................................................... 60 
9.4.3.4. 
Exploratory Analysis .............................................................................................. 60 
9.5. 
Interim Analyses ..................................................................................................... 61 
9.6. 
Safety Review Committee (SRC) ............................................................................ 61 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .............................................................................................. 62 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations........................................ 62 
10.1.1. 
Regulatory and Ethical Considerations.................................................................... 62 
10.1.2. 
Financial Disclosure ............................................................................................... 62 
10.1.3. 
Informed Consent Process ...................................................................................... 63 
10.1.4. 
Data Protection ....................................................................................................... 63 
10.1.5. 
Dissemination of Clinical Study Data ..................................................................... 64 
10.1.6. 
Data Quality Assurance .......................................................................................... 64 
10.1.7. 
Source Documents .................................................................................................. 65 
10.1.8. 
Study and Site Start and Closure ............................................................................. 65 
10.1.9. 
Publication Policy ................................................................................................... 66 
10.1.10. 
Good Clinical Practice Compliance ........................................................................ 67 
10.2. 
Clinical Laboratory Tests ........................................................................................ 68 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ....................................................................................... 70 
10.3.1. 
Definition of AE ..................................................................................................... 70 
10.3.2. 
Definition of SAE ................................................................................................... 71 
10.3.3. 
Suspected Unexpected Serious Adverse Reactions Definition ................................. 71 
10.3.4. 
Recording and Follow-Up of AE and/or SAE ......................................................... 71 
10.3.5. 
Reporting of SAEs .................................................................................................. 73 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information .......................... 74 
10.4.1. 
Definitions .............................................................................................................. 74 
10.4.2. 
Contraception Guidance.......................................................................................... 74 
10.4.2.1. 
Guidance for Female Participants ........................................................................... 75 
10.4.2.2. 
Guidance for Male Participants ............................................................................... 76 
10.4.3. 
Collection of Pregnancy Information ...................................................................... 76 
10.4.3.1. 
Male Participants with Partners Who Become Pregnant .......................................... 77 
10.4.3.2. 
Female Participants Who Become Pregnant ............................................................ 77 
10.5. 
Biomarkers ............................................................................................................. 78 
10.6. 
Acute Infusion Reaction Algorithm ........................................................................ 79 
10.7. 
COVID-19 Risk/Benefit Assessment ...................................................................... 80 
10.8. 
Abbreviations ......................................................................................................... 82 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
10.9. 
Protocol Amendment History ................................................................................. 84 
11.
REFERENCES ....................................................................................................... 97 
LIST OF TABLES 
Table 1: 
Schedule of Activities - Study Overview for the First Participant in Each 
Cohort .................................................................................................................... 18 
Table 2: 
Schedule of Activities - Study Overview for Subsequent Participants in Each 
Cohort .................................................................................................................... 23 
Table 3: 
Schedule of Activities – Each Dosing Day for All Participants ............................... 27 
Table 4: 
Objectives and Endpoints ....................................................................................... 35 
Table 5: 
Predicted ALXN1850 PK Exposure, Exposure Margin, and Percentage of 
Population with Normalized Mineralization Response in Humans .......................... 38 
Table 6: 
Dose Reference Chart for Study ALXN1850-HPP-101 ........................................... 43 
Table 7: 
Protocol-Required Safety Laboratory Assessments ................................................. 68 
Table 8: 
Potential Risks and Mitigation Measures Due to COVID-19 ................................... 80 
Table 9: 
Abbreviations and Specialist Terms ........................................................................ 82 
LIST OF FIGURES 
Figure 1: 
Study Schema ......................................................................................................... 16 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Protocol Title: A Phase 1, Open-label, Dose-escalating Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of ALXN1850 in Adults with 
Hypophosphatasia 
Short Title: Safety and Tolerability, Pharmacokinetic, and Pharmacodynamic Study of 
ALXN1850 in Participants with Hypophosphatasia (HPP) 
Rationale: 
Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by deficient activity of the 
tissue non-specific isoenzyme of alkaline phosphatase (TNSALP), typically due to 
loss-of-function mutation(s) in the ALPL gene. As a direct result of deficient TNSALP, 
progressive damage to vital organs along with other clinical sequelae may occur, including 
deformity and softness of bones (rickets-like bone deformities and osteomalacia), fractures and 
pseudofractures, pain, profound muscle weakness, respiratory failure (primarily in infants), 
seizures (mainly in infants), impaired renal function, impaired mobility, and dental 
abnormalities. Asfotase alfa (STRENSIQ®) is currently the only approved treatment for patients 
with pediatric-onset HPP. ALXN1850 is an investigational enzyme replacement therapy (ERT) 
that addresses the underlying cause of HPP by replacing the defective enzyme, thus reversing the 
mineralization defects of the skeleton and improving systemic manifestations of HPP. 
ALXN1850 is a human recombinant TNSALP-fragment crystallizable (Fc)-deca-aspartate fusion 
protein. It is a soluble glycoprotein comprised of 2 polypeptide chains of 724 amino acids made 
from the catalytic domain of human TNSALP (SwissProt, P05186), the human immunoglobulin 
(Ig) G2/4 Fc domain (SwissProt P01859 and Genebank K01316; to facilitate purification and 
extend half-life), and a deca-aspartate peptide (to target the bone). 
The purpose of this first-in-human (FIH), open-label, dose-escalating study is to assess the safety 
and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) parameters and 
immunogenicity of ALXN1850 when given intravenously (IV) and subcutaneously (SC) to adult 
participants with HPP. This FIH study is designed to support an efficient and tolerable 
pharmacologically effective dose in participants with HPP for whom ALXN1850 has been 
designed to deliver the required enzyme with less frequent SC administration than asfotase alfa, 
and therefore reduce the burden of treatment for this group of patients. 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
Objectives and Endpoints 
Objective
Endpoints
Primary 
Assess the safety and tolerability of ALXN1850 given 
IV as a single dose and given SC in 3 qw doses 
Incidence of TEAEs and TESAEs 
Secondary 
Assess the PK of single IV and 3 SC doses of 
ALXN1850 
ALXN1850 PK (activity) over time profiles and PK 
parameters 
Assess the absolute bioavailability of ALXN1850 SC 
AUCtau values of the first SC versus IV administration 
Assess the PD effects of single IV and 3 SC doses of 
ALXN1850 
Absolute change and percent change from baseline in 
plasma concentrations of PPi and PLP and PLP/PL 
ratio over time  
Assess the immunogenicity potential of ALXN1850 
Incidence of ADAs and NAbs 
Exploratory  
Explore role of ALXN1850 on calcium and bone 
homeostasis and other PD biomarkers 
Absolute, change, and percent change from baseline in 
ionized Ca, phosphorus, magnesium, PTH, CTX-1 
(sCTX), P1NP, osteocalcin, and PA over time 
Abbreviations: ADA = antidrug antibody; AUCtau = area under the plasma concentration versus time curve within 
the dosing interval; Ca = calcium; IV = intravenous; NAb = neutralizing antibody; P1NP = N-terminal propeptide 
of type I procollagen; PA = pyridoxic acid; PD = pharmacodynamics(s); PK = pharmacokinetic(s); 
PL = pyridoxal; PLP = pyridoxal-5’-phosphate; PPi = inorganic pyrophosphate; PTH = parathyroid hormone; 
qw = weekly; SC = subcutaneous; CTX-1 (sCTX) = serum C-telopeptide cross-link of type 1 collagen; 
TEAE = treatment emergent adverse event; TESAE = treatment emergent serious adverse event. 
Overall Design 
This is an open-label, dose-escalating study to assess safety, tolerability, PK, PD, and 
immunogenicity of ALXN1850 when given IV and SC to adults with HPP.  
Study participants will be enrolled into 3 cohorts in a sequential fashion. The first participant in 
each cohort will begin dosing before the rest of the cohort. A Safety Review Committee (SRC) 
will convene after the first participant in each cohort has completed the first IV dose to assess 
safety and tolerability, and to endorse initiation of SC study drug administration to the first 
participant as well as IV and SC study drug administration to the remaining participants in the 
cohort. Once at least 3 participants in Cohort 1 have received a single IV dose and 3 weekly (qw) 
SC doses, the SRC will convene again to review safety and tolerability data, and to determine if 
the dose escalation may proceed. If the SRC endorses dose escalation, Cohort 2 will begin 
dosing at the next dosing level. Cohort 3 will begin dosing after the SRC has reviewed all 
relevant safety, tolerability, and PK data from participants in Cohorts 1 and 2 and endorsed dose 
escalation. The study design is presented in Figure 1. 
Participants who are positive for ADAs at the last assessment of the study will be given options 
to enable further monitoring of their ADA values after the end of the study; these options may 
include enrollment in the Global HPP Registry.  
Disclosure Statement: This is a sequential dose-escalating treatment study with 3 cohorts that is 
open-label. 
Number of Participants: Approximately 15 eligible participants (approximately 5 in each 
Cohorts 1, 2, and 3), will be enrolled to allow for at least 9 participants (3 per cohort) to 
“complete” (ie, participant completed EoT assessments, all PK/PD sampling was performed 
within window, and all doses were received per the SoA). Participants who withdraw/are 
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withdrawn from the study after “completion” but before the EoT Visit do not need to be replaced 
unless at least 3 participants in their cohort have “completed” or are on track to “complete”. 
Intervention Groups and Duration: The planned study duration for each participant is up to 
22.5 weeks (approximately 5 months) in total: up to 8 weeks for Screening, 71 days for first 
participants and 63 days for subsequent participants for the Treatment Period, and 34 days for the 
post-dosing Follow-up Period to further monitor safety/tolerability, PK/PD, and immunogenicity. 
Dosing will be staggered within and between cohorts. The end of study is anticipated to be 
Day 85 (-7/+14 days) for the first participant in each cohort and Day 78 (-7/+14 days) for 
subsequent participants in each cohort.  
Safety Review Committee: A SRC will assess all available data and will provide 
recommendations for cohort clearance and dose escalation decisions.
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1.2.
Schema
Figure 1:
Study Schema 
Notes: Further details of SRC meeting requirements and timelines are provided in the SRC charter. 
Completion of EoT assessments (Day 65 [1st participant in each cohort]/ Day 57 [subsequent participants in each cohort] Visit) is the end of the Treatment 
Period, while completion of EoS assessments (Day 85 [first participant in each cohort]/ Day 78 [subsequent participants in each cohort] Visit) is end-of-study.
For the timing of each visit during the study, whether it should be an Outpatient or Inpatient Visit (or either at the Investigator’s discretion), its permitted time 
window, and the assessments to be performed, see Table 1, Table 2, and Table 3.
Telemedicine visits may be performed by study site staff for safety reasons/AE FU. 
Abbreviations: D = day; ED = early discontinuation; EoS = end-of-study; EoT = end-of-treatment; FU = follow-up; IV = intravenous; PD =pharmacodynamics; 
PK = pharmacokinetics; qw = weekly; SC = subcutaneous; SRC = Safety Review Committee
D-56
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1.3. 
Schedule of Activities  
Assessment details can be found in the following SoA tables: Study Overview for the First 
Participant in Each Cohort (Table 1), Study Overview for Subsequent Participants in Each 
Cohort (Table 2), and Each Dosing Day for All Participants (Table 3).  
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Table 1: 
Schedule of Activities - Study Overview for the First Participant in Each Cohort 
Assessments 
Screening 
Treatment Period
EoT/ED 
Assessment
FU/ EoS 
Assessment
Inpatient (I) or 
Outpatient (O)a  
O 
I/O 
I 
I 
I/O 
O 
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
I 
I 
I/O 
O 
O 
O 
O 
Study Day 
-56 to -2
-1
1 
2 
3 
5 
8 
14 
15 
16 
17 
19 
21 
22 
23 
28 
29 
30 
31 
36 
51 65 
85 
Permitted Day(s) 
Window  
±1 
± 1 
± 1 
± 1 
± 3 -3/
+7
-7/
+14
Hours postdoseb 
24 
48 
96 
168 
24 
48 
96 
24 
24 
48 
168 
Informed consentc 
X 
IV Dosing Day (See Table 3) 
SC Dosing Day (See Table 3) 
SC Dosing Day (See Table 3) 
SC Dosing Day (See Table 3) 
Inclusion/ 
Exclusion Criteria 
X 
X 
Medical history 
X 
Demographics 
X 
Genetic testing (ALPL 
gene mutation)d 
X
 
 
 
 
25-OH vitamin D
X 
Hepatitis B and C 
screen 
X
 
 
 
 
HIV (Types 1 and 2) 
screen 
X
 
 
 
 
FSH teste 
X
Weight 
X 
X 
X 
X 
X 
Height and BMI 
X 
Alcohol test 
X
Urine drug screenf 
X 
X 
X 
X 
X 
Serum pregnancy testg 
X 
Urine pregnancy testg 
X 
IV 
Do
X 
S
C
X 
S
C
X 
S
C
X 
X 
X 
X 
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Table 1: 
Schedule of Activities - Study Overview for the First Participant in Each Cohort 
Assessments 
Screening 
Treatment Period
EoT/ED 
Assessment
FU/ EoS 
Assessment
Inpatient (I) or 
Outpatient (O)a  
O 
I/O 
I 
I 
I/O 
O 
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
I 
I 
I/O 
O 
O 
O 
O 
Study Day 
-56 to -2
-1
1 
2 
3 
5 
8 
14 
15 
16 
17 
19 
21 
22 
23 
28 
29 
30 
31 
36 
51 65 
85 
Permitted Day(s) 
Window  
±1 
± 1 
± 1 
± 1 
± 3 -3/
+7
-7/
+14
Hours postdoseb 
24 
48 
96 
168 
24 
48 
96 
24 
24 
48 
168 
Full PE 
X 
Abbreviated PEh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign 
measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmological 
examinationi 
X 
X 
Renal ultrasoundi 
X 
X 
Glycated hemoglobin 
(HbA1c) 
X 
Hematology labs 
(except HbA1c) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry labs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation labs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PKj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD (PPi, PLP, PL, PA)j 
IV Dosing 
Day (See
X 
X 
X 
X 
SC Dosing 
Day (See
X 
X 
X 
SC Dosing 
Day (See
X 
 SC 
Dosing
X 
X 
X 
X 
X 
X 
Bone biomarkers 
(sCTX, P1NP, 
osteocalcin) 
X 
X 
X 
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Table 1: 
Schedule of Activities - Study Overview for the First Participant in Each Cohort 
Assessments 
Screening 
Treatment Period
EoT/ED 
Assessment
FU/ EoS 
Assessment
Inpatient (I) or 
Outpatient (O)a  
O 
I/O 
I 
I 
I/O 
O 
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
I 
I 
I/O 
O 
O 
O 
O 
Study Day 
-56 to -2
-1
1 
2 
3 
5 
8 
14 
15 
16 
17 
19 
21 
22 
23 
28 
29 
30 
31 
36 
51 65 
85 
Permitted Day(s) 
Window  
±1 
± 1 
± 1 
± 1 
± 3 -3/
+7
-7/
+14
Hours postdoseb 
24 
48 
96 
168 
24 
48 
96 
24 
24 
48 
168 
Blood for PTH 
X 
X 
Immunogenicity test 
(ALXN1850 ADA and 
NAb)k 
X 
X 
X 
X 
X 
Immunogenicity test 
(asfotase alfa ADA and 
NAb)k 
X 
CRIM (Day 1 only)
Urine for calcium, 
phosphorus, and 
creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine PEA (optional) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALXN1850 
administration 
Injection/ 
infusion site 
evaluationm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypersensitivity rxn 
monitoring 
←Monitor continually after 1st dose→ 
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Table 1: 
Schedule of Activities - Study Overview for the First Participant in Each Cohort 
Assessments 
Screening 
Treatment Period
EoT/ED 
Assessment
FU/ EoS 
Assessment
Inpatient (I) or 
Outpatient (O)a  
O 
I/O 
I 
I 
I/O 
O 
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
I 
I 
I/O 
O 
O 
O 
O 
Study Day 
-56 to -2
-1
1 
2 
3 
5 
8 
14 
15 
16 
17 
19 
21 
22 
23 
28 
29 
30 
31 
36 
51 65 
85 
Permitted Day(s) 
Window  
±1 
± 1 
± 1 
± 1 
± 3 -3/
+7
-7/
+14
Hours postdoseb 
24 
48 
96 
168 
24 
48 
96 
24 
24 
48 
168 
Hypersensitivity rxn 
labs (tryptase, IgE, 
C5b-9)n 
←See footnote m → 
Concomitant 
medications 
← Monitor continually after ICF is signed → 
Adverse events 
review/evaluation 
← Monitor continually after ICF is signed → 
Note: Participants who complete the EoT assessments but withdraw/are withdrawn prior to completion of the end-of-study assessments will be considered 
“completed” and do not require replacement if they completed all prior PK/PD sampling within window and received all doses per the SoA. Participants who 
withdraw/are withdrawn prior to the end-of-treatment visit should have the end-of-treatment assessments performed, if possible, and will be replaced unless 
3 participants in their cohort have already “completed” or are on track to “complete”. 
a Visits designated “I/O” may be performed Inpatient or Outpatient at the Investigator’s discretion. 
b All postdose timepoints are relative to the start of the IV infusion/time of the SC injection (ie, Time 0) except the vital signs measurements, PK and PD sample, 
and infusion site evaluation performed/collected at the EoI (see Table 3). 
c Signed and dated IEC-approved ICF must be obtained before any study-specific screening procedures are performed. 
d If available, historical results are acceptable, and a confirmatory test is not required. 
e Female participants who claim postmenopausal status will have an FSH test to confirm status. 
f A negative drug screen is required for participant enrollment. Results from drug screens collected at timepoints prior to dosing (Days -1, 14, 21, 28) are not 
required to confirm a negative result prior to dosing. The drug screen results received after sampling will be noted, and if positive, the participant will be 
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discontinued from the study. If negative, the results will serve as clearance to proceed with dosing for future pre-dosing days. A positive drug test result for a 
non-prescribed substance received at any visit will lead to discontinuation 
g Pregnancy test must be performed on all participants of child-bearing potential at the specified time points. Additional pregnancy tests may also be performed 
at any time at the Investigator’s discretion. 
h Predose and postdose abbreviated PEs are allowed at the predose or dosing day, and on the day after dosing or 2 days after dosing, depending on when the 
participant is admitted and discharged. 
i If a potential participant is rescreened, these assessments do not need to be performed again unless more than 12 months will have elapsed between each test 
and enrollment. 
j A window of ± 30 minutes from each time point is permitted for PK/PD timepoints except the PK sample collected at end of infusion (+ 15 minutes). Predose 
PK/PD windows are -1 hour (SC doses) and 3 hours (IV dose). For all assessments, their window and the visit window should not be calculated together to 
determine the permitted assessment time.  
k Asfotase alfa ADA and NAb will only be tested in participants who have previously received asfotase alfa. Participants do not need to be retested for ADAs 
and NAbs if they are re-screened. 
l Each 12-lead ECG will be performed in triplicate (sequentially within a 15-minute period) and should not be assessed after any major meal (ie, major meals
should be withheld until after ECG assessments). All ECGs should be performed before the vital signs assessment and PK/PD sampling (in that order if 1 or
both of the latter are also scheduled during an ECG timepoint). Each ECG shown in this table has a window of ± 30 minutes.
m Injection/infusion site evaluations will be performed within 15 minutes (± 5 minutes) after injection/EoI and ± 15 minutes of the rest of the timepoints. 
n  If the participant is in the clinic, collect the first sample ASAP (preferred) or within 1 hour of the suspected hypersensitivity reaction. The 2 subsequent 
samples also have a permitted + 1 hour window. If the participant is not in the clinic, these samples do not need to be collected and suspected hypersensitivity 
reaction will be reported as an AE only. If the suspected hypersensitivity reaction persists beyond 8 hours, the CRU should contact the MM for guidance. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; ALPL = alkaline phosphatase; ASAP = as soon as possible; BMI = body mass index; C5b-9 = 
terminal complement complex C5b-9; CRIM = cross-reactive immunological material; CRU = clinical research unit; ECG = electrocardiogram; ED = early 
discontinuation; EoI = end of infusion; EoS = end-of-study; EoT = end-of-treatment; FSH = follicle stimulating hormone; FU = follow-up; HIV = human 
immunodeficiency virus; I = inpatient; ICF = informed consent form; IEC = Independent Ethics Committee; IgE = immunoglobulin E; IV = intravenous; 
MM = medical monitor; NAb = neutralizing antibody; O = outpatient; PA = pyridoxic acid; PCP = phencyclidine; PD = pharmacodynamics; PE =physical 
examination; P1NP = N-terminal propeptide of type I procollagen; PEA = phosphoethanolamine; PK = pharmacokinetics; PL = pyridoxal; PLP = pyridoxal 
5′-phosphate; PPi = inorganic pyrophosphate; PTH = parathyroid hormone; rxn = reaction; CTX-1 (sCTX) = serum Ctelopeptide cross-link of type 1 collagen; 
SoA = schedule of activities; SC = subcutaneous. 
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Table 2: 
Schedule of Activities - Study Overview for Subsequent Participants in Each Cohort 
Assessments 
Screening 
Treatment Period 
EoT Assessments
FU/ EoS 
Assessments
Inpatient (I) or Outpatient (O)a  
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
I 
I 
I/O 
O 
O 
O 
O 
Study Day 
-56 to -2 
-1
1 
2 
3 
5 
7 
8 
9 
10 
12 
14 
15 
16 
21 
22 
23 
24 
29 
43 
57 
78 
Permitted Day(s) Window 
±1 
±1 
± 1 
±3 
-3/
+7
-7/
+1
4
Hours postdoseb
24 
48 
96 
24 
48 
96 
24 
 
24 
48 
168 
Informed consentc 
X 
IV Dosing Day (See Table 3) 
SC Dosing Day (See Table 3) 
SC Dosing Day (See Table 3) 
SC Dosing Day (See Table 3) 
Inclusion/ 
Exclusion Criteria 
X 
X 
Medical history 
X 
Demographics 
X 
Genetic testing (ALPL gene 
mutation)d 
X 
25-OH vitamin D
X 
Hepatitis B and C screen 
X 
HIV (Types 1 and 2) screen 
X 
FSH teste 
X 
Weight 
X 
X 
X 
X 
X 
Height and BMI 
X 
Alcohol test 
X 
Urine drug screenf 
X 
X 
X 
X 
X 
Serum pregnancy testg 
X 
Urine pregnancy testg 
X 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
Abbreviated PEh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements 
X 
I
V
X 
X 
X 
S
C
X 
X 
X 
X 
S
C
X 
X 
X 
X 
X 
X 
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Table 2: 
Schedule of Activities - Study Overview for Subsequent Participants in Each Cohort 
Assessments 
Screening 
Treatment Period 
EoT Assessments
FU/ EoS 
Assessments
Inpatient (I) or Outpatient (O)a  
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
I 
I 
I/O 
O 
O 
O 
O 
Study Day 
-56 to -2 
-1
1 
2 
3 
5 
7 
8 
9 
10 
12 
14 
15 
16 
21 
22 
23 
24 
29 
43 
57 
78 
Permitted Day(s) Window 
±1 
±1 
± 1 
±3 
-3/
+7
-7/
+1
4
Hours postdoseb
24 
48 
96 
24 
48 
96 
24 
 
24 
48 
168 
Ophthalmological examinationi 
X 
SC Dosing Day (See Table 3) 
X 
Renal ultrasoundi 
X 
X 
Glycated hemoglobin (HbA1c) 
X 
Hematology labs (except HbA1c) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry labs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation labs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PKj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD (PPi, PLP, PL, PA)j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone biomarkers (sCTX, P1NP, 
osteocalcin) 
X 
X 
X 
Blood for PTH 
X 
X 
Immunogenicity test (ALXN1850 
ADA and NAb)k 
X 
X 
X 
X 
Immunogenicity test (asfotase alfa, 
ADAs, and NAbs)k 
X 
IV 
Dosin
SC 
Dosing
SC 
Dosing
SC 
Dosing
CRIM (Day 1 only) 
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Table 2: 
Schedule of Activities - Study Overview for Subsequent Participants in Each Cohort 
Assessments 
Screening 
Treatment Period 
EoT Assessments
FU/ EoS 
Assessments
Inpatient (I) or Outpatient (O)a  
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
O 
I/O 
I 
I 
I/O 
I 
I 
I/O 
O 
O 
O 
O 
Study Day 
-56 to -2 
-1
1 
2 
3 
5 
7 
8 
9 
10 
12 
14 
15 
16 
21 
22 
23 
24 
29 
43 
57 
78 
Permitted Day(s) Window 
±1 
±1 
± 1 
±3 
-3/
+7
-7/
+1
4
Hours postdoseb
24 
48 
96 
24 
48 
96 
24 
 
24 
48 
168 
Urine for calcium, phosphorus, and 
creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine PEA (optional) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGl
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALXN1850 administration 
Injection/infusion site evaluationm 
X 
X 
X 
X 
X 
X 
X 
X 
Hypersensitivity rxn monitoring 
←Monitor continually after 1st dose→ 
Hypersensitivity rxn labs (tryptase, 
IgE, C5b-9)n 
←See footnoten → 
Concomitant medications 
← Monitor continually after ICF is signed → 
Adverse events review/evaluation 
← Monitor continually after ICF is signed → 
Note: Participants who complete the end-of-treatment assessments but withdraw/are withdrawn prior to completion of the end-of-study assessments will be 
considered “completed” and do not require replacement if they completed all prior PK/PD sampling within window and received all doses per the SoA. 
Participants who withdraw/are withdrawn prior to the end-of-treatment visit should have the end-of-treatment assessments performed, if possible, and will be 
replaced unless 3 participants in their cohort have already “completed” or are on track to “complete”. 
a Visits designated “I/O” may be performed Inpatient or Outpatient at the Investigator’s discretion. 
b All postdose timepoints are relative to the start of the IV infusion/time of the SC injection (ie, Time 0) except the vital signs measurements, PK and PD sample, 
and infusion site evaluation performed/collected at the EoI (see Table 3). 
c Signed and dated IEC-approved ICF must be obtained before any study-specific screening procedures are performed. 
d If available, historical results are acceptable, and a confirmatory test is not required. 
e Female participants who claim postmenopausal status will have an FSH test to confirm status. 
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f A negative drug screen is required for participant enrollment. Results from drug screens collected at timepoints prior to dosing (Days -1, 7, 14, 21) are not 
required to confirm a negative result prior to dosing. The drug screen results received after sampling will be noted, and if positive, the participant will be 
discontinued from the study. If negative, the results will serve as clearance to proceed with dosing for future pre-dosing days. A positive drug test result a non-
prescribed substance received at any visit will lead to discontinuation. 
g Pregnancy test must be performed on all participants of child-bearing potential at the specified time points. Additional pregnancy tests may also be performed 
at any time at the Investigator’s discretion. 
h Predose and postdose abbreviated PEs are allowed at the predose or dosing day, and on the day after dosing or 2 days after dosing, depending on when the 
participant is admitted and discharged. 
i If a potential participant is rescreened, these assessments do not need to be performed again unless more than 12 months will have elapsed between each test and 
enrollment. 
j  A window of ± 30 minutes from each time point is permitted for PK/PD timepoints except the PK sample collected at end of infusion (+ 15 minutes). Predose 
PK/PD windows are -1 hour (SC doses) and 3 hours (IV dose). For all assessments, their window and the visit window should not be calculated together to 
determine the permitted assessment time.  
k Asfotase alfa ADA and NAb will only be tested in participants who have previously received asfotase alfa. Participants do not need to be retested for ADAs and 
NAbs if they are re-screened. 
l Each 12-lead ECG will be performed in triplicate (sequentially within a 15-minute period) and should not be assessed after any major meal (ie, major meals
should be withheld until after ECG assessments). All ECGs should be performed before the vital signs assessment and PK/PD sampling (in that order if 1 or
both of the latter are also scheduled during an ECG timepoint). Each ECG shown in this table has a window of ± 30 minutes.
m Injection/infusion site evaluations will be performed within 15 minutes (± 5 minutes) after injection/EoI and ± 15 minutes of the rest of the timepoints.
n If the participant is in the clinic, collect the first sample ASAP (preferred) or within 1 hour of the suspected hypersensitivity reaction. The 2 subsequent samples
also have a permitted + 1 hour window. If the participant is not in the clinic, these samples do not need to be collected and suspected hypersensitivity reaction 
will be reported as an AE only. If the suspected hypersensitivity reaction persists beyond 8 hours, the CRU should contact the MM for guidance.  
Abbreviations: ADA = antidrug antibody; AE = adverse event; ALPL = alkaline phosphatase; ASAP = as soon as possible; BMI = body mass index; C5b-9 = 
terminal complement complex C5b-9; CRIM = cross-reactive immunological material; CRU = clinical research unit; ECG = electrocardiogramEoI = end of 
infusion; EoS = end-of-study; EoT = end-of-treatment; FSH = follicle stimulating hormone; FU = follow-up; HIV = human immunodeficiency virus; 
I = inpatient; ICF = informed consent form; IEC = Independent Ethics Committee; IgE = immunoglobulin E; IV = intravenous; MM = medical monitor; NAb = 
neutralizing antibody; O = outpatient; PA = pyridoxic acid; PCP = phencyclidine; PE =physical examination; P1NP = N-terminal propeptide of type I 
procollagen; PD = pharmacodynamics; PEA = phosphoethanolamine; PK = pharmacokinetics; PL = pyridoxal; PLP = pyridoxal 5′-phosphate; PPi = inorganic 
pyrophosphate; PTH = parathyroid hormone; rxn = reaction; CTX-1 (sCTX) = serum Ctelopeptide cross-link of type 1 collagen; SoA = schedule of activities; SC 
= subcutaneous  
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Table 3: 
Schedule of Activities – Each Dosing Day for All Participants 
Assessments 
Each Dosing Day (Inpatient Visits) 
Study Day (First Participant) 
Days 1, 15, 22, 29 
Study Day for (Subsequent Participants) 
Days 1, 8, 15, 22 
Day/Time 
Day 1 
Only 
Each Dosing Day 
Predose
Dose
Postdosea 
Predose 
Per Window 
(if specified) 
-0.5 hr
0 hr 
EoI (IV 
Dose 
Only) 
Every 15 min 
for 1st hr 
2 
6 
12 
Admission to IP Unitb
X
12-lead ECG (triplicate)c
X 
Xd 
X 
X 
X 
Vital signs measurements  
X 
Xe 
X 
X 
X 
PKf 
X 
Xd 
X 
X 
X 
PD (PPi, PLP, PL, PA) f 
X 
Xd
Bone biomarkers (sCTX, P1NP, osteocalcin) 
X 
Immunogenicity testing (ALXN1850 ADA and 
NAb) 
X 
CRIM assay 
X 
ALXN1850 administration 
X 
Injection/infusion site evaluationg 
X 
X 
X 
X 
X 
X 
Abbreviated PE h 
X 
Hypersensitivity reaction monitoring  
←Monitor continually→ 
Hypersensitivity reaction labs (tryptase, IgE, 
C5b-9, chemistry, hematology, and urinalysis) 
X 
← Xi→ 
Concomitant medications 
←Monitor continually after ICF is signed→ 
Adverse events review/evaluation 
←Monitor continually after ICF is signed→ 
Note: When scheduled at the same timepoint, the triplicate ECG should be performed first, followed by vital signs assessments, and then PK/PD sampling.  
a  All postdose timepoints are relative to the start of the IV infusion/time of the SC injection (ie, time 0 hr) except the ECG, PK/PD sample, and infusion site 
evaluation performed/collected at the EoI (see footnote d). 
b  Only if the Investigator approves the day prior as an Outpatient Visit. 
c  Each 12-lead ECG will be performed in triplicate (sequentially within a 15-minute period) and should not be assessed after any major meal (ie, major meals 
should be withheld until after ECG assessments). At least the last of the 3 predose triplicate 12-lead ECG will be performed within half an hour prior to dosing. 
The ECGs at 2, 6, and 12 hours postdose have a window of ± 30 minutes. 
d  ECG and PK/PD (in that order) performed/collected at EoI (tmax) each have a window of + 15 minutes. 
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e  Vital signs will be measured every 15 minutes for the first hour after dosing, with a window of ± 5 minutes. Other vital signs measurements have a window of 
± 15 minutes. 
f  A window of ± 30 minutes from each postdose time point is permitted for all PK/PD timepoints except EoI. Predose PK/PD windows are -1 hour (SC doses) 
and -3 hours (IV dose). 
g  Injection/infusion site evaluations will be performed during the infusion, after I/EoI, and then within 15 minutes (+ 5 minutes) after I/EoI. The rest of the 
timepoints have a window of ± 15 minutes.  
h  Predose and postdose abbreviated PEs are allowed at the predose or dosing day, and on the day after dosing or 2 days after dosing, depending on when the 
participant is admitted and discharged.  
i  If a hypersensitivity reaction is suspected, samples should be collected as soon as possible (within 1 hour of the reaction) and again at 2 and 8 hours (+ 1 hour 
window each) after the 1st sample. The Day 1 predose sample will only be analyzed for participants with a reported suspected hypersensitivity reaction at any 
time following the first dose. 
Abbreviations: ADA = antidrug antibody; C5b-9 = terminal complement complex C5b-9; CRIM = cross-reactive immunological material; ECG = 
electrocardiogram; EoI = end of infusion; hr = hour; ICF = informed consent form; IgE = immunoglobulin E; IV = intravenous; min = minutes; NAb = 
neutralizing antibody; PA = pyridoxic acid; P1NP = N-terminal propeptide of type I procollagen; PD = pharmacodynamics; PE = physical examination; 
PK = pharmacokinetics; PL = pyridoxal; PLP = pyridoxal 5′-phosphate; PPi = inorganic pyrophosphate; CTX-1 (sCTX) = serum Ctelopeptide cross-link of 
type 1 collagen; SC = subcutaneous; tmax = time to maximum observed plasma concentration  
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2.
INTRODUCTION
2.1. 
Study Rationale
ALXN1850 is a human recombinant TNSALP-Fc-deca-aspartate fusion protein being developed 
as an investigational ERT to address the underlying cause of HPP by replacing the defective 
TNSALP enzyme. It is a soluble glycoprotein comprised of 2 polypeptide chains of 724 amino 
acids made from the catalytic domain of human TNSALP (SwissProt, P05186), the human Ig 
G2/4 Fc domain (SwissProt P01859 and Genebank K01316; to facilitate purification and extend 
half-life), and a deca-aspartate peptide (to target the bone). ALXN1850 is designed for SC 
administration. Nonclinical pharmacology, PK, and toxicology studies of ALXN1850 have been 
conducted to support the clinical testing of ALXN1850 in humans. The Phase 1 FIH study is 
designed to evaluate the safety, tolerability, PK, and PD of ALXN1850 when given IV and SC to 
adults with HPP.  
This FIH study will enroll adult participants with HPP who have a confirmed mutation for the 
gene (ALPL) that encodes the enzyme TNSALP, resulting in the presence of decreased serum 
alkaline phosphatase (ALP) activity and elevated serum pyridoxine and inorganic 
pyrophosphate, which are the genetic and biochemical hallmarks of the disease. The 
characteristics of this population represent patients with HPP who currently do not require ERT 
but could qualify for future Phase 2 and Phase 3 studies, depending on the disease burden. This 
study has been designed to minimize risk to participants; it is a study with strict 
inclusion/exclusion criteria and there is a robust safety monitoring and risk mitigation plan in 
place to address potential safety and tolerability findings. Because of the potential for 
immunogenicity, this study will enroll participants with HPP who are not anticipated to require 
continued treatment with ERT, based on their signs and symptoms, and the Investigator’s clinical 
assessment of their current condition.  
ALXN1850 and asfotase alfa, the only approved treatment for HPP, have the same mechanism of 
action and address the underlying cause of HPP by replacing the defective enzyme, thus 
reversing the mineralization defects of the skeleton and improving systemic manifestations of 
HPP. ALXN1850 differs from asfotase alfa in the following ways: it is altered by an amino acid 
change to enhance substrate hydrolysis by its active site; its Fc domain is an IgG2/4, to improve 
half-life and bioavailability; 2 N-linked glycans have been removed from each TNSALP 
polypeptide chain via asparagine to glutamine mutations, and other enhancements to its glycan 
profile which should alter the PK of the active moiety and increase its exposure and half-life. 
Currently, the recommended dosage regimen of asfotase alfa for the treatment of pediatric-onset 
HPP is 6 mg/kg per week administered SC as either 2 mg/kg 3 times per week, or 1 mg/kg 
6 times per week. However, patients using asfotase alfa are burdened with a high rate of injection 
site reactions and an inconvenient administration frequency (3 to 6 times per week). ALXN1850 
is a next-generation HPP therapy developed with the intent to deliver a molecule with equivalent 
potency and improved activity compared to asfotase alfa, providing higher exposure, longer 
half-life, and better bioavailability. These improvements may address current asfotase alfa 
limitations and support lower doses and longer dosing intervals. Patient experience is expected to 
improve by reducing injection volumes and dosing frequency, which may also translate to fewer 
injection site reactions and higher patient compliance. 
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2.2. 
Background 
A detailed description of the chemistry, pharmacology, and toxicology data available for 
ALXN1850 is provided in the Investigator’s Brochure (IB). 
2.2.1. 
Hypophosphatasia 
Hypophosphatasia is a rare, inherited, metabolic disease caused by deficient activity of the 
TNSALP, typically due to loss-of-function mutation(s) in the ALPL gene. TNSALP is a 
glycosylphosphatidylinositol anchored ectoenzyme, which although widely expressed, is 
expressed at particularly high concentrations on the surface of osteoblasts. During normal bone 
mineralization, TNSALP dephosphorylates inorganic pyrophosphate (PPi), producing inorganic 
phosphate (Pi). Inorganic phosphate then precipitates calcium (Ca2+) in the extracellular matrix 
to form calcium phosphate that is then transformed into hydroxyapatite crystals, which give 
bones their strength and rigidity. Other known endogenous substrates for ALP include 
pyridoxal-5´-phosphate (PLP) and phosphoethanolamine (PEA) (Whyte, 2012; Whyte, 1994). 
In HPP, low TNSALP activity leads to extracellular accumulation of PPi, which inhibits bone 
mineralization by blocking hydroxyapatite crystal formation (Russell, 1965; Fleisch, 1966; 
Rockman-Greenberg, 2013). Consequently, Ca2+ and PPi accumulate in the bloodstream, causing 
disturbances in calcium/phosphate homeostasis (Linglart, 2016). In addition, TNSALP 
dephosphorylates PLP, the circulating form of vitamin B6, producing pyridoxal (PL), which 
crosses the blood-brain barrier and is rephosphorylated into PLP, where it plays an important 
role in the synthesis of multiple neurotransmitters (Whyte, 1994; Whyte, 2012). The role of PEA 
is not completely understood but may be a component of the phosphatidylinositol-glycan linkage 
apparatus that couples TNSALP and many other proteins to cell surfaces. 
As a direct result of deficient TNSALP, progressive damage to vital organs along with other 
clinical sequelae may occur; including deformity and softness of bones (rickets-like bone 
deformities and osteomalacia), fractures and pseudofractures, pain, profound muscle weakness, 
respiratory failure (primarily in infants), seizures (mainly in infants), impaired renal function, 
impaired mobility, and dental abnormalities. Hypophosphatasia is associated with a high-fracture 
and orthopedic/dental surgical burden, pain, need for assistive walking devices (due to impaired 
mobility), and impairments in activities of daily living in children and adults. Severe disease 
associated with rachitic changes in the chest often lead to diminished respiratory function (due to 
lack of rib cage support) and risk of ventilator dependence and premature death (mainly in 
infants). The deficiency of PLP in the central nervous system in patients with HPP can result in 
infantile seizures which are responsive to pyridoxine (Baumgartner-Sigl, 2007; Whyte, 1985). 
2.2.2. 
ALXN1850 
2.2.2.1. 
Chemistry 
ALXN1850 is a human recombinant tissue nonspecific alkaline phosphate 
(TNSALP)-Fc-aspartate fusion protein. It is expressed by a vector in Chinese Hamster Ovary 
(CHO) cells using cell culture technology in bioreactors and is formulated to a concentration of 
100 mg/mL. ALXN1850 has a deglycosylated molecular weight of 160 KDa confirmed by 
electrospray ionization mass spectrometry. The purified soluble Fc fusion protein is modified by 
an amino acid change to enhance substrate hydrolysis by its active site; its Fc domain is an 
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IgG2/4, to improve half-life and bioavailability; 2 N-linked glycans have been removed from 
each TNSALP polypeptide chain via asparagine to glutamine mutations, and other enhancements 
to its glycan profile which were designed to improve the PK of the active moiety and increase its 
exposure and half-life. 
2.2.2.2. 
Pharmacology 
Preclinical efficacy studies with ALXN1850 were conducted in a murine knockout model 
(designated Akp2GW-/-) of human HPP created by inactivating the TNSALP gene according to 
the homologous recombination method used by the laboratory of Dr José Millán  
(Narisawa, 1997) to generate the Akp2-/- mouse model which supported the Investigational New 
Drug (IND) filing for asfotase alfa. The Akp2GW-/- model was similarly maintained on a mixed 
background of C57BL6 and 129J strains. As occurs in human infantile HPP and Akp2-/-mice, 
Akp2GW-/- mice demonstrate a range of mineralization and bone deficits with shortened 
survival. Compared to wild-type littermates, Akp2GW-/- mice display excess unmineralized 
matrix early in life, experience seizures likely due to defective vitamin B6 metabolism, and die 
before postnatal day 26 despite dietary pyridoxine (B6 vitamer) supplementation 
(Study RTR-0032). 
The efficacy of ALXN1850 in Akp2GW-/- mice was evaluated in prophylactic SC injection 
treatments initiated 1 day after birth. The efficacy endpoints evaluated in preclinical studies with 
Akp2GW-/- mice were bone mineralization defects, growth (body weight and bone lengths of 
femur and tibia), and survival. Additional outcome measures included plasma and femur alkaline 
phosphate enzymatic activity. 
ALXN1850 increased bone mineralization and had a beneficial effect on bone length, body 
weight gain, and survival time. ALXN1850 improved upon the potency of asfotase alfa, with 
higher enzymatic activity on bone, higher frequency of normalized bone mineralization, and 
increased bone length, at lower doses and at less-frequent dosing intervals than asfotase alfa. 
2.2.2.3. 
Toxicology 
Nonclinical safety/toxicology studies conducted to date to support ALXN1850 FIH study 
consisted of definitive/Good Laboratory Practices (GLP) nonclinical safety studies in rats 
(Study 1727-227) and monkeys (Study 1727-228). The GLP toxicology studies evaluated the 
systemic toxicity of the administration of SC ALXN1850 in rat and monkeys; these studies 
included safety pharmacology endpoints (cardiovascular, respiratory in monkey study and 
neurofunctional in rat study), toxicokinetic evaluations, immunogenicity evaluations, and a 
recovery period to assess the reversibility of any treatment-related effects. ALXN1850 did not 
result in any systemic organ toxicity in rats or monkeys. ALXN1850 was well tolerated locally 
following SC administration to rats and monkeys, with no adverse findings observed at injection 
sites. The no observed adverse effect levels (NOAELs) in rat and monkey studies were the 
highest doses evaluated in rats (30 mg/kg/dose) and monkeys (20 mg/kg/dose). In conclusion, 
SC administered ALXN1850 to rats and monkeys did not identify any new or unexpected 
systemic toxicity or local tolerability findings in rats or monkeys. 
In rat 28-day toxicity study, administration of ALXN1850 via SC injection once every 3 days 
(q3d) for 28 days (Days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28) for a total of 10 doses to male and 
female CD® rats was well tolerated up to 30 mg/kg/dose, the highest SC dose evaluated in this 
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study. Additionally, administration of ALXN1850 at 10 mg/kg IV was also well tolerated after a 
single injection. There were no ALXN1850-related changes in clinical observations, body 
weights, body weight gains, quantitative food consumption, ophthalmology, functional 
observational battery observations, hematology, urinalysis, gross pathology, and organ weights. 
At the end of the dosing phase, there were dose-related increases in ALP activity (anticipated 
pharmacology effect) at ≥ 2 mg/kg/dose ALXN1850 SC which were fully resolved following a 
28-day recovery period. Non-adverse microscopic changes were related to the injection
procedures with associated reactive changes in the draining lymph nodes. There was no
discernible ALXN1850-associated alteration in the incidence, severity, or microscopic character
of the changes at the injection sites or draining lymph nodes. Microscopic changes in the
injection sites and draining lymph nodes of recovery animals were similar to those noted in the
terminal necropsy animals, although less pronounced in the recovery group animals. In
conclusion, the dose level of 30 mg/kg/dose is considered to be the NOAEL for SC
administration that corresponds to Day 24 males and females combined maximum observed
serum concentration (Cmax) value of 43.9 μg/mL and area under the concentration-time curve
from time zero to 72 hours (AUC0-72h) value of 2120 h*μg/mL.
Single IV bolus injection of ALXN1850 at 10 mg/kg was well tolerated in rats with no 
noteworthy toxicity or injection site reactions and resulted in an AUC0-72h of 3690 h*μg/mL. The 
SC bioavailability for ALXN1850 (based on SC AUC0-72h values at 10 mg/kg/dose) in rats was 
approximately 44.2%. 
In a monkey 28-day toxicity study, administration of ALXN1850 via SC injection once q3d for 
28 days (Days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28) for a total of 10 doses to male and female 
cynomolgus monkeys was well tolerated up to 20 mg/kg/dose, the highest dose evaluated in this 
study. There were no ALXN1850-related changes in injection site reactions (dermal scoring), 
body weights, body weight gains, qualitative food consumption, ophthalmology, manual 
respiratory rates, indirect blood pressures, qualitative electrocardiography, hematology, 
urinalysis, gross pathology, and organ weights. At the end of the dosing phase, there were 
dose-related increases in ALP activity (anticipated pharmacology effect) which were fully 
(1 mg/kg/dose) or mostly (≥5 mg/kg/dose) resolved following a 28-day recovery period. 
Non-adverse ALXN1850 related microscopic changes were confined to the injection sites and 
included minimal to mild degeneration/necrosis, mineralization, and mixed cell 
inflammation/infiltration. Partial recovery of degeneration/necrosis and mixed cell 
inflammation/infiltration of the injection site(s) were observed within the recovery groups, while 
minimal to mild mineralization persisted in recovery males at ≥ 1 mg/kg/dose and females at 
20 mg/kg/dose. Heart rate increases were observed in all animals at 1 mg/kg/dose and in some of 
the animals at ≥ 5 mg/kg/dose. Heart rate and electrocardiogram (ECG) values remained within a 
normal range of biological variation for monkeys of this age, and therefore these heart rate 
increases were not considered to be adverse, given the incongruity with systemic exposure data. 
In conclusion the dose level of 20 mg/kg/dose is considered to be the NOAEL that corresponds 
to Day 24 males and females combined mean Cmax value of 254 μg/mL and mean AUC0-72h value 
of 15400 h*μg/mL, respectively. 
In conclusion, SC administration of ALXN1850 to rats or monkeys did not identify any new or 
unexpected systemic toxicity or local tolerability findings. The NOAEL dose of 20 mg/kg/dose 
from the ALXN1850 GLP monkey toxicity study was used to select the Phase 1 study starting 
dose. The observed exposure of the NOAEL at 20 mg/kg/dose from the GLP SC monkey toxicity 
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study is approximately 113× (for IV) and 83× (for SC) of the projected AUC exposure of the 
proposed human starting single dose of 15 mg IV or 15 mg qw × 3 SC (Section 4.3). Given the 
exposure margins and the lack of systemic toxicity or local tolerability findings in 28-day rat and 
monkey toxicology studies with ALXN1850, the safety risk for humans on the 15 mg starting 
dose is considered to be very low. 
As per the current FIH study design the fourth dose will be administered by Day 28 (1 IV dose 
followed by 3 SC doses; Section 1.2). The 28-day toxicology studies in rats and monkeys with 
10 SC doses administered with q3d dosing frequency are sufficient to support the FIH duration 
of dosing (ICH M3 [R2] and ICH S6 [R1] guidance). 
2.3. 
Benefit/Risk Assessment 
Identified potential risks are described below. More detailed information about the known and 
expected benefits and risks and reasonably expected adverse events (AEs) of ALXN1850 may be 
found in the IB. 
2.3.1. 
Risk Assessment 
Potential risks of study participation include: 
x Injection/infusion site reactions (ISRs) 
x Injection/infusion associated reactions (including hypersensitivity) 
x Formation of anti-ALXN1850 antibodies 
x Ectopic calcifications 
2.3.1.1. 
Coronavirus Disease 2019 
The coronavirus disease 2019 (COVID-19) pandemic is active in many countries at the time of 
the original protocol and this protocol amendment. Given this unique circumstance, specific 
consideration has been given to the risks and benefits of the study as they relate to COVID-19, 
and the global and local changes that exist as a result of the pandemic. This assessment is 
described in Section 10.7. 
2.3.2. 
Benefit Assessment 
No direct medical benefit is anticipated in participants in any of the cohorts during this short 
course of treatment with ALXN1850. HPP is a chronic systemic disease that requires long term 
ERT in patients for whom it is indicated. The decision to continue ERT for HPP after the patient 
has ended the study will be made by the patient and their physician and, if requested, treatment 
with asfotase alfa will be made available. 
2.3.3. 
Overall Benefit Risk Conclusion 
This is the first time that ALXN1850 will be administered to humans. Because of the potential 
for immunogenicity, this study will enroll adults with HPP who are not anticipated to require 
continued treatment with ERT, based on their signs and symptoms, and the Investigator’s clinical 
assessment of their current condition. 
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This study has been designed to minimize the identified potential risks to participants; there are 
strict inclusion/exclusion criteria with a robust safety monitoring and risk mitigation plan in 
place. A SRC will evaluate the available study data at prespecified time points for participant 
safety and make recommendations on dose escalation, dose modification, or termination of the 
study. There is no added medical benefit for the participants. 
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3.
OBJECTIVES AND ENDPOINTS
The study objectives and corresponding endpoints are presented in Table 4. 
Table 4: 
Objectives and Endpoints 
Objective
Endpoints
Primary 
Assess the safety and tolerability of ALXN1850 given 
IV as a single dose and given SC in 3 qw doses 
Incidence of TEAEs and TESAEs 
Secondary 
Assess the PK of single IV and 3 SC doses of 
ALXN1850 
ALXN1850 PK (activity) over time profiles and PK 
parameters 
Assess the absolute bioavailability of ALXN1850 SC 
AUCtau values of the first SC versus IV administration 
Assess the PD effects of single IV and 3 SC doses of 
ALXN1850 
Absolute change and percent change from baseline in 
plasma concentrations of PPi and PLP and PLP/PL 
ratio over time  
Assess the immunogenicity potential of ALXN1850 
Incidence of ADAs and NAbs 
Exploratory  
Explore role of ALXN1850 on calcium and bone 
homeostasis and other PD biomarkers 
Absolute, change, and percent change from baseline in 
ionized Ca, phosphorus, magnesium, PTH, CTX-1 
(sCTX), P1NP, osteocalcin, and PA over time 
Abbreviations: ADA = antidrug antibody; AUCtau = area under the plasma concentration versus time curve within 
the dosing interval; Ca = calcium; IV = intravenous; NAb = neutralizing antibody; P1NP = N-terminal propeptide 
of type I procollagen; PA = pyridoxic acid; PD = pharmacodynamics(s); PK = pharmacokinetic(s); 
PL = pyridoxal; PLP = pyridoxal-5’-phosphate; PPi = inorganic pyrophosphate; PTH = parathyroid hormone; 
qw = weekly; SC = subcutaneous; CTX-1 (sCTX) = serum Ctelopeptide cross-link of type 1 collagen; 
TEAE = treatment emergent adverse event; TESAE = treatment emergent serious adverse event 
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4.
STUDY DESIGN
4.1. 
Overall Design
This is an open-label, dose-escalating study to assess safety, tolerability, PK, PD, and 
immunogenicity of ALXN1850 when given IV and SC to adult participants with HPP. 
Study participants will be enrolled into 3 cohorts in a sequential fashion. The first participant in 
each cohort will begin dosing before the rest of the cohort. A SRC will convene after the first 
participant in each cohort has completed the first IV dose to assess safety and tolerability, and to 
endorse initiation of SC study drug administration to the first participant as well as IV and SC 
study drug administration to the remaining participants in the cohort.  
Once Cohort 1 participants have received a single IV dose and 3 qw SC doses, the SRC will 
convene again to review safety and tolerability data, and to determine if the dose escalation may 
proceed. If the SRC endorses dose escalation, Cohort 2 will begin dosing at the next dosing 
level. Cohort 3 will begin dosing after the SRC has reviewed all relevant safety, tolerability, and 
PK data from participants in Cohorts 1 and 2 and endorsed dose escalation. The study design is 
presented in Figure 1. Further details are provided in Section 6.6.1 and in the SRC charter. 
4.2. 
Scientific Rationale for Study Design 
As this is the first time ALXN1850 will be dosed in humans, an open-label dose escalating 
design was chosen for initial assessment of the safety, tolerability, PK, and PD of ALXN1850 IV 
and SC in adults with HPP.  
The scientific rationale for each aspect of the study design is discussed below: 
x This study will be conducted in adult participants with HPP because ALXN1850 is 
designed as a TNSALP ERT that is expected to lead to improvement in this patient 
population. Because of the potential for immunogenicity, this study will enroll adults 
with HPP who are not anticipated to require continued treatment with ERT, based on 
their signs and symptoms, and the Investigator’s clinical assessment of their current 
condition. 
x A single ALXN1850 IV dose will provide the reference necessary for assessing 
absolute bioavailability. 
x Weekly SC dose will provide the PK and PD information that will support the 
intended dose regimen in this patient population. 
x Three weekly doses of SC ALXN1850 will provide accumulation information for this 
study drug. 
x The qw SC dose range proposed for this study (15 to 90 mg) is expected to cover the 
therapeutic range in humans. 
x An 8-week follow-up will provide enough time to assess immunogenicity and 
possible risks to the participants. 
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4.3. 
Justification for Dose 
First-in--human dose selection was based on PK data collected from a wild-type mouse study; rat 
and monkey dose range finding studies; 4-week GLP toxicology studies in rats and monkeys; 
and efficacy data from 2 Akp2GW -/- mouse efficacy studies. A model-based approach 
employing dose response and population PK (PopPK) models was used to characterize the SC 
dose (15 mg [0.15 mL], 45 mg [0.45 mL], and 90 mg [0.90 mL]) after performing body 
weight-based forecasting to humans for the FIH study. A NOAEL based approach was used to 
determine the starting dose (15 mg IV). A summary of the expected exposure margin 
and- expected percentage of population with normalized mineralization response in humans for 
ALXN1850 is provided in Table 5. Given previous experience with asfotase alfa, it is expected 
that the ALXN1850 safety multiple will support flat dosing. The trade-off of flat dosing versus 
mg/kg dosing is some increase in PK variability (within a cohort) with a gain of reduction in 
potential errors in dosing and operational factors. 
The 15 mg IV starting dose is considered the maximum recommended starting dose (MRSD). 
The starting dose was selected based on NOAEL from the 4-week GLP toxicology study in 
monkeys dosed SC q3d. Monkey was selected because it has relevant biology with humans. The 
monkey NOAEL was determined to be 20 mg/kg/q3d or 46 mg/kg/week. Assumptions of 1) no 
allometric scaling for a molecule with molecule weight > 100 kDa (Food and Drug 
Administration (FDA) guidance: Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Health Volunteers, 2005), 2) applying safety factor of 150, and 
3) SC bioavailability (75%), 4) adult body weight of 70 kg, were factored into the calculation of
the starting dose. Based on dose simulation results, the observed exposure of the NOAEL at
20 mg/kg/dose from the GLP monkey toxicity study is approximately 113-fold of projected
exposure from the 15 mg IV starting dose (Table 5).
Cohort 1 will receive 15 mg as a single IV dose, followed by 15 mg SC at 1-week intervals for 
3 doses. The 15 mg SC dose was calculated (based on dose-response modeling of mouse data) to 
produce normalized bone mineralization in 66% of a treated population.  
Cohort 2 will receive 45 mg as a single IV dose, followed by 45 mg SC at 1-week interval for 
3 doses. A 45 mg SC dose is expected to achieve normal bone mineralization in 85% of a treated 
population and is selected as the target effective dose. Based on the asfotase alfa clinical 
definition for this efficacy endpoint, the dose producing normal bone mineralization in 85% of 
the treated population (ED85) is considered as the target effective dose. Mouse ED85 was 
calculated using a dose response model developed using ALXN1850 preclinical efficacy studies 
in Akp2GW (-/-) mouse model of HPP and allometrically scaled to a weekly flat dose of 
45 mg/week in humans. 
Cohort 3 will receive 90 mg as a single IV dose, followed by 90 mg SC at 1-week intervals for 
3 doses. A 90 mg SC dose is projected to achieve normalized bone mineralization in 91% of a 
treated population and is expected to cover the therapeutic range in humans. 
In the monkey 28-day toxicology study, a total of 10 doses were administered SC at a dose 
interval of once every 3 days (q3d). The proposed Phase 1 dosing schedule includes 
administering a total of 4 doses (1 IV and 3 SC doses) once-a-week (qw) (see Section 4.1 for 
more details), resulting in a total dosing duration of 3 weeks (4 weeks for first participant of the 
cohort) for ALXN1850 administration. Although, the total duration of ALXN1850 proposed 
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administration in the Phase 1 study is at most the same duration as the monkey toxicology study, 
more doses were administered in the monkey toxicology study at a more frequent dosing interval 
(10 doses at q3d) than the proposed dosing regimen in this Phase 1 study (4 qw doses). 
Therefore, the existing nonclinical toxicology data (rat and monkey) support the proposed 
Phase 1 dosing regimen in a clinical setting. 
Table 5: 
Predicted ALXN1850 PK Exposure, Exposure Margin, and Percentage of 
Population with Normalized Mineralization Response in Humans 
Cohort 
N 
Dose 
Predicted 
AUC0-168h 
(μg × hour/ 
mL) 
Predicte
d Cmax 
(μg/mL) 
Expected 
exposure 
margin 
for AUC0-
168h
Expected 
exposure 
margin 
for Cmax 
Expected % of 
population with 
normalized 
mineralization 
response  
1 
5 
15 mg IV 
325 
4.3 
113 
59 
NA 
15 mg SC 
qw × 3 
441 
3.2 
83 
26 
66% 
2 
5 
45 mg IV 
1084 
13 
38 
18 
NA 
45 mg SC 
qw × 3 
1318 
9.6 
28 
13 
85% 
3 
5 
90 mg IV 
1951 
26 
19 
10 
NA 
90 mg SC 
qw x 3 
2645 
19 
14 
13 
91% 
Note: A NOAEL dose of 20 mg/kg/dose was derived from a 4-week SC monkey toxicology study. 
Abbreviations: AUC0-168h = area under the concentration-time curve from time zero to 168 hours; Cmax = maximum 
observed serum concentration (measured after dosing); HPP = hypophosphatasia; IV = intravenous; N = number 
of participants; NA = not available; NOAEL = no- observed- adverse- effect level; PK = pharmacokinetic(s); 
q3d = every 3 days; SC = subcutaneous; qw = weekly 
4.4. 
End of Study Definition  
A participant is considered to have completed the study if he/she has completed all visits 
including the last scheduled visit specified in the SoA (Section 1.3). 
Details on participant withdrawal from the study as well as stopping rules can be found in 
Section 7. 
The end of the study is defined as the date of the last scheduled visit (including follow-up) as 
shown in the SoA [Section 1.3]). 
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5.
STUDY POPULATION
Participants will be enrolled in the study if all inclusion criteria and no exclusion criteria are met. 
Because of the potential for immunogenicity, this study will enroll adults with HPP who do not 
currently require asfotase alfa and are not anticipated to require ERT after study completion, 
based on their signs and symptoms, and the Investigator’s clinical assessment of their current 
condition and disease burden. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, will not be permitted. 
5.1. 
Inclusion Criteria 
Age 
1. Male or female aged ≥ 18 years at the time of signing the informed consent form (ICF).
Type of Participant and Disease Characteristics 
2. Clinical diagnosis of HPP confirmed by the following:
a.
Documented ALPL gene mutation(s) (pathogenic or likely pathogenic variant, or a
variants of unknown significance) from the certified laboratory;
b. Serum ALP level below the laboratory age- and sex-adjusted normal range at
Screening.
3. Not anticipated to require further treatment with ERT to treat their HPP after study
completion.
Pregnancy and Contraception 
4. Female participants of childbearing potential and male participants must follow
protocol-specified contraception guidance as described in Section 10.4.
Informed Consent 
5. Must be willing and able to give written informed consent and to comply with all study
visits and procedures as well as requirements and restrictions listed in the ICF and in this
protocol.
5.2. 
Exclusion Criteria 
Medical Conditions 
1. Primary or secondary hyperparathyroidism or hypoparathyroidism.
2. Current or recurrent concomitant disease that could affect clinical assessments or clinical
laboratory evaluations.
3. Current or relevant history of physical or psychiatric illness that is not stable or may
require a change in treatment, use of prohibited therapies during the study, or make the
participant unlikely to fully comply with the requirements of the study or complete the
study, or any condition that presents undue risk from the study drug or study procedures.
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4. Any other significant disease or disorder which, in the opinion of the Investigator, may
put the participant at risk.
5. ECGs showing a PR value of less than 120 ms or greater than 240 ms, QRS > 110 ms,
and QT interval corrected using Fridericia’s formula (QTcF) > 450 ms for men and
QTcF > 470 ms for women at Screening. If the results of the first triplicate ECG are
abnormal, 2 additional triplicate ECGs will be performed. Both of the subsequent
triplicate ECGs must be within normal ranges or the participant is not eligible for the
study.
6. Heart rate > 120 beats per minute (bpm) at Screening.
7. Human immunodeficiency virus (HIV) infection (evidenced by HIV type 1 or type 2
antibody titer), acute or chronic hepatitis B virus (HBV) infection (evidenced by hepatitis
B surface antigen), or acute or chronic hepatitis C virus (HCV) infection (evidenced by
antibody titer)
8. Fracture within 12 weeks of screening.
9. History of significant allergic reaction (eg, anaphylaxis or angioedema) to any product
(eg, food, pharmaceutical).
 
Prior/Concomitant Therapy 
10. Use of nonprescription/ over-the-counter medications, including herbal remedies and
supplements, within 7 days before dosing Day 1, except with prior approval of Alexion.
11. Use of vitamin B6 (including vitamin supplements that contain vitamin B6) within
2 weeks prior to screening.
12. Oral bisphosphonate use within 6 months (depending on the half-life of the drug as
assessed by the Investigator) and IV bisphosphonate use within 12 months prior to
screening.
13. Asfotase alfa use within 6 months or positive for asfotase alfa antidrug antibody
(ADA)/neutralizing antibodies (NAbs) [only required for patients with a history of
asfotase alfa use].
14. Teriparatide/parathyroid hormone (PTH) analog use within 2 months prior to screening.
15. Treatment with strontium or sclerostin inhibitors within 6 months prior to the first dose of
study drug.
16. History of allergy or hypersensitivity to excipients of asfotase alfa or ALXN1850 (eg,
sodium phosphate, sodium chloride).
Prior/Concurrent Clinical Study Experience 
17. Current enrollment or past participation, within the last 30 days, before signing of
informed consent form in any other clinical study involving an investigational study drug.
Participants, involved in interventional studies, are not eligible unless the time since last
treatment has exceeded 30 days or 5 half-lives of the study drug, whichever is longer.
 
Diagnostic Assessments 
18. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2.
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19. Serum 25-hydroxy (25-OH) vitamin D below 20 ng/mL,
20. PTH levels > ULN of the laboratory reference range at Screening.
21. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > ULN of the
reference range of the testing laboratory at Screening.
22. Any clinically significant abnormal hematological parameters (per the Investigator’s
discretion).
23. Positive urine drug toxicology screen for non-prescribed substances at Screening.
Weight
24. Body mass index (BMI) > 40 kg/m2 at baseline.
Other Exclusions
25. Female participants who are pregnant, planning to become pregnant, or breastfeeding.
26. Current employees of Alexion.
27. Investigational site personnel involved directly in the study and/or their immediate
families. Immediate family is defined as a spouse, parent, child, or sibling, whether
biological or legally adopted.
28. Major surgery or hospitalization within 90 days prior to dosing on Day 1.
29. Currently smokes nicotine or tobacco products in any form and is unwilling to refrain
from smoking during inpatient stays.
30. History of drug and/or alcohol abuse (according to current Diagnostic and Statistical
Manual of Mental Disorders) within 1 year of Screening that would limit patient
participation in the study as determined by the Investigator.
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
x Participants are required to abstain from ingesting food containing poppy seeds 
within 48 hours prior to each dose. 
5.3.2. 
Alcohol, and Tobacco 
Participants will be required to abstain from: 
x Ingesting alcohol 48 hours before each dose through discharge from the inpatient 
facility, and 24 hours before each study follow-up visit. 
x Smoking nicotine or tobacco products from 2 hours before admission through 
discharge from the inpatient facility. 
5.3.3. 
Activity 
Participants will be required to remain in supine position for dosing and for approximately 
15 minutes after study drug administration. Vigorous activity (strenuous, beyond the 
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participant’s routine physical activities) will be prohibited at all times throughout confinement at 
the inpatient unit. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered into the study. 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 publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details (eg, failed 
eligibility criteria), and any AEs, including any serious adverse events (SAEs) and any related 
concomitant medication, occurring during the Screening Period. 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a 
reason that is expected to resolve or has resolved, may be rescreened based on discussion and 
agreement between the Investigator and the Medical Monitor. Investigational sites are permitted 
to rescreen participants who do not meet inclusion/exclusion criteria. 
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6.
STUDY INTERVENTION
Study drug is defined as any investigational drug product(s), marketed product(s), or placebo 
intended to be administered to a study participant according to the study protocol. 
6.1. 
Study Interventions Administered 
The study drug composition and doses to be administered in this study are presented in Table 6. 
Detailed description of the study drug is provided in the Pharmacy Manual.  
Table 6: 
Dose Reference Chart for Study ALXN1850-HPP-101 
Intervention Name 
ALXN1850 SC 
ALXN1850 IV 
Type  
Biologic 
Biologic 
Dose Formulation 
ALXN1850 is formulated at pH 7.3 and 
each vial contains 100 mg of 
ALXN1850 in 10 mM sodium 
phosphate, 140 mM proline, 140 mM 
sucrose, 0.05% w/v polysorbate 80. The 
concentration is 100 mg/mL. 
ALXN1850 is formulated at pH 7.3 and 
each vial contains 100 mg of 
ALXN1850 in 10 mM sodium 
phosphate, 140 mM proline, 140 mM 
sucrose, 0.05% w/v polysorbate 80. The 
concentration is 100 mg/mL. 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
15, 45, and 90 mg (3 × qw), 
15, 45, and 90 mg single dose 
Route of Administration 
SC 
IV 
Use 
Experimental 
Experimental 
Dosing Instructions 
ALXN1850 will be administered via 
the SC route once a week (qw) over 
3 weeks (a total of 3 doses) at a 15, 45, 
or 90 mg dose. 
SC doses will be administered as a 
manual SC injection in either the 
abdomen or thigh at the Investigator’s 
discretion.  
For more detailed instructions on study 
drug dosing refer to the Pharmacy 
Manual. 
A single dose of ALXN1850 at 15, 45, 
or 90 mg will be administered as an IV 
infusion per cohort.  
For more detailed instructions on study 
drug dosing refer to the Pharmacy 
Manual. 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by Alexion 
Provided centrally by Alexion 
Packaging and Labeling 
Study drug will be provided in kits. 
There will be 1 vial per kit. Both kits 
and vials will be labeled according to 
the protocol and local regulatory 
requirements. 
Study drug will be provided in kits. 
There will be 1 vial per kit. Both kits 
and vials will be labeled according to 
the protocol and local regulatory 
requirements.  
Abbreviations: IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational medicinal 
product; qw = weekly; SC = subcutaneous 
6.2. 
Preparation/Handling/Storage/Accountability 
Details regarding preparation, handling, storage, accountability, and administration of the study 
drug are discussed below. Additional guidance is provided in the Pharmacy Manual. 
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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.
2. Only participants enrolled in the study may receive the study drug and only authorized
site staff may supply or administer the study drug. All study drug must be stored in a
secure, environmentally controlled, and monitored (manual or automated) area in
accordance with the labeled storage conditions with access limited to the Investigator and
authorized site staff.
3. The Investigator, institution, or the head of the medical institution (where applicable) is
responsible for study drug accountability, reconciliation, and record maintenance (ie,
receipt, reconciliation, and final disposition records).
4. Further guidance regarding preparation, handling, storage, administration (including
infusion rate), and accountability and information for the final disposition of unused
study intervention is provided in the Pharmacy Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a Phase 1, open-label study; therefore, there will be no randomization of study 
participants in this study. Approximately 15 participants will be enrolled in the study to allow for 
at least 9 participants (3 per cohort) to complete the study. Participants presenting during the 
Screening Period who meet all the eligibility criteria will be offered participation in the study. 
Those that accept will be assigned to the next available cohort. 
6.4. 
Study Intervention Compliance 
Participants will be administered study drug in a controlled setting under the supervision of the 
Investigator or designee, thereby ensuring compliance with study drug administration. The date 
and time of each dose administered in the clinic will be recorded in the source documents and 
recorded in the electronic case report form (eCRF). 
For additional information on study intervention compliance and management, refer to the 
Pharmacy Manual. 
6.5. 
Concomitant Therapy 
A concomitant therapy is any drug or substance (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
x Reason for use 
x Dates of administration including start and end dates 
x Dosage information including dose and frequency 
x Any AEs related to concomitant drug administration 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
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6.5.1. 
Allowed Medicine and Therapy 
The use of hormonal contraceptives will be allowed and recorded in the eCRFs. 
Prescription medications will be permitted during the study at the Investigator’s discretion and 
recorded in the eCRFs. 
The occasional use of nonprescription medications, over-the-counter, herbal preparations, and 
multivitamins, antipyretics, or analgesics (eg, acetaminophen) may be allowed during the study, 
at the discretion of the Investigator and documented. 
6.5.2. 
Disallowed Medicine and Therapy 
Use of vitamin B6 (including vitamin supplements that contain vitamin B6) must be 
discontinued at least 2 weeks before Screening. 
Use of oral bisphosphonate and IV bisphosphonate must be discontinued 6 months and 
12 months, respectively, before Screening. Treatment with strontium or sclerostin inhibitors must 
be discontinued at least 6 months before the first dose of study drug. Use of teriparatide/ PTH 
analog must be discontinued at least 2 months before Screening. 
Use of asfotase alfa within 6 months of Screening and throughout the study is prohibited. 
A concomitant procedure is any therapeutic intervention (eg, surgery/biopsy, physical therapy) 
or non-study diagnostic assessment (eg, blood gas measurement, bacterial cultures) performed 
from the time the participant is screened for the study until the last study visit. Concomitant 
procedures are not allowed unless medically indicated. 
6.6. 
Dose Modification 
Decisions to continue, modify (explore the dose cohort further), or escalate dosing will be made 
by the SRC. 
The SRC will meet to review safety data after the first participant in each cohort completes IV 
dosing to assess for safety and to support multiple dosing for the first participant as well as study 
drug administration for the remaining participants in each cohort. Initiation of Cohort 2 can only 
occur after review of accumulated safety data from Cohort 1. Initiation of Cohort 3 can only 
occur after review of accumulated safety and PK data from Cohorts 1 and 2. If dosing is stopped 
because a safety event occurs or a stopping criterion is met, dosing may not resume until there is 
documented agreement between the Investigator and Alexion’s Medical Monitor. 
After review of the safety data, the SRC may agree to any of the following options: 
x Continue dose escalation as described in the protocol 
x Administer the same dose to an additional cohort 
x Administer a higher intermediate dose between the current dose and the next protocol 
specified dose level 
x Administer a lower intermediate dose between the current dose and the previously 
administered dose 
x Discontinue further dosing in the study 
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Safety review and decisions of the SRC will be documented in a memorandum that must be 
approved by Alexion and Investigator prior to initiating dosing of the next cohort. The study 
design is presented in Figure 1. Further details are provided in Section 6.6.1 and in the SRC 
charter. 
6.6.1. 
Dose Escalation 
Before initiating Cohort 2, accumulated safety data from Cohort 1 will be reviewed. After at 
least 3 participants in Cohort 1 have received a single IV dose and 3 weekly (qw) SC doses, the 
SRC will convene again to review safety and tolerability data, and to determine if the dose 
escalation may proceed. The SRC will review available data including treatment emergent 
adverse events (TEAEs), safety laboratory results, 12-lead ECG findings, and vital sign 
measurements. 
For dose escalation between Cohort 1 and Cohort 2, PK data will not be provided. 
The decision to begin Cohort 3 will be determined by the SRC, who, at minimum, will review 
the following data (see SRC charter for full description of data required for each safety review): 
x All available accumulated safety data from all participants in Cohorts 1 and 2 
x Up to Day 36 PK data from the first participant in Cohort 1 
x Up to Day 29 PK data from the 2nd and 3rd participants in Cohort 1 
x Up to Day 22 (168 hours post SC dose) PK data from the first participant in Cohort 2 
x Up to Day 8 (168 hours post IV dose) PK data from the 2nd and 3rd participants in 
Cohort 2 
Predicted ALXN1850 human PK exposure (Table 5) indicates Cohort 3 PK exposure will not 
exceed 50% of the NOAEL exposure (AUC0-168h = 36800 h*μg/mL and Cmax = 254 μg/mL) 
established in the GLP 4week monkey toxicology study. In the event that PK exposure in 
Cohort 3 is predicted to exceed 50% of the NOAEL exposure, a lower dose may be selected so 
that the above criteria can be met. 
Dose escalation requires agreement between Alexion and Investigator; Alexion may not overrule 
the Investigator if there are concerns that dosing should be stopped. 
In the event of an acute safety event, dosing should be stopped until assessment of causality has 
taken place and an appropriate risk mitigation strategy is put into place before dosing the 
remainder of the cohort. 
6.7. 
Intervention After the End of the Study 
Upon completion of the last study visit, participants will return to the care of their treating 
physician. 
Participants who are positive for ADAs at the last assessment of the study will be given options 
to enable further monitoring of their ADA values after the end of the study; these options may 
include enrollment in the Global HPP Registry. 
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7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Stopping rules provide explicit guidance for the discontinuation of treatment cohorts and 
discontinuation of individual participants. The following rule sets apply to TEAEs that are 
assessed by the Investigator to be related to study drug (unless specified otherwise). While 
stopping rules provide an explicit guide for dose discontinuation, the Investigator and/or Alexion 
may elect to discontinue dosing at any time. Dose continuation or escalation will proceed as 
scheduled and the study will continue as planned provided no prespecified toxicity events occur 
(as determined by the SRC). 
The entire study will be suspended if any severe or life-threatening treatment-emergent serious 
adverse events (TESAEs) occur. 
Participants who do not complete the study but have been dosed should make every effort to 
undergo all scheduled safety, PK, and PD evaluations required by the protocol (refer to SoA, 
Section 1.3) in relation to the last dose they received. Alexion and site monitor will be notified as 
soon as possible. 
If a participant withdraws consent and is unwilling to attend all scheduled procedures, every 
attempt will be made to encourage them to complete the ED visit at a minimum. 
7.1. 
Discontinuation of Study Intervention 
7.1.1. 
Cohort Stopping Rules 
Within cohort dosing will be temporarily halted if any of the following are observed: 
x Two or more participants experience CTCAE Grade 2 TEAE (excluding ISR and 
injection/infusion associated reactions) with the same PT or medical concept that are 
considered to be related to study drug and do not show signs of reversibility by the 
following visit. 
x One participant experiences a CTCAE Grade 3 (or higher) TEAE considered to be 
related to study drug. 
x Severe (Grade 3) injection site reaction in more than 50% of a cohort, assessed by the 
Investigator to be related to the study drug 
x The PK stopping limit defined as 50% of the NOAEL exposure (mean Cmax and 
AUC0-168h values) established in the GLP 4-week monkey toxicology study. This 
stopping rule will only be assessed before dose-escalating between Cohort 2 and 
Cohort 3. 
In the event of suspension of dosing, continuation of the study will require a protocol 
amendment. 
7.1.2. 
Individual Participant Stopping Rules 
Individual participant dosing will be temporarily halted if any of the following are observed: 
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x Participant experiences any CTCAE Grade 3 (or higher) TEAE considered to be 
related to study drug. 
x Participant experiences any CTCAE Grade 2 TEAE considered to be related to study 
drug and is considered to be a safety concern by the Investigator. 
x Severe (Grade 3) ISR assessed by the Investigator to be related to the study drug. 
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
Dosing may continue if appropriate risk mitigation steps are enacted to allow for safe 
continuation of the study. Assessment of adverse event intensity should be performed by the 
Investigator taking into consideration clinical judgment as described in the clinical protocol. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
x 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 
eCRF. 
x 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.  
x At any visit, a positive drug test result for a non-prescribed substance will lead to 
participant discontinuation.
x A positive pregnancy test result at any time during the study will lead to participant 
discontinuation.
x Participants diagnosed with COVID-19 with clinical manifestations of the disease 
will be evaluated for potential treatment and/or study discontinuation according to the 
CRU’s COVID-19 protocol. 
x At the time of discontinuing from the study, if possible, an Early Discontinuation visit 
should be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be 
collected at the time of discontinuation and follow-up and for any further evaluations 
that need to be completed. 
x 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. 
x 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. 
x Participants who withdraw/are withdrawn from the study following completion of 
EoT assessments but prior to completion of EoS assessments will be considered 
“completed” if all PK/PD sampling was performed within window and all doses were 
administered per the SoA. “Completed” participants do not need to be replaced. 
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x Participants who withdraw/are withdrawn from the study prior to completion of the 
end-of-treatment assessments should be replaced unless at least 3 participants in their 
cohort have already “completed” or are on track to “complete”. 
x If a participant misses a dosing visit, they do not need to be withdrawn or 
discontinued from treatment or the study; however, they will not be considered 
“completed” even if they continue on to complete the end-of-treatment assessments. 
These participants should be replaced unless at least 3 participants in their cohort 
have already “completed” or are on track to “complete. 
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: 
x The site must attempt to contact the participant to reschedule the missed visit as soon 
as possible, 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. 
x 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. 
x Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up. 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 
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8.
STUDY ASSESSMENTS AND PROCEDURES
x Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
x Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
x Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
x 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. 
x Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol--specified criteria and 
were performed within the time frame defined in the SoA (Section 1.3). 
x See Section 10.2 for the list of clinical laboratory tests. 
8.1. 
Efficacy Assessments 
No efficacy assessments will be performed during this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
x A full physical examination will be performed at Screening and will include 
assessments of the general appearance; skin; head, ears, eyes, nose, and throat; neck; 
lymph nodes; chest; heart; abdominal cavity; limbs; central nervous system; and 
musculoskeletal system. 
x At all other timepoints indicated in Section 1.3, an abbreviated physical examination 
will be performed that will target certain assessments listed above at the 
Investigator’s discretion. 
x During both full and abbreviated physical examinations, Investigators or designee 
should pay special attention to clinical signs related to previous serious illnesses. 
x Height and weight will be measured and recorded at the timepoints indicated in 
Section 1.3. 
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8.2.2. 
Vital Signs 
Vital sign measurements will be taken after the participant has been resting in the supine or 
semi-recumbent position for at least 5 minutes and will include temperature (°C; tympanic or 
oral), respiratory rate, blood pressure, and pulse.  
The timing of vital sign measurements is described in the SoA (Section 1.3). Of note, vital signs 
measurements will be performed every 15 minutes for the first hour after dose administration to 
monitor for anaphylaxis. 
Out of range blood pressure or pulse measurements will be repeated at the Investigator’s 
discretion. Confirmed, clinically significant vital sign measurements will be recorded as AEs. 
8.2.3. 
Electrocardiograms 
Triplicate 12-lead ECGs will be recorded at the time points described in the SoA (Section 1.3) 
but should not be performed after any major meal (ie, major meals should be withheld until after 
ECG assessments). All ECGs should occur before the vital signs assessment and PK/PD 
sampling (if 1 or both are scheduled in addition to an ECG during a timepoint). 
Electrocardiograms recorded during Screening will be stored electronically. Only ECGs recorded 
electronically will be valid ECGs for any purpose other than safety assessment. Each ECG 
recorder will be set up to the required technical specifications and containing the information 
required to identify the records. Each ECG recording will be clearly identified (participant ID, 
visit date, and the actual times of ECG recordings). 
Recording of each 12-lead ECG will be made after the participants have been resting in a supine 
position for at least 10 minutes. The participants will avoid postural changes during the ECG 
recording and clinical staff will ensure that participants are awake during the ECG recording. 
At each time point, the ECG will be recorded in triplicate, to reduce variance and improve the 
precision of measurement. The triplicates will be performed sequentially within a 15-minute 
window and each ECG recording (trace) will last 10 seconds; repeat ECGs will be performed 
until these criteria are met. 
ECGs will be assessed per applicable standard operating procedure to enable reading and 
analyzing at least 5 complexes per derivation. 
8.2.3.1. 
Safety Review of 12-lead Electrocardiograms 
All recorded ECGs will be reviewed by the Investigator or qualified designee. If a participant 
shows a clinically significant abnormal ECG, additional safety recordings may be made, and the 
abnormality will be followed to resolution. 
8.2.4. 
Clinical Safety Laboratory Assessments 
All protocol-required assessments, as defined in Section 10.2, must be conducted in accordance 
with the SoA (Section 1.3) and the Laboratory Manual. Clinical and laboratory assessments to 
assess safety will be performed by a central laboratory. 
x 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 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
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significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant’s condition. 
x All laboratory tests with values considered clinically significantly abnormal during 
participation in the study will 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. 
 If laboratory values from non-protocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the Investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the eCRF.  
The maximum total blood volume collected from participants in the study will not exceed 
500 mL in 16 weeks. The American Red Cross at the time of completion of this protocol 
(https://www.redcrossblood.org/faq.html) states that people can give up to 470 mL every 
56 days. Therefore, the 500 mL per 16 weeks permitted in this study is approximately consistent 
with current clinical practice. 
8.2.5. 
Drug and Alcohol Screen 
A urine sample for drug screen will be analyzed for the substances listed in Section 10.2. Timing 
for urine drug screen and alcohol tests is specified in the SoA (Section 1.3). 
8.2.6. 
Pregnancy 
Pregnancy data from female participants and female spouses/partners of male participants will be 
collected from the first dose of ALXN1850 and at the time points specified in the SoA 
(Section 1.3). Any female participant who becomes pregnant during the study should be 
considered for discontinuation 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 10.4.3. 
8.2.7. 
Injection or Infusion Site Evaluation 
Subcutaneous injection- or IV infusion-site evaluations will be performed at the time points 
specified in the SoA (Section 1.3).  
8.2.8. 
Ophthalmological Examination 
Ophthalmological examinations will be performed at the timepoints indicated in Section 1.3.The 
examination will assess for papilledema and signs of ectopic calcification and will include 
slit-lamp examination and fundoscopy. The ophthalmology examination should be performed by 
a qualified ophthalmologist or an optometrist (ie, Doctor of Optometry) as long as the 
optometrist works under the supervision of an ophthalmologist.  
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8.2.9. 
Renal Ultrasound 
A renal ultrasound will be performed at the timepoints indicated in Section 1.3 to assess for the 
presence of nephrocalcinosis. 
8.3. 
Adverse Events and Serious Adverse Events  
The definitions of AEs and SAEs can be found in Section 10.3. All AEs will be reported to the 
Investigator or qualified designee by the participant. 
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 drug (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 
All AEs and SAEs will be collected from the signing of the ICF until the final follow-up- visit 
(See Section 1.3). 
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be considered as pretreatment AEs. 
All SAEs will be recorded and reported to Alexion 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 awareness. 
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 
nonleading 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. 
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8.3.4. 
Regulatory Reporting Requirements for SAEs 
x Prompt notification of an SAE by the Investigator to Alexion is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
x Alexion has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. Alexion will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
x Alexion is required to submit individual suspected unexpected serious adverse 
reaction (SUSAR) reports (defined in Section 10.3.3) in the format of 
MedWatch 3500 or Council for International Organizations of Medical Sciences 
(CIOMS) I Form to health authorities and Investigators as required. 
x 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. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Any increase on frequency and/or intensity in the signs/symptoms of the disease under study will 
be reported as AEs. 
8.3.6. 
Adverse Events of Special Interest 
8.3.6.1. 
Injection Site Reactions 
Injection site reactions (ISRs) are defined as AEs localized to the site of study drug 
administration that occur at any time during study participation that are assessed by the 
Investigator as possibly, probably, or definitely related to study drug. AE intensity reporting 
procedures are outlined in Section 10.3.4. 
Injection site reactions may occur at any timepoint after study drug administration. There is no 
additional laboratory testing required for ISRs.  
The Investigator is responsible for monitoring for ISRs in patients throughout the duration of the 
study. As part of the study-required physical examinations, Investigators should evaluate 
injection sites for signs of reaction(s). 
8.3.6.2. 
Injection-associated Reactions 
Injection-associated reactions are defined as systemic AEs (eg, fever, chills, flushing, alterations 
in heart rate and blood pressure, dyspnea, nausea, vomiting, diarrhea, and generalized skin 
rashes) occurring during or within 24 hours of the start of SC injection that are assessed by the 
Investigator to be related to the study drug. AE intensity reporting procedures are outlined in 
Section 10.3.4. 
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8.4. 
Treatment of Overdose 
For this study, any dose of ALXN1850 greater than that specified in this protocol will be 
considered an overdose. 
Overdoses are medication errors that are not considered AEs unless there is an untoward medical 
occurrence resulting from the overdose. There is no specific treatment for an overdose. 
In the event of an overdose, the Investigator 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
eCRF.
8.5. 
Pharmacokinetics 
x Whole blood samples will be collected for measurement of plasma concentrations of 
ALXN1850 as specified in the SoAs (see Section 1.3). Additional samples may be 
collected during the study if warranted and agreed upon between the Investigator and 
Alexion. 
x 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. Permitted collection windows are specified in the SoAs (see Section 1.3). 
x Samples will be used to evaluate the PK of ALXN1850. Samples collected for 
analyses of ALXN1850 plasma concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study. Unused samples 
may be retained for a period of up to 5 years (or per regional requirements) to 
perform additional PK assessments as necessary. 
x Samples may be used for research to develop methods, assays, for prognosis, 
diagnostics, and/or treatment monitoring related to the mechanism of action of 
ALXN1850. 
8.6. 
Pharmacodynamics 
x Whole blood samples will be collected for measurement of PLP/PL, PA, and PPi as 
specified in the SoA (see Section 1.3). Additional samples may be collected during 
the study if warranted and agreed upon between the Investigator and Alexion. 
x 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. Permitted collection windows are specified in the SoAs (see Section 1.3). 
x Samples will be used to evaluate the PD of ALXN1850. Samples collected for 
analyses of ALXN1850 concentration may also be used to evaluate safety or efficacy 
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aspects related to concerns arising during or after the study. Unused samples may be 
retained for a period of up to 5 years (or per regional requirements) to perform 
additional PD assessments as necessary. 
x Samples may be used for research to develop methods, assays, for prognosis, 
diagnostics, and/or treatment monitoring related to the mechanism of action of 
ALXN1850. 
8.7. 
Genetics 
To confirm eligibility, genetic testing for ALPL gene mutation will be performed during the 
Screening Period. No additional samples will be obtained for other genetic analysis during this 
study. 
8.8. 
Biomarkers 
Hypophosphatasia is characterized by interdependent clinical manifestations, emanating from a 
failure to mineralize bone matrix due to elevated concentrations of the TNSALP substrates, 
including PPi and PLP. Failure to mineralize bone matrix results in osteomalacia (softening of 
bones). Bone turnover markers such as osteocalcin, N-terminal propeptide of type I procollagen 
(P1NP), and serum C-telopeptide cross-link of type 1 collagen (sCTX) are a series of protein or 
protein derivative biomarkers released during bone remodeling due to activity of osteoblasts or 
osteoclasts. Bone turnover markers respond rapidly to changes in bone physiology; therefore, 
they have utility in determining patient response to and compliance with therapies for bone 
metabolic disorders (Greenblatt, 2017). 
Blood samples for bone turnover marker analysis (osteocalcin, P1NP, and sCTX) will be 
collected at the time points indicated in Section 1.3. 
Unused samples may be retained for a period of up to 5 years (or per regional requirements) to 
perform additional assessments as necessary. 
Samples may be used for research to develop methods, assays, for prognosis, diagnostics, and/or 
treatment monitoring related to the mechanism of action of ALXN1850. 
8.9. 
Immunogenicity Assessments 
Antibodies to ALXN1850 (ie, ADA) will be evaluated in serum samples collected from all 
participants according to the SoA (see Section 1.3). Additionally, serum samples should also be 
collected at the final visit from participants who discontinued the study intervention or were 
withdrawn from the study. These samples will be tested by Alexion or Alexion’s designee. 
Serum samples will be screened for antibodies binding to ALXN1850 and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to further characterize the 
immunogenicity of ALXN1850. 
The detection and characterization of antibodies to ALXN1850 will be performed using a 
validated assay method by or under the supervision of Alexion. Samples collected at the same 
time points as those collected for detection of ALXN1850 antibodies will be evaluated for 
ALXN1850 concentration to enable interpretation of the antibody data. Antibodies may be 
further characterized and/or evaluated for their ability to neutralize the activity of the study drug. 
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Samples will be analyzed on a per batch basis. In the event that a participant experiences an SAE 
potentially related to immunogenicity, that participant’s sample or set of samples will be sent for 
analysis at the time of the event and data will be provided to the SRC. Unused samples may be 
retained for a period of up to 5 years (or per regional requirements) to perform additional 
assessments as necessary. 
Samples may be used for research to develop methods, assays, for prognosis, diagnostics, and/or 
treatment monitoring related to the mechanism of action of ALXN1850. 
Participants who are positive for ADAs at the last assessment of the study will be given options 
to enable further monitoring of their ADA values after the end of the study; these options may 
include enrollment in the Global HPP Registry. 
Antibodies to asfotase alfa will also be evaluated in participants who have previously received 
asfotase alfa at Screening. 
8.10. 
Health Economics Data and Medical Resource Utilization 
Health economics data and medical resource utilization will not be collected or evaluated in this 
study. 
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9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses
No statistical hypotheses are planned for this study. 
9.2. 
Sample Size Determination 
The sample size is empiric and selected to support assessment of safety, tolerability, and PK 
parameters. Approximately 15 participants will be enrolled to allow for at least 9 participants 
(3 per cohort) to “complete” (ie, participant completed EoT assessments, all PK/PD sampling 
was performed within window, and all doses were received per the SoA) the study. It is expected 
that 9 “completed” participants will support adequate characterization of safety, tolerability, and 
PK/PD for the ALXN1850 compound. 
9.3. 
Populations for Analyses 
The population sets used for analysis sets are defined in the following: 
Population
Description
Safety Set 
All participants who receive any amount of study drug will be included in 
the Safety Set. Participants will be analyzed according to the study drug 
received. 
Pharmacokinetic Set 
All treated participants for whom the PK profile of ALXN1850 can be 
adequately characterized will be included in the PK Set. Pharmacokinetic 
analyses will be based upon the study drug received. 
Pharmacodynamic Set 
All treated participants for whom the PD profile of ALXN1850 can be 
adequately characterized will be included in the PD Set. 
Immunogenicity Set 
All treated participants for whom pre and postdose anti-ALXN1850 
antibody samples are obtained will be included in the Immunogenicity 
Set. 
9.4. 
Statistical Analyses 
In general, descriptive statistics for continuous variables will include number of non-missing 
values, arithmetic mean, standard deviation, median, minimum, and maximum. Descriptive 
statistics for PK parameters will include number of observations, arithmetic mean, standard 
deviation, arithmetic coefficient of variation (%CV), median, minimum, maximum, geometric 
mean, and geometric %CV. Categorical variables will be summarized using percentages and 
frequency counts, by cohort and time point. 
A statistical analysis plan (SAP) will be developed and finalized before first data cutoff/database 
lock and will further describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data as appropriate. This section is a 
high-level summary of the planned statistical analyses of the primary and secondary endpoints. 
9.4.1. 
Efficacy Analyses 
No efficacy analyses will be performed for this study. 
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9.4.2. 
Safety Analyses 
The primary objective of the study is to assess the safety and tolerability of ALXN1850. The 
endpoints to support the primary objective include incidence of TEAEs and treatment-emergent 
serious adverse events (TESAEs). The incidence of TEAEs and TESAEs will be summarized by 
System Organ Class (SOC) and Preferred Term by administration and cohort overall, by 
severity, and by relationship to study intervention. Adverse events will be categorized by the 
type of administration being received at the date of onset (ie, IV or SC). Treatment-emergent 
AEs and TESAEs resulting in withdrawal from the study will be listed. Participants having 
multiple AEs within a category (eg, overall, SOC, Preferred Term) will be counted once in that 
category. For severity tables, a participant’s most severe event within a category will be counted. 
Adverse events of special interest will be analyzed similarly. 
Changes from baseline in vital signs and laboratory assessments (as displayed in Table 7) will be 
summarized by visit for each cohort. Laboratory parameter values will be graded based on the 
National Cancer Institute CTCAE grading for severity (v5.0, published 27 Nov 2017). Shift 
tables by treatment group will be produced for these laboratory parameters. These tables will 
summarize the number of participants with each baseline grade relative to the normal ranges and 
changes to the worst highest grade assessed postdose during the study. 
Electrocardiogram parameters will be measured at the specified time points, including heart rate, 
PR, RR, QRS, QT, and QTcF intervals. The average of the triplicate ECG readings at the time 
points collected will be calculated, and changes from pretreatment baseline values will be 
assessed. 
An outlier analysis will be performed that will summarize the frequency and percentage of 
participants who meet any of the following outlier criteria at each visit. 
x QT, QTcF interval > 450 msec 
x QT, QTcF interval > 480 msec 
x QT, QTcF interval > 500 msec 
x QT, QTcF interval increases from baseline > 30 msec 
x QT, QTcF interval increases from baseline > 60 msec 
Physical examination results will be classified as Normal, Abnormal Not Clinically Significant 
(NCS), Abnormal Clinically Significant (CS), and Not Examined. The results will be 
summarized by visit for each administration. 
All concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary, and the frequency and percentage of concomitant medications will be summarized. 
While safety analyses will be performed on the Safety Set (defined in Section 9.3), all safety data 
collected will be listed by participant. 
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9.4.3. 
Other Analyses 
9.4.3.1. 
Pharmacokinetic Analyses 
All PK analyses will be performed on the PK Set and will be reported by each cohort. The 
individual plasma concentration data from participants who receive ALXN1850 with actual 
sampling dates and times will be used to derive the PK parameters by noncompartmental 
analyses methods using Phoenix WinNonlin 8 or higher. 
The following PK parameters will be derived: 
PK Parameters 
Definition 
Cmax 
Maximum observed plasma concentration 
tmax 
Time to maximum observed plasma concentration 
AUCt 
Area under the plasma concentration versus time curve from time 0 to the last 
quantifiable concentration 
AUCtau 
Area under the plasma concentration versus time curve during the dosing interval 
AUC∞ 
Area under the plasma concentration versus time curve from time 0 (dosing) to time 
infinity 
t½ 
Terminal elimination half-life 
λz 
Terminal-phase elimination rate constant 
CL or CL/F 
Total body clearance 
Vd or Vd/F 
Volume of distribution 
R 
Subcutaneous accumulation ratio (Dose 3/Dose 1) 
F 
Absolute bioavailability after subcutaneous administration 
9.4.3.2. 
Pharmacodynamic Analyses 
All PD analyses will be performed on the PD Set and will be reported by each cohort. 
Absolute, change, and percent change from the baseline in plasma PLP, PLP/PL ratio, and PPi 
concentration versus time data will be presented graphically by treatment over time. 
Biomarker assays may be conducted as exploratory analyses on collected samples. 
9.4.3.3. 
Immunogenicity Analysis  
Immunogenicity, as measured by ADAs and NAbs to ALXN1850 and asfotase alfa (at 
Screening, only for participants who have previously received asfotase alfa), will be 
summarized. 
Participants who are positive for ADAs at the last assessment of the study will be given options 
to enable further monitoring of their ADA values after the end of the study; these options may 
include enrollment in the Global HPP Registry. 
9.4.3.4. 
Exploratory Analysis 
Change in ionized calcium, phosphorus, magnesium, PTH, PA, sCTX, P1NP, and osteocalcin 
versus time will be presented graphically by treatment over time. 
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9.5. 
Interim Analyses  
Interim analyses may be performed as needed. In particular, an interim analysis may be 
conducted for each cohort at the end of the Day 29 after all participants in the corresponding 
cohort have completed or withdrawn. This analysis will allow for further evaluation of the doses 
and for subsequent ALXN1850 Phase 2/3 studies planning purpose. 
The SAP will describe the planned interim analyses in greater detail. 
9.6. 
Safety Review Committee (SRC) 
An SRC consisting of, but not limited to, the Investigator, Safety Monitor, Medical Monitor, 
Study Statistician, and Clinical Pharmacologist, will evaluate the study data at prespecified time 
points for participant safety and make recommendations on dose escalation, dose modification, 
or termination of the study. The SRC charter will include a description of membership, schedule 
of meetings, data required for each safety review, and requirements for documenting meeting 
discussions and outcome. For more details refer to Section 6.6. 
In addition to planned meetings, ad hoc SRC meetings may be held to discuss urgent issues 
should the need arise. The ad hoc SRC must convene within 48 hours in the case of a 
treatment-emergent SAE or the withdrawal of any participant due to an adverse reaction. 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
x This study will be conducted in accordance with the protocol and the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
 Applicable International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
Guidelines 
 Applicable laws and regulations 
x The protocol, substantial 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. 
x Any substantial amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
x 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, Directive 2001/20/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 
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10.1.3. 
Informed Consent Process 
x It is the responsibility of the Investigator or designee to obtain signed (written or 
electronic signature) informed consent from all study participants prior to performing 
any study-related procedures including screening assessments. 
x The Investigator or designee 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. 
x 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 
GCP guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
x The participant’s medical record must include a statement that signed (written or 
electronic) informed consent was obtained before any screening procedures were 
performed with a participant, and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF(s). 
x Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study, as applicable. 
x 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. Original signed (written or electronic) consent forms must remain in each 
participant’s study file and must be available for verification at any time. 
Participants who are rescreened outside of the screening window are required to sign a new ICF 
(see Section 5.4). 
10.1.4. 
Data Protection 
x 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, initials, or any information which would make the participant identifiable will 
not be transferred. 
x Participants must be informed that their personal study-related data will be used in 
accordance with applicable data protection law, and participants must also be 
informed of any individuals rights they may have with regard to their personal data. 
Participants will be informed about how their personal study-related data will be 
disclosed, and will be required to agree to the information contained in the informed 
consent and provide consent to the processing of their personal data, if required by 
applicable data protection law. 
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x Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Alexion, 
appropriate IRB/IEC members, and inspectors from regulatory authorities. 
x Alexion as a data controller has implemented privacy and security controls designed 
to help protect participant personal data, including information security controls, 
firewalls, incident detection, and secure transfer measures. 
x In the event of any accidental or unlawful destruction, loss, alteration, unauthorized 
disclosure of, or access to, personal data (“breach”), the controller has implemented 
procedures and measures to promptly address and mitigate any risk to the data 
participant. In the event of a breach, the controller will notify the appropriate 
regulatory authorities and/or the data participant in accordance with applicable data 
protection law. 
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 
10.1.6. 
Data Quality Assurance 
x All participant data relating to the study will be recorded on printed CRF or eCRF 
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. 
x The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
x The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
x Alexion or designee is responsible for the data management of this study including 
quality checking of the data. 
x Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF 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. 
 Remote source data verification may be employed where permitted by local 
regulations. 
 The scope of the source data verification will be described in detail in the Clinical 
Monitoring Plan. 
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x Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator after study completion per local regulations 
or institutional policies. No records may be destroyed 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 eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. Electronic case report forms must 
be completed by the Investigator or designee as indicated in the site delegation log. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available to Alexion, Alexion delegates, and health 
authorities, as requested. Source documents are filed at the investigational site. 
Per ICH E6 (R2) guidelines and good documentation practice requirements, source documents 
and study records in all media (eg, paper, electronic) must be Attributable, Legible, 
Contemporaneous, Original, Accurate, and Complete. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is consented. 
Alexion reserves the right to close the study site or terminate the study at any time for any reason 
at its sole discretion. 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 the electronic data capture system, all required documents and study supplies have 
been collected and reconciled, 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: 
x Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Alexion’s procedures, or ICH GCP guidelines 
x Inadequate recruitment of participants by the Investigator 
x Decision on the part of Alexion to suspend or discontinue testing, evaluation, or 
development of the study drug 
x Discovery of an unexpected, serious, or unacceptable risk to participants enrolled in 
the study 
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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 
x 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. 
x 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. 
x 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 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. 
x 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. 
 Encore congress publications may be appropriate to allow communication of 
research findings to relevant audience and geographical regions. 
x Alexion will comply with the requirements for publication of study results as defined 
by the Pharmaceutical Research and Manufacturers of America and the International 
Committee of Medical Journal Editors and per the Alexion Publication Policy. 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. 
x 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. 
x Alexion will Publish Patient Lay Summaries and include participants and/or 
caregivers as reviewers for readability and understanding of lay person language. 
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10.1.10. 
Good Clinical Practice Compliance 
Alexion and any third party to whom aspects of the study management or monitoring have been 
delegated will undertake their assigned roles for this study in compliance with all applicable 
industry regulations, ICH GCP Guideline E6 R2, EU Directive 2001/20/EC, as well as all 
applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of Alexion and/or the company 
organizing/managing the research on behalf of Alexion to inspect study data, participants’ 
medical records, and eCRFs in accordance with current GCP and respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
Alexion ensures that local regulatory authority requirements are met before the start of the study. 
Alexion (or designee) is responsible for the preparation, submission, and confirmation of receipt 
of any regulatory authority approvals required prior to release of ALXN1850 for shipment to the 
site. 
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10.2. 
Clinical Laboratory Tests 
x The clinical safety tests detailed in Table 7 will be performed by a local laboratory or 
by Alexion, as indicated. 
x Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5. 
x Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
x The results of each test must be entered in the eCRF. 
x Pregnancy testing: Women of childbearing potential should only be enrolled after a 
negative serum pregnancy test result at Screening. Urine pregnancy testing will be 
performed for women of childbearing potential at all subsequent timepoints specified 
in the SoA (Section 1.3). Additional pregnancy tests may also be performed at any 
time at the Investigator’s discretion. 
Table 7: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Red blood cell count 
Hematocrit 
Red blood cell indices: 
Mean corpuscular volume  
Mean corpuscular hemoglobin  
%Reticulocytes 
Glycated hemoglobin (HbA1c)a 
White blood cell count 
with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils  
Platelet count  
Clinical chemistryb 
Blood urea nitrogen 
Potassium  
Creatinine 
Sodium 
Aspartate aminotransferase 
/serum glutamic-oxaloacetic 
transaminase 
Gamma glutamyltransferase  
Total and direct bilirubin 
Indirect bilirubin 
Total protein  
Albumin 
Chloride  
Glucose  
Total carbon dioxide 
Alanine aminotransferase /serum 
glutamic-pyruvic transaminase  
Alkaline phosphatase (ALP)a 
Calciumc 
Phosphate 
Magnesium 
Coagulation 
Prothrombin time 
Partial thromboplastin time 
International normalized 
ratio 
Other safety 
laboratory tests 
Parathyroid hormone, intact 
25-OH Vitamin D
Antidrug antibodies (Alexion)
Neutralizing antibodies (Alexion)
The following tests are to be conducted in 
case of an acute injection-associated 
reaction: 
Tryptase (Alexion) 
C5b-9 (Alexion) 
IgE (Alexion) 
Hematology, chemistry, and urinalysis 
panels 
Other urine tests 
Routine urinalysis: Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, erythrocytes, leukocyte esterase (by dipstick) 
Microscopic examination (if any leukocytes, trace protein, nitrites, and blood [if not 
menstruating] are abnormal)  
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Table 7: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Further urinalysis for calcium, phosphorus, creatinine and calcium/creatinine 
Urine pregnancy tests (after Screening, for women of childbearing potential)  
Other screening tests 
Alcohol test 
Urine drug screen (to include amphetamines; barbiturates; benzodiazepines; cocaine; 
opiates; phencyclidine; methamphetamine; 3,4 methylenedioxy-methamphetamine; and 
methadone) 
FSH test (confirmation of post-menopausal state) 
HIV-1 and HIV-2 antibodies, hepatitis B surface antigen (HbsAg), anti-HBC IgG + IgM 
(if IgG positive) and hepatitis C virus antibodies (anti-HCV) 
Serum human chorionic gonadotropin pregnancy test (for women of childbearing 
potential) 
a Only collected at Screening. 
b Clinical chemistry must be fasting only at Screening. 
c Includes ionized calcium. 
Abbreviations: 25-OH = 25-hydroxy; C5b-9 = terminal complement complex C5b-9; eCRF = electronic case report 
form; FSH = follicle-stimulating hormone; HBC = hepatitis B core antigen; HIV = human immunodeficiency virus 
IgG = immunoglobulin G; IgM = immunoglobulin M; PLP = pyridoxal 5ˈ-phosphate 
Investigators must document their review of each laboratory safety report. 
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10.3. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
x 
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered 
a pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment (ICH E2A). 
x 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease [new or exacerbated] temporally associated with the use of the study 
intervention, whether or not considered related to the study intervention. 
Events Meeting the AE Definition 
x 
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. 
x 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
x 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
x 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x 
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 
x 
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).  
x 
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.  
x 
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.  
x 
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.  
x 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than expected for 
the participant’s condition. 
x 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the participant’s condition. 
x 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
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10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1.
Results in death
2.
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it
was more severe.
3.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as
to whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not
considered an AE.
4.
Results in persistent disability/incapacity
x 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions.
x 
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:
x 
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. 
x 
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. 
Suspected Unexpected Serious Adverse Reactions Definition 
A suspected unexpected serious adverse reaction (SUSAR) is defined as: 
An event that is assessed as serious by the Investigator and/or Alexion that is not listed in the appropriate 
Reference Safety Information (IB) and has been assessed that there is at least a reasonable possibility that the 
event is related to the Investigational Medicinal Product by the Investigator and/or Alexion. 
Alexion has procedures that will be followed for the recording, medical assessment, and expedited reporting of 
SUSARs that are consistent with global regulations, legislation, and guidance documents. 
Suspected unexpected serious adverse reactions will undergo expedited reporting to the national regulatory 
authorities, IRBs/IECs, and Investigators following local regulatory reporting requirements where applicable. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE 
Recording of AE and/or SAE 
x 
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. 
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Recording of AE and/or SAE 
x 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
x 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to Alexion 
or designee in lieu of completion of the AE/SAE eCRF page. 
x 
There may be instances when copies of medical records for certain cases are requested by Alexion or 
designee. In this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission to Alexion or designee. 
x 
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 v5.0, published 27 Nov 2017:  
x 
Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
x 
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
x 
Grade 3: Severe (incapacitating, with inability to perform normal activities) 
x 
Grade 4: Life-threatening 
x 
Grade 5: Fatal 
Changes in the severity of an AE should be documented to allow an assessment of the AE duration at each level 
of intensity to be evaluated. Adverse events characterized as intermittent require documentation of onset and 
duration of each episode, if the severity of the intermittent event changes.  
An event is defined as “serious” when it meets at least 1 of the predefined criteria as described in the definition 
of SAE, NOT when it is rated as severe.  
Assessment of Causality 
x 
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 eCRF 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.
x 
The Investigator will use clinical judgment to determine the relationship. 
x 
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. 
x 
The Investigator will also consult the IB and/or Product Information, for marketed products, in his/her 
assessment. 
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Assessment of Causality 
x 
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. 
x 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to 
include in the initial report to Alexion or designee. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the SAE data to 
Alexion or designee. 
x 
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. 
x 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
Follow-up of AEs and SAEs 
x 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by Alexion or designee to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
x 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide Alexion or designee with a copy of any postmortem findings including 
histopathology. 
x 
New or updated information will be recorded in the originally completed eCRF. 
x 
The Investigator will submit any updated SAE data to Alexion or designee within 24 hours of receipt of the 
information. 
10.3.5. 
Reporting of SAEs 
SAE Reporting to Alexion via Paper Safety Reporting Form 
1.
All SAEs will be recorded and reported to Alexion immediately and within 24 hours of awareness.
2.
All SAEs will be reported using the Safety Reporting Form and submitted to Alexion Global Drug Safety
(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: clinicalsae@alexion.com or Fax: + 1.203.439.9347 
3.
Additional follow-up information, if required or available, should be entered into the eCRF 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.
4.
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 
5.
All paper forms and follow-up information submitted to Alexion GDS must be accompanied by a cover
page signed by the Investigator.
6.
Paper source documents and/or reports should be kept in the appropriate section of the study file.
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10.4. 
Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the Following Categories Are Not Considered WOCBP 
1. Premenarchal
2. Premenopausal female with one of the following:
x Documented hysterectomy 
x Documented bilateral tubal ligation or bilateral salpingectomy 
x Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female
x A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause prior to the Day 1 Visit. 
 A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
may be required. In the absence of 12 months of amenorrhea the reason for not 
obtaining FSH levels should be documented by the Investigator at the time of 
Screening. 
x Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
4. Permanent sterilization at least 6 weeks prior to the Day 1 Visit.
10.4.2. 
Contraception Guidance 
Contraceptive use by male or female participants should be consistent with local regulations 
regarding the methods of contraception utilized for those participating in clinical studies. If 
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teratogenic effects are suspected to be transferred to a fetus/embryo from a female spouse/partner 
of a male participant, pregnancy follow-up information will be obtained for the partner who 
becomes pregnant (refer to Section 10.4.3.1). In these cases, follow-up will be conducted on the 
pregnant partner in the same manner as a female participant who becomes pregnant during the 
study. 
10.4.2.1. Guidance for Female Participants 
Female participants of childbearing potential must have a negative pregnancy test (serum) at 
Screening. Additional requirements for pregnancy testing during and after dosing with 
ALXN1850 are indicated in the SoA (Section 1.3). 
The Investigator is responsible for the review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
The Investigator should evaluate the potential for contraceptive method in relationship to the first 
dose of ALXN1850. 
Female participants of childbearing potential must use a highly effective method of 
contraception, including at least 1 of the following until at least 3 months after the final dose of 
ALXN1850. 
1. Intrauterine device in place for at least 6 weeks prior to first dose of ALXN1850.
2. Progestogen-only hormonal contraception associated with inhibition of ovulation (either
oral, injectable, or implantable) for at least 6 weeks prior to first dose of ALXN1850.
3. Intrauterine progestogen releasing system for at least 6 weeks prior to first dose of
ALXN1850.
4. Bilateral tubal occlusion for at least 6 weeks prior to first dose of ALXN1850.
5. Combined (estrogen- and progestogen-containing) hormonal contraception (either oral,
intravaginal, or transdermal) for at least 6 weeks prior to first dose of ALXN1850.
6. Surgical sterilization of the male partner (medical assessment of azoospermia is required
if vasectomy was performed within 6 months prior to first dose of ALXN1850). Male
partner is still required to use condom during sexual intercourse.
7. Sexual abstinence for female participants:
a.
Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse. In this study, abstinence is only acceptable
if consistent with the participant’s preferred and usual lifestyle. Abstinent female
participants must refrain from heterosexual intercourse for at least 3 months after the
final dose of ALXN1850.
The following methods of contraception are considered unacceptable in this study: 
 Periodic abstinence (calendar, symptothermal or post ovulation methods 
 Withdrawal (coitus interruptus) 
 Spermicides only 
 Lactational amenorrhea method 
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 Female condom and male condom should not be used together 
10.4.2.2. Guidance for Male Participants 
Contraception is the responsibility of the heterosexually active male participants in the study, 
regardless of his female partner’s method of contraception. 
Male participants who have had a vasectomy > 6 months prior to the first dose of ALXN1850 
must use a condom during heterosexual intercourse. Male participants who have had a 
vasectomy < 6 months prior to the first dose of ALXN1850 and those who have not had a 
vasectomy must use a condom with spermicide during heterosexual intercourse for at least 
3 months after their final dose of ALXN1850. 
10.4.2.2.1. Sexual Abstinence for Male Participants 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse. In this study, abstinence is only acceptable if consistent with the 
participant’s preferred and usual lifestyle. Abstinent male participants who become 
heterosexually active must use a condom with spermicide during intercourse. 
Periodic abstinence (eg, calendar, symptothermal, or post ovulation methods for a female 
partner) is not considered a highly effective method of contraception for male participants. 
Male participants must not donate sperm from the Day 1 Visit until at least 3 months after their 
final dose of ALXN1850. 
10.4.3. 
Collection of Pregnancy Information 
Pregnancy data will be collected during this study for all female participants and female 
spouses/partners of male participants from the first dose of ALXN1850 until 3 months after the 
final dose of ALXN1850 is administered. Any female participant who becomes pregnant during 
the study should be considered for discontinuation from the study intervention. Exposure during 
pregnancy (also referred to as exposure in utero) can be the result of either maternal exposure or 
transmission of study intervention via semen following paternal exposure. If a female 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 GDS via facsimile or email. When the outcome of the pregnancy becomes known, the 
form should be updated and submitted to Alexion GDS. If additional follow-up is required, the 
Investigator will be requested to provide the information. 
Exposure of an infant to study intervention during breastfeeding must also be reported (via the 
“Pregnancy/Breastfeeding Reporting and Outcome Form”) and any AEs experienced by the 
infant must be reported to Alexion GDS via email or facsimile. 
Pregnancy is not regarded as an AE unless there is a suspicion that the study intervention may 
have interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet the criteria for an SAE 
(eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly). Elective abortions without complications should not be reported as AEs. 
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10.4.3.1. Male Participants with Partners Who Become Pregnant 
x The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive ALXN1850. 
x After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
“Pregnancy/Breastfeeding Reporting and Outcome Form” and submit it to Alexion 
within 24 hours of learning of the partner’s pregnancy. The female partner will also 
be followed to determine the outcome of the pregnancy. Information on the status of 
the mother and child will be forwarded to Alexion. Generally, the follow-up will be 
no longer than 3 months following the delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
10.4.3.2. Female Participants Who Become Pregnant 
x The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial Information will be 
recorded on the appropriate form and submitted to Alexion within 24 hours of 
learning of a participant’s pregnancy. 
x 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 Investigator will collect follow-up information on 
the participant and the neonate and the information will be forwarded to Alexion. 
Generally, follow-up will not be required for longer than 3 months beyond the 
estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
x Pregnancy is not considered as an AE unless there is a suspicion that the study 
intervention may have interfered with the effectiveness of a contraceptive medication. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. A spontaneous abortion (occurring at < 22 weeks 
gestational age) or still birth (occurring at > 22 weeks gestational age) is always 
considered to be an SAE and will be reported as such. Any poststudy pregnancy 
related SAE considered reasonably related to the study intervention by the 
Investigator will be reported to Alexion. While the Investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of an 
SAE through spontaneous reporting. 
x Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention but will not be withdrawn from the study. 
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10.5. 
Biomarkers 
x Blood samples will be collected for biomarker analyses and the data will be used for 
research (eg, exploratory) related to ALXN1850 or HPP and related diseases. The 
samples may also be used to develop tests/assays including diagnostic tests related to 
ALXN1850 and/or other TNSALP ERT interventions and HPP. 
x The samples may be analyzed as part of a multistudy assessment of biomarkers in 
response to ALXN1850 or TNSALP ERT interventions to understand study disease 
or related conditions. 
x The results of biomarker analyses may be reported in the clinical study report (CSR) 
or in a separate study summary. 
x Alexion or designee will store the samples obtained for biomarker analyses in a 
secure storage space with adequate measures to protect confidentiality. 
x The samples will be retained while research on ALXN1850, TNSALP ERT 
interventions, or HPP continues but no longer than 5 years or other period as per local 
requirements. 
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10.6. 
Acute Infusion Reaction Algorithm 
Abbreviations: NCI CTC = National Cancer Institute Common Terminology Criteria; i.v. = intravenous. 
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10.7. 
COVID-19 Risk/Benefit Assessment  
Hypophosphatasia can cause irreversible morbidity and even mortality, if untreated. As such, and 
due to the limited number of available treatment options, the benefit a participant may receive 
from joining a clinical study with a new investigational treatment, which may improve current 
treatment options available for adults with HPP, is potentially significant. In this case, the fact 
that the study is open-label and every participant is treated with the study interventional drug 
also contributes to the potential benefit a participant may derive from partaking in the study. The 
site Investigator will balance the risk/benefit considerations in the study participant taking these 
factors into account. 
The potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Table 8. 
Table 8: 
Potential Risks and Mitigation Measures Due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Potentially higher risk 
population for 
SARS-CoV-2 
infection 
Based on Alexion’s understanding 
of the mechanism of action for 
asfotase alfa and the currently 
collected safety data, it does not 
appear that participants treated with 
ALXN1850 have a higher risk of 
developing a viral infection. 
During the time that the COVID-19 pandemic is 
active, Alexion will recommend that sites in a 
position to start the study and enroll participants 
follow the national and institutional guidances 
regarding prevention of SARS-CoV-2 infection. 
Additionally, during that time period, it is 
expected that Investigators and their staff will 
take all possible precautions in order to 
minimize a participant’s potential exposure to 
SARS-CoV-2 infection. Depending on the site, 
this will consist of measures such as social 
distancing, temperature screening, enhanced 
cleaning, and use of personal protective 
equipment for participants, staff, and caregivers 
as necessary. 
Healthcare institution 
availability for 
non-COVID-
19-related activities
COVID-19 pandemic may impact 
the workload of healthcare 
institutions globally and may reduce 
staff availability to perform 
non-urgent activities and non-
COVID-19-related activities. 
During the time that the COVID-19 pandemic is 
active, Alexion will not open study sites or 
enroll new participants at sites unless the sites 
have the resourcing and capabilities to 
implement the study per protocol. 
Data quality and 
integrity 
Lack of availability of site 
personnel to perform study 
assessments and capture 
study-specific data in a timely 
manner and to maintain adequate 
quality standards. 
Lack of availability of site 
personnel to ensure adequate and 
During the time that the COVID-19 pandemic is 
active, Alexion will only open study sites that 
report enough personnel capacity to sufficiently 
conduct clinical study-related activities.  
During this timeframe, participants eligibility as 
well as site capacity will be reviewed by the site 
Investigator and the study Medical Monitor prior 
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Table 8: 
Potential Risks and Mitigation Measures Due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
continuous chain of custody, storage 
conditions, and monitoring for 
investigational product and 
biological samples. 
Inability of study monitors and 
quality personnel to conduct in-
person visits to exercise adequate 
oversight of study execution at 
investigational sites. 
Missing data (COVID-19 pandemic 
may impact study visit schedules, 
and increase missed visits and/or 
participant study discontinuations 
inadvertently resulting in missing 
data [eg, for protocol-specified 
procedures]). 
to Screening. Each site is also evaluated for the 
capacity to perform remote safety monitoring. 
During the time that the COVID-19 pandemic is 
active, it will be important to capture specific 
information in the eCRF that explains the reason 
for missing data (eg, missed study visits or 
participant study discontinuations due to 
COVID-19). 
Abbreviation: COVID-19 = coronavirus disease 2019; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2. 
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10.8. 
Abbreviations 
Table 9: 
Abbreviations and Specialist Terms 
Abbreviation or Term 
Explanation 
%CV 
arithmetic coefficient of variation 
ADA 
antidrug antibodies 
AE 
adverse event 
AUC0-72h 
area under the concentration-time curve from time zero to 72 hours 
AUC0-168h 
area under the concentration-time curve from time zero to 168 hours 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum observed serum concentration 
COVID 
 coronavirus disease 2019 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED85 
85% of the treated population 
ERT 
enzyme replacement therapy 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GDS 
Global Drug Safety 
GLP 
Good Laboratory Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HPP 
hypophosphatasia 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IgG 
immunoglobulin G 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
NAb 
neutralizing antibodies 
NOAEL 
no observed adverse effect level 
P1NP 
N-terminal propeptide of type I procollagen
PA 
pyridoxic acid 
PCP 
phencylidine 
PD 
pharmacodynamic(s) 
PEA 
phosphoethanolamine 
PK 
pharmacokinetic(s) 
PLP 
pyridoxal 5ˈ-phosphate 
Pop-PK 
population pharmacokinetic(s) 
PPi 
inorganic pyrophosphate 
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Table 9: 
Abbreviations and Specialist Terms 
Abbreviation or Term 
Explanation 
PTH 
parathyroid hormone 
q3d 
every 3 days 
QTcF 
QT interval corrected using Fridericia’s formula 
qw 
every week/weekly 
TNSALP 
tissue non-specific isoenzyme of alkaline phosphatase 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SoA 
schedule of activities 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse events 
TESAE 
treatment-emergent serious adverse event 
TNSALP 
tissue nonspecific alkaline phosphatase 
ULN 
upper limit of normal 
WHO 
World Health Organization 
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10.9. 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
DOCUMENT HISTORY 
Protocol/Amendment Updates 
Release Date 
Amendment 4 
27 Oct 2021 
Amendment 3 
14 May 2021 
Amendment 2 
31 Mar 2021 
Amendment 1 
02 Feb 2021 
Original protocol 
12 Nov 2020 
Amendment 1 (02 Feb 2021) 
Overall Rationale for the Amendment 
The protocol was amended to address comments by the US FDA regarding monitoring of ectopic 
calcification, anaphylaxis, and ADAs. In addition, minor changes for clarification, consistency, 
and accuracy were made. 
Changes to the protocol in Amendment 1 are detailed below. 
Section 
Description of Change 
Brief Rationale and/or Clarification 
1.1 Synopsis, Overall 
Design 
8.9 Immunogenicity 
Assessments 
9.4.3.3 
Immunogenicity 
Analysis 
Addition of text stating that participants 
who are positive for ADAs at the last 
assessment of the study will be given 
options to enable further monitoring of 
their ADA values after the end of the 
study; these options may include 
enrollment in the Global HPP Registry. 
In response to a suggestion by the US FDA 
to continue monitoring participants who 
develop ADAs until the ADAs return to 
baseline values. 
1.2 Schedule of 
Activities, Table 1 
and Table 2 
10.2 Clinical 
Laboratory Tests, 
Table 6 
Removal of alcohol test from visits, 
except for at Screening. 
“Breath” removed from “alcohol breath 
test” so that the type of test is not 
specified. 
An alcohol test is required as part of the 
assessment of exclusion criterion 35 (ie, 
whether participants have a history of 
alcohol abuse) but is not required after 
Screening during the study. 
The type of test is not specified as site may 
not have access to an alcohol breath test. 
1.2 Schedule of 
Activities, Table 1 
Addition of text stating that the 
ophthalmological examination occurs 
during Screening and must be completed 
by Day -1. 
To clarify when the ophthalmological 
examination must take place. 
1.2 Schedule of 
Activities, Table 2 
Text added noting that PTH is only 
measured at Screening and the Day 36 
visit. 
To clarify the time points at which PTH will 
be measured. 
Addition of calcium to the urine test. 
In response to a suggestion by the US FDA 
to monitor ectopic calcification. 
Addition of PEA to the urine test. 
In response to a request by the planned 
Principal Investigator as PEA has been 
shown to have potential as a marker of 
treatment efficacy. 
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Section 
Description of Change 
Brief Rationale and/or Clarification 
1.2 Schedule of 
Activities, Table 2 
8.2.2 Vital Signs 
Addition of text stating that vital signs 
measurements will be performed every 
15 minutes for the first hour after dose 
administration. 
In response to a suggestion by the US FDA 
to monitor participants closely for 
anaphylaxis following dose administration. 
2.1 Study Rationale 
2.3.3 Overall Benefit 
Risk Conclusion 
4.2.2 Scientific 
Rationale for Study 
Design 
5 Study Population 
Addition of rationale for the population 
that will be enrolled in the study.  
In response to a suggestion by the US FDA, 
the rationale has been included. Because of 
the potential for immunogenicity, this study 
will enroll participants with HPP who are 
not anticipated to require further treatment 
with ERT, based on their signs and 
symptoms, and the Investigator’s clinical 
assessment of their current condition. 
5.2 Exclusion 
Criteria 
Exclusion criterion 21 amended so that 
the glomerular filtration rate in exclusion 
criterion changed from < 30 to 
< 60 mL/min/1.73m2. 
A cutoff of < 30 mL/min/1.73m2 was 
considered to be too low as 
60 – 90  mL/min/1.73m2 is considered to be 
mildly decreased function. 
9.6 Safety Review 
Committee (SRC) 
Addition of provision for ad hoc SRC 
meetings. 
To allow for ad hoc meetings if safety 
issues arise during the study. 
All 
Minor edits to text. 
For consistency and accuracy. 
Abbreviations: ADA = antidrug antibodies; ERT = enzyme replacement therapy; FDA = Food and Drug 
Administration; HPP = hypophosphatasia; PEA = phosphoethanolamine; PTH = parathyroid hormone; 
SRC = Safety Review Committee 
Amendment 2 (31 Mar 2021) 
This amendment is considered to be substantial according to 21 CFR part 312.30(b) and any 
applicable local regulations. 
Overall Rationale for the Amendment 
This protocol has been amended to address a request by the US Food and Drug Administration 
(FDA) to update the protocol inclusion criteria to clarify that participants are not anticipated to 
require further treatment with enzyme replacement therapy (ERT). In addition, the assessments 
at the 60-hour time point were removed. 
Changes to the protocol in Amendment 2 are detailed below. 
Section 
Description of Change 
Brief Rationale and/or Clarification 
5.1 Inclusion Criteria 
Addition of the following to the 
inclusion criteria:  
x Not anticipated to require further 
treatment with ERT to treat their 
HPP after study completion. 
To address a request by the US FDA to 
clarify the participant population. 
1.2 Schema, Figure 1 
Study schema updated to account for 
removal of time point at 60 hours. 
Per Principal Investigator 
recommendation, the time point at 
60 hours has been removed because 
participants will be monitored for 48 hours 
post-first administration of study 
intervention, which is considered sufficient 
for monitoring for safety purposes. 
Removal of this time point will also reduce 
participant burden. 
Visit window of +/- 1 day added for 
Outpatient Visits. 
To address a request by the site to enable 
flexibility around holidays and weekends. 
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Section 
Description of Change 
Brief Rationale and/or Clarification 
Inclusion of footnote noting that some 
visits may be conducted by a home 
healthcare professional at the 
participant’s home 
To limit participant travel, some visits may 
be conducted at the participant’s home. 
Lines denoting SRC meetings removed. 
Terminology aligned with the SRC 
charter added, and reference to the SRC 
charter and Table 1 included in the 
Figure 1 footnote. 
For alignment with the SRC charter and to 
improve the readability of Figure 1. 
1.3 Schedule of 
Activities (SoA), Table 2 
Moved the physical examination 
assessment at 60 hours to 48 hours. 
Rationale as provided above for the 
removal of the time point at 60 hours. 
1.3 Schedule of 
Activities (SoA), Table 1 
and Table 2 
8.9 Immunogenicity 
Assessments 
9.4.3.3 Immunogenicity 
Analysis 
Addition of testing for antibodies to 
asfotase alfa in participants who have 
previously received asfotase alfa 
(STRENSIQ®). 
To assess immunogenicity relating to 
asfotase alfa in participants who have 
previously received asfotase alfa. 
5.3.1 Meals and Dietary 
Restrictions 
Removal of the restriction on outside 
food or drink at the inpatient facility. 
To enable participants to order food from 
onsite restaurants at the facility, if they 
choose, rather than being restricted to food 
provided by the facility. 
5.3.2 Caffeine, Alcohol, 
and Tobacco 
Removal of the restriction on ingesting 
caffeine- or xanthine-containing 
products. 
A restriction on caffeine- and xanthine-
containing products is not required in this 
study. 
Abbreviations: ERT = enzyme replacement therapy; FDA = Food and Drug Administration; 
HPP = hypophosphatasia; SRC = Safety Review Committee 
Amendment 3 (14 May 2021) 
This amendment was considered to be substantial according to 21 CFR part 312.30(b) and any 
applicable local regulations. 
Overall Rationale for the Amendment 
This protocol was amended to clarify assessment time points and samples that are required 
during the study, following discussion with the study site.  
In addition, minor changes for clarification, consistency, and accuracy were made. 
Changes to the protocol in Amendment 3 are detailed below. 
Section 
Description of Change 
Brief Rationale and/or 
Clarification 
Section 1.2 Schedule of 
Activities, Figure 1 
Footnote on home healthcare visits revised 
to include remote locations and to state that 
telemedicine visits will be performed by 
study site staff. 
To provide options for remote visits 
and to clarify that study site staff will 
perform telemedicine visits. 
Sampling days revised to reflect that Day 3 
time point has been added back (which was 
removed in protocol amendment 2). 
Subsequent days corrected for first 
participant from 18, 25, and 42 to 17, 24, 
and 31 and for subsequent participants from 
It was realized that removing Day 3 
impacted on the 48-hour time point, 
which will need to take place on 
Day 3. 
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Section 
Description of Change 
Brief Rationale and/or 
Clarification 
11, 18, and 25 to 10, 17, and 24 (as per 
protocol amendment 1). 
Section 1.3 Schedule of 
Activities, Table 1 & 
Table 2 
Section 8.2.1 Physical 
Examinations 
Section 8.2.3 
Electrocardiograms 
Section 8.5 
Pharmacokinetics 
Removed references to a Study Operations 
Manual throughout the protocol. 
A Study Operations Manual will not 
be created for this study. 
Section 1.3 Schedule of 
Activities, Table 1 
Note revised to state that ophthalmological 
assessments are only needed at Screening 
(to be completed before predose Day 1) and 
ED/EoS 
To clarify when ophthalmological 
assessments are required. 
Note on renal ultrasound revised to state 
that it is only assessed at Screening (must 
be completed on or before predose Day 1) 
and at the ED/EoS visit for all participants 
during the study. 
To clarify when renal ultrasound is 
required 
Addition of note clarifying that chemistry 
laboratory tests at screening must include 
alkaline phosphatase and PLP 
To clarify that alkaline phosphatase 
and PLP must be assessed at 
screening. 
Removal of PK sample at screening 
PK sample is not required at screening 
Removal of immunogenicity testing for 
ALXN1850 ADA and NAb at Screening. 
Immunogenicity testing for 
ALXN1850 ADA and NAb will be 
performed at predose. 
Revised the note to state that a CRIM for 
assay only needs to be collected on Day 1. 
To avoid misreading the assessments 
as also being needed at unnecessary 
time points. 
Footnote added describing permitting 
windows for assessments, and that ECG and 
vital signs must be done in conjunction with 
each other, within 30 minutes, and before 
PK/PD sample collection. 
To clarify the permitted assessment 
window and order of assessments, in 
conjunction with the removal of 
references to a Study Operations 
Manual throughout the protocol. 
Section 1.3 Schedule of 
Activities, Table 2 
Day 3 time point (which was removed in 
protocol amendment 2) added back. 
Subsequent days corrected for first 
participant from 18, 25, and 42 to 17, 24, 
and 31 and for subsequent participants from 
11, 18, and 25 to 10, 17, and 24 (as per 
protocol amendment 1). 
It was realized that removing Day 3 
impacted on the 48-hour time point, 
which will need to take place on 
Day 3. 
Deleted the 36-hour timepoint column. 
There are no assessments at the 
36-hour timepoint, so this column is
unnecessary.
Note revised to state that ophthalmological 
assessments can occur at screening or Day -
1 but must be completed by predose on Day 
1.  
To clarify when ophthalmological 
assessments are required. 
Note on renal ultrasound revised to state 
that it is only assessed at screening (must be 
To clarify when renal ultrasound is 
required. 
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Section 
Description of Change 
Brief Rationale and/or 
Clarification 
completed on or before predose Day 1) and 
at the ED/EoS visit for all participants 
during the study. 
Note added that PTH, ionized calcium 
magnesium, and phosphorus are also 
required at Day 29 for subsequent 
participants.  
Blood for PTH, ionized calcium, 
magnesium, and phosphorus on dosing days 
(Days 1, 8/15, 15/22, 22/29), and on the 
days after dosing (Days 2, 9/16, 16/23, 
23/30) removed. 
To clarify when these assessments are 
required and to remove time points at 
which these assessments are not 
required. 
Section 5.1 Inclusion 
Criteria 
Removed the word “central” before 
“laboratory” in inclusion criterion 2a. 
This study will not use a central 
laboratory for genetic testing. 
Section 8.5 
Pharmacokinetics 
Section 8.6 
Pharmacodynamics 
Note added that PK and PD samples 
collected +/-30 minutes of the scheduled 
time, whichever is less, will not be 
considered a protocol deviation. 
To clarify the permitted assessment 
window and order of assessments. 
Section 9.5 Interim 
Analyses 
Text has been added noting that interim 
analyses may be needed. 
To make provision for interim 
analyses, if needed. 
All 
Minor edits to text. 
For consistency and accuracy. 
Abbreviations: CRIM = cross-reactive immunological material; ERT = enzyme replacement therapy; FDA = Food 
and Drug Administration; HPP = hypophosphatasia; SRC = Safety Review Committee 
Amendment 4 (27 Oct 2021) 
This amendment was considered substantial according to 21 CFR part 312.30(b) and any 
applicable local regulations. 
Overall Rationale for the Amendment 
The protocol was amended to address the recommendation from the FDA to add a PK sample 
collection timepoint at the end of infusion for IV doses. Additional changes to assist 
recruitment/reduce participant burden were made, and the SoA tables were revised to ease 
readability. The clarifications in the IRB-approved Administrative Change Letters were 
incorporated. Additional minor changes were made in the amendment for clarification, 
consistency, and accuracy. 
Changes to the protocol in Amendment 4 are detailed below. 
Section 
Description of Change 
Brief Rationale and/or 
Clarification 
Section 1.1 Synopsis 
Section 1.2 Study Schema 
Section 1.3 Schedule of 
Activities  
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Section 9.2 Sample Size 
Determination 
Designated Day 65 (1st participant)/ 
Day 57 (subsequent participants) as 
the End-of-Treatment Visit, which will 
now be considered the end of the 
Treatment Period (added to all except 
Sections 7.2 and 9.2) 
Added to all except Section 1.2 that 
participants who withdraw/are 
withdrawn from the study following 
completion of end-of-treatment 
Alexion decided the End-of-Treatment 
Visit should be the last critical PK/PD 
timepoint (5.5 half-lives for study drug) 
that is also sufficient for safety follow-
up 
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10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or 
Clarification 
procedures will be considered 
“completed” if they completed all 
prior PK/PD sampling within window 
and received all doses per the SoA. 
“Completed” participants do not need 
to be replaced. 
Section 1.1 Synopsis 
Section 1.3 Schedule of 
Activities  
Permitted visit windows for the last 3 
study visits were expanded from ± 1 
day to ± 3 days (Day 51 [1st 
participant]/Day 43 [subsequent 
participants]), -3/+ 7 (EoT), -7/+14 
days (EoS) 
Recalculated the planned study 
duration, including the period lengths 
comprising duration, due to these 
window changes  
Expanding these windows is not 
expected to impact PK, PD, or safety 
assessments, and should reduce 
participant burden and drop-out 
tendency towards the end of this study 
Section 1.1 Synopsis 
Changed “Four participants will be 
assigned to each of the 3 cohorts 
(Cohorts 1, 2, and 3)” to “Five 
participants will be assigned to 
each of the 3 cohorts (Cohorts 1, 2, 
and 3)”  
Four participants per cohort does not 
accommodate for potential dropouts. 
Total numbers have not changed 
(15 participants must be enrolled to 
complete at least 9) 
Section 1.1 Synopsis and 
Section 4.1 Overall 
Design Section 6.6 Dose 
Modification  
Changed “remaining 3 participants 
in each cohort” to “remaining 4 
participants…” 
Section 1.1 Synopsis 
Section 3 Objectives and 
Endpoints 
Moved the exploratory objective 
“Explore the immunogenicity potential 
of ALXN1850” to a secondary 
objective and changed “Explore” to 
“Assess” 
Per the advice of Alexion’s 
Immunologist, in alignment with 
ALXN1850 current anticipated Risk 
Profile (detailed in Section 2.3.1 Risk 
Assessment) 
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10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or 
Clarification 
Section 1.1 Synopsis and 
Section 6.6.1 Dose 
Escalation 
Changed “all participants” to “at 
least 3 participants” in Cohort 1  
Changed “subsequent” to “2nd and 
3rd” in bullets 3 and 5 (Section 
6.6.1only) 
To describe more accurately the 
SRC review and dose escalation 
process 
Section 1.1 Synopsis and 
Section 6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Changed “at least 12” to “at least 9 
participants (3 per cohort)”  
9 “completed” participants (3 per 
cohort) were determined sufficient 
for PK, PD, and safety analyses  
Section 1.2 Study 
Schema 
Removed mention of home 
healthcare visits from the Notes 
Revised the Schema and its 
remaining Notes to align with the 
other changes described in this 
summary of changes  
Home healthcare visits will not be 
conducted in this study 
For clarity/consistency 
Section 1.3 Schedule of 
Activities  
Section 1.3 Schedule of 
Activities (cont.) 
The 2 SoAs with assessment notes in 
the last column were reformatted into 
3 SoAs with footnotes at the bottom of 
each table.  
To ease readability and add clarity 
Notes specifying days were deleted as 
unnecessary 
All Inpatient and Outpatient Visit days 
are now shown separately instead of 
grouped together 
Permit some Inpatient Visits to be 
changed to Outpatient Visits at the 
Investigator’s discretion 
To ease participant burden and take 
holidays into account. This permission, 
at the Investigator's discretion, will not 
present any change in the safety 
assessments or pose any additional risk 
for the participants 
Permitted windows for applicable 
visits are now shown in a header row 
as some changed while others should 
not (in PA3, all Outpatient Visits were 
permitted a ± 1 day window)  
For clarity because Inpatient Visits 
changed to Outpatient should not have 
the ± 1 day window of an Outpatient 
Visit. Also, the windows for last 3 study 
visits were increased to reduce potential 
participant dropout towards the end of 
this long study. It was determined these 
window changes will not significantly 
impact PK/PD and safety follow-up  
For all participants, removed 3 
scheduled visits: 48 and 96 hrs after 
the 3rd dose, and at 96 hrs after the 4th 
dose 
Alexion PK/PD and Medical/Safety 
determined that these time points are not 
necessary to assess the study endpoints, 
which will reduce participant burden 
The following assessments previously 
scheduled at the last study visit (End-
of-Study) are now performed at the 
End-of-Treatment Visit: ECG, 
ophthalmological examination, renal 
ultrasound, hematology/chemistry/ 
coagulation labs, and urinalysis 
Completion of the end-of-treatment 
assessments is now when a participant 
will be considered “completed”, so 
having all key assessments at this 
timepoint is more critical than 
performing them at EoS. Participants 
discontinued prior to the end-of-
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Section 
Description of Change 
Brief Rationale and/or 
Clarification 
Section 1.3 Schedule of 
Activities (cont.) 
treatment visit should also have the 
assessments for that visit performed, if 
possible, which is noted under the SoAs 
Added a PK/PD sample collection at 
the end of infusion (for IV doses only) 
in (new) Table 3  
Following the FDA’s recommendation 
received after Protocol Amendment 3 
submission, Alexion decided this 
timepoint would allow a better 
assessment of the ALXN1850 IV PK/PD 
parameters 
Added a footnote in the SoAs that a 
positive drug test result for a non-
prescribed substance received at any 
visit will lead to participant 
discontinuation  
For clarity and alignment within the 
protocol 
Removed “24-hour Holter ECG” from 
the SoA and added an “X” in the “12-
lead ECG (triplicate)” assessment row 
at the Screening timepoint 
24-hour Holter ECG was determined by
Safety and Medical to be unnecessary as
a 12-lead ECG at Screening is sufficient,
which will reduce participant/site burden
For the assessment row “Urine for 
calcium, phosphorus, calcium, PEA, 
and creatinine” 
Removed the duplicate “calcium”  
Removed the associated note 
“Morning spot urine vs. 24-hour 
urine.” 
Clarified that a Baseline sample is 
collected only on Day -1  
Typo 
Participants may now be admitted to the 
site on the dosing day (if day prior is 
approved Outpatient), which would 
burden them with collecting morning 
urine at home prior to coming to the site. 
24-hour urine was determined sufficient.
To appropriately assess the significance
of any changes in these parameters, a
Baseline urine sample is needed predose
on the same day as the blood sample for
clinical chemistry
Added predose Day 1 assessment for 
bone biomarkers (sCTX, P1NP, 
osteocalcin) 
To clarify that this assessment is needed 
predose on Day 1 for all participants 
(not just the first participant) 
Included clarifications regarding the 
following assessments: 
Chemistry tests: ionized calcium, 
phosphorus, and magnesium 
Blood PTH 
Blood for PTH was listed in the same 
assessment row as ionized calcium, 
phosphorous, and magnesium; however, 
the latter should instead be included in 
the chemistry assessment (already listed 
in Table 7, previously Table 6)   
Removed timepoints for urine drug 
screen on Days 51, 65, and 85 
Added a footnote that a negative PCP 
result at Screening is required for 
participant enrollment; however, drug 
screens collected on the days prior to 
each dose are not required to confirm a 
negative PCP result prior to dosing. 
Once the PCS result is received, the 
participant will be discontinued from 
the study if positive 
These timepoints were determined 
unnecessary by Alexion as no further 
dosing will be performed during these 
last 3 study visits (ie, potential drug 
interaction is no longer a concern). 
Participants are already made aware that 
they must refrain from illicit drug use 
throughout the study 
For clarity because PCP results will not 
be received until 3-5 days after sampling 
Added a timepoint at EoT/ED (Day 65 
[1st participant]/Day 57 [subsequent 
These timepoints should have been 
added as part of the EoS/ED safety 
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Section 
Description of Change 
Brief Rationale and/or 
Clarification 
participants]) for hematology (except 
HbA1c), chemistry, urinalysis, and 
coagulation laboratory tests 
assessments in previous protocol 
versions. Now that most EoS 
assessments will be done at EoT 
Reduced the number of glycated 
hemoglobin (HbA1c) collection 
timepoints (now only required at 
Screening). For clarity, HbA1c was 
separated from hematology in the 
SoAs 
Clinically significant changes in HbA1c 
between the visits are not expected, and 
this will reduce participant/site burden  
Expanded the permitted time window 
for the ophthalmological and renal 
examinations from 40 days to 
≤ 6 months prior to enrollment for 
rescreening only 
As it is not expected to impact 
participant safety and should ease 
participant burden 
Added injection/infusion site 
evaluation timepoints to indicate every 
15 minutes for the 1st hour and at 2, 8, 
and 12 hours postdose (all relative to 
start-of- infusion [IV dose]/time of 
injection [SC doses]), 
Greater frequency for this assessment 
will increase participants' safety 
monitoring while not increasing their 
burden  
Added permitted assessment windows 
in the footnotes regarding the ECG 
and PK timepoints at Tmax (EoI) 
For consistency because all other ECG 
and PK timepoints have permitted 
windows indicated 
Modified when samples should be 
collected following a suspected 
hypersensitivity reaction from 
“2 hours and 24 hours postdose” to “as 
soon as possible (within 1 hour of the 
reaction) and again at 2 and 8 hours 
(+ 1 hour window each) after the 1st 
sample.”  
Based on similar past studies and 
immunologist advice, it is expected that 
modifying these timepoints will capture 
more accurate suspected hypersensitivity 
reaction test results  
Added a note to each SoA that all 
postdose assessment timepoints are 
relative to the start of infusion (IV 
dose) or time of SC injection except 
the end-of-infusion vital signs, PK/PD 
sample, and infusion site evaluation 
(IV dose only) 
For clarity 
For all participants on each dosing day 
(now Table 3), combined the 4- and 8-
hr postdose assessments (same for 
both) into a new 6-hr postdose column 
and removed the 4- and 8-hr postdose 
columns from the table 
It was determined that a PK/PD sample 
collection at 6-hr postdose would be 
more appropriate, and with this 
timepoint added, the 4- and 8-hr 
postdose samples are no longer needed. 
This change is not expected to affect the 
assessment of safety/tolerability 
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10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or 
Clarification 
Section 1.3 Schedule of 
Activities  
Section 8.2.1 Physical 
Examinations 
Separated full and brief PEs in the 
SoAs and Section 8.2.1 
Removed “(including fundoscopy)” 
within the 1st bullet of Section 8.2.1 
To decrease participant and site burden, 
a full PE at all visits indicated in PA3 
was deemed unnecessary. Alexion 
Safety and Medical determined which 
study visits should include a full or brief 
PE. 
Fundoscopy is already listed in 
Section 8.2.8 (Ophthalmological 
Examination) and does not need to be 
performed during PEs 
Section 1.3 Schedule of 
Activities  
Section 8.2.3 
Electrocardiograms 
Added that all ECG assessments 
should not be performed after any 
major meal  
Clarified that the order should read 
ECGs performed first, then vitals, then 
PK/PD collection at any ECG 
timepoint where 1 or both of the latter 
assessments are also scheduled 
(instead of PA3’s wording that ECGs 
in conjunction with vitals should be 
assessed before PK/PD sampling) 
To avoid overlapped effects in QTc 
baseline due to a heavy meal 
For clarity as ECGs must be performed 
first and the site can not assess ECG and 
vitals simultaneously, anyway 
Section 5.1 Inclusion 
Criteria 
Added “or a variants of unknown 
significance” within 2a 
Will likely assist participant enrollment 
without impacting data (PD/biomarkers) 
associated with VUS, and often VUS 
change to likely pathogenic 
Removed the following from 2b 
“AND a plasma PLP level greater than 
the ULN at Screening” 
Participants considered for enrollment 
will have mild HPP and may not 
manifest elevation in PLP because levels 
of PLP, in general, are highly variable in 
this population  
Diagnosis of HPP for inclusion criteria 
will be based on genetic testing, low 
ALP and clinical history, which will 
more adequately characterize the 
population that is intended to be enrolled 
Removal of this criteria will not present 
any change in the safety assessments or 
pose any additional participant risk  
Section 5.2 Exclusion 
Criteria 
Removed exclusion criteria #5, #20, 
and #22 
These criteria further complicate a study 
that is a Phase 1B study and not a study 
in healthy volunteers. Investigator 
discretion should be able to address 
conditions that may disqualify the 
candidate, and no impact on participant 
safety is expected from this change 
considering ALXN1850’s current risk 
profile. 
Removed “predose on Day 1” from 
exclusion #7 
These exclusion criteria should apply to 
Screening only 
In exclusion criteria #6 (now #5), 
replaced "the mean of the 3 values will 
Safety and medical agreed that if the 1st 
ECG measurements are out-of-range, 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or 
Clarification 
be calculated to determine participant 
inclusion" with wording that at least 1 
of the 3 readings must be inside the 
noted ECG eligibility ranges  
then 2 replicate measures should be 
performed; however, what determines 
eligibility is that at least 1 of the 3 
measures, not their mean, is in the 
inclusion range  
Slightly revised exclusion criterion #6 
to say that participants with a PR value 
of less than 120 ms or greater than 240 
ms will not qualify (instead of “120 
ms > PR > 240 ms”, which can be 
misread) 
To clarify this ECG exclusion criterion 
Removed (former smokers may be 
permitted to enroll at the Investigator’s 
discretion) exclusion criterion #23 
Text is unnecessary/possibly confusing 
as this criterion states that current 
smokers may be enrolled if they agree to 
abstain during the inpatient stays 
For exclusion criterion #28: 
removed “Day -1”  
added “for non-prescribed substances” 
drug screen results for PCP take 3-5 
days to obtain, so Day -1 results will not 
be available before enrolling participants 
ALXN1850 is unlikely to affect the PK 
of co-administered small molecules and 
vice versa 
Changed BMI from ≥ 35 kg/m2 to 
> 40 kg/m2 in exclusion criterion #29
Change will assist participant enrollment 
without significantly impacting 
ALXN1850 safety or PK/PD  
Section 5.2 Exclusion 
Criteria 
Section 6.5.2 Disallowed 
Medicine and Therapy 
Removed exclusion criterion #14 
about denosumab  
Removed the sentence about 
denosumab  
Consideration of denosumab is 
unnecessary for ALXN1850 
Section 5.3 Lifestyle 
Considerations 
Changed “24 hours” to “48 hours” and 
“admission” to “each dose” in the 1st 
and 2nd bullets 
Align with the change noted above 
regarding admission to the research site 
being permitted either the day prior to 
dosing or predose on the dosing day at 
the Investigator’s discretion 
Section 5.3.3 Activity 
Added “(strenuous, beyond the 
participant’s routine physical 
activities)”  
To clarify what is meant by vigorous 
activity 
Section 6.5.1 Allowed 
Medicine and Therapy 
Section 6.5.2 Disallowed 
Medicine and Therapy 
Added “Prescription medications will 
be permitted during the study at the 
Investigator’s discretion and recorded 
in the eCRFs” from Section 6.5.1 and 
removed “Use of 
nonprescription/over-the-counter 
medications, including herbal 
remedies and supplements, must be 
discontinued within 7 days before Day 
1, except with prior approval from 
Alexion” from Section 6.5.2 
ALXN1850 is unlikely to affect the PK 
of co-administered small molecules and 
vice versa, so permitting prescription 
medication at the Investigator’s 
discretion should assist participant 
recruitment and retention. Also, these 
Sections had different wording 
regarding the use of herbal preparations 
and supplements in PA3, so they were 
combined in Section 6.5.1 of PA4  
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Added the following: 
bullets for a positive drug (except 
prescription medications) or 
pregnancy tests during the study  
For clarity and consistency within the 
protocol 
Site requested and Alexion approved 
For clarity and alignment within the 
protocol 
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Protocol Amendment 5 
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10 Mar 2022 
Section 
Description of Change 
Brief Rationale and/or 
Clarification 
wording to the pre-existing bullet 
regarding a COVID-19 diagnosis that 
these participants will be evaluated for 
potential discontinuation from 
treatment and/or study according to 
the research site’s COVID-19 protocol 
participants who miss a dosing visit or 
completes it out-of-window do not 
need to be withdrawn or discontinued 
from treatment but won’t be 
considered “completed”  
Section 8.2.3 
Electrocardiograms 
Added “(all 3 should be performed 
sequentially within a 15-minute 
period)” after “The triplicates will be 
performed at approximately 1-minute 
intervals” 
For clarity 
Section 8.5 
Pharmacokinetics 
Section 8.6 
Pharmacodynamics 
Replaced specific collection windows 
with a statement to refer to the SoAs 
To the reduce redundancy and the SoA 
is better designed to convey the nuances 
of this information  
Section 10.2 Clinical 
Laboratory Tests  
Changed “central” to “local” in the 1st 
bullet and deleted the 2nd bullet 
A local laboratory is used for safety 
laboratory tests 
Modified the 6th (now 5th) bullet in 
Section 10.2 to match the SoA note 
(serum pregnancy test at Screening 
and urine pregnancy tests at 
subsequent timepoints) 
For clarity, because the information in 
these 2 sections slightly conflicted in 
Protocol Amendment 3  
Section 10.2 Clinical 
Laboratory Tests, Table 6 
Removed free hemoglobin, 
erythrocytes, corpuscular hemoglobin 
content, mean platelet volume, 
segmented (after neutrophils), urea, 
and PLP 
Removed tetrahydrocannabinol 
(cannabinoids) 
Added a footnote for glycated 
hemoglobin (HbA1c) to indicate that it 
only needs to be collected at Screening 
Added a footnote that clinical 
chemistry must be fasting only at 
Screening 
These tests were determined redundant 
as the information they provide may be 
obtained from other laboratory tests 
already scheduled 
Recreational use of cannabis use is now 
legal in several US states and 
decriminalized/permitted for medicinal 
use in other states and countries 
(medicinal use of cannabis may relieve 
some symptoms of HPP). No drug 
interactions are anticipated with 
ALXN1850, given experience with 
asfotase alfa and its mechanism of 
action 
Clinically significant changes in HbA1c 
between the visits are not expected, and 
this will reduce participant/site burden  
For clarity 
10.4.2.1 Guidance for 
Female Participants  
Modified the first sentence to indicate 
that a negative serum pregnancy test is 
required at Screening instead of within 
1 day before the first dose 
To align with the SoA and the 
clarification noted above for Section 
10.2  
Abbreviations: BMI = body mass index; ECG = electrocardiogram; eCRFs = electronic case report forms; 
ED = early discontinuationa; EoS = end-of-study; EoT = end-of-treatment; FDA = Food and Drug Administration; 
HPP = hypophosphatasia; P1NP = propeptide of type I procollagen PD = pharmacodynamics; 
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Protocol Amendment 5 
ALXN1850-HPP-101 
10 Mar 2022 
PK = pharmacokinetics; PLP = pyridoxal-5ˈ-phosphate; sCTX = serum C-terminal Telopeptide of Type 1 
Collagen; SoA = Schedule of Assessments; SRC = Safety Review Committee; ULN = upper limit of normal; 
VUS = variants of unknown significance  
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10 Mar 2022 
11.
REFERENCES
Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first 
symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, 
p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone.
2007;40(6):1655-1661.
Fleisch H, Russell RG, Straumann F. Effect of pyrophosphate on hydroxyapatite and its 
implications in calcium homeostasis. Nature. 1966;212(5065):901-903. 
Greenblatt MB, Tsai JN, Wein MN. Bone Turnover Markers in the Diagnosis and Monitoring of 
Metabolic Bone Disease. Clin Chem. 2017;63(2):464-474. 
Linglart A, Biosse-Duplan M. Hypophosphatasia. Curr Osteoporos Rep. 2016;14(3):95-105. 
Narisawa S, Frohlander N, Millan JL. Inactivation of two mouse alkaline phosphatase genes and 
establishment of a model of infantile hypophosphatasia. Dev Dyn. 1997;208(3):432-446. 
Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10 Suppl 2:380-388. 
Russell RG. Excretion of inorganic pyrophosphate in hypophosphatasia. Lancet. 
1965;2(7410):461-464. 
Whyte M. Hypophosphatasia. In: Glorieux FH, Pettifor JM, Juppner H, editors Pediatric bone; 
biology and diseases London, UK: Academic Press. 2012:771-794. 
Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. 
Endocr Rev. 1994;15(4):439-461. 
Whyte MP, Mahuren JD, Vrabel LA, Coburn SP. Markedly increased circulating pyridoxal-5'-
phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism. J 
Clin Invest. 1985;76(2):752-756. 
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KLJ-: 
N . 
Form - Source Copy 
AstraZeneca Rare Disease 
Clinical Note to File, Form for ALXN-SOP-0005179 
Document Number 
Version 
Status 
Effective Date 
ALXN-FRM--0007589 
2.0 
Effective 
03Sep2021 
CLINICAL NOTE TO FILE 
Protocol Number: 
ALXN1850-HPP-101 
Site Number: 
NA 
I 
Subject Number: NA 
Re: 
Protocol Administrative Change Letter #5 - Incorrect PA version date 
FILE 
(Check at least one) 
Sponsor Trial Master File: I 
Investigator Site File: D 
Other: 0 
Please specify: 
Note to File: 
This Note to file is to correct the date of the finalised Protocol Amendment #5 in the Administrative 
Clarification Letter#S. 
Current: 
Protocol Version: 
I Amendment 5 
Corrected: 
Protocol Version: 
Amendment 5 
1-l-l--lleb 2 022 
10 Mar 2022 
Alexion Confidential I Page 
I 
____________________________________________________________
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________________________________________________________________________
Alexion Confidential

Form - Source Copy 
AstraZeneca Rare Disease 
Clinical Note to File, Form for ALXN-SOP-0005179 
Document Number 
Version 
Status 
Effective Date 
ALXN-FRM-0007589 
2.0 
Effective 
03 Sep 2021 
Prepared by: 
 
Title: 
 
Signature: 
Date: 
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Alexion Confidential

Administrative Change Letter #6
Date of Letter: 29 Jun 2022
Page 1 of 5
Alexion Confidential
Protocol: ALXN1850-HPP-101
Protocol Title: A Phase 1, Open-label, Dose-escalating Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ALXN1850 in Adults with Hypophosphatasia
Protocol Version:
Amendment 5
10 Mar 2022
Protocol Administrative Change Letter #6
Subject of the Administrative Change Letter: Clarification needed regarding the following: 
x
Postdose timepoints evaluation
x
Injection/infusion site evaluation
x
Hypersensitivity Reaction Labs
To the sites participating in the above named and numbered clinical study, this letter serves to inform 
you about the following administrative change to the above referenced protocol version.
x
Clarifications in Section 1.3 Schedule of Activities, Table 1, 2 and 3: Postdose timepoints 
evaluation
This document provides clarification that all postdose timepoints are relative to the START of the IV 
infusion/injection (time 0) EXCEPT for ECG and PK/PD samples, performed/collected at EoI.
x
Clarifications in Section 1.3 Schedule of Activities, Table 1, 2 and 3: Injection/infusion site 
evaluation
This document provides clarification on the timeframes for injection/infusion site evaluation. 
Injection/infusion site evaluations have to be performed from Time 0h and every 15 minutes (+ 5 
minutes) until the 1st hr after the start of the injection/infusion. The rest of the timepoints have a window 
of ± 15minutes. 
x
Clarifications in Section 1.3 Schedule of Activities, Table 1, 2 and 3: Hypersensitivity 
Reaction Labs
The Hypersensitivity Reaction labs have been clarified to reconcile the information from Table 1 and 
Table 2 with Table 3.
x
If a hypersensitivity reaction is suspected, in general study overview for 1st and subsequent 
participants (table 1 and 2): hypersensitivity reaction labs (tryptase, IgE, C5b-9) as well as
chemistry, hematology, and urinalysis samples should be collected as soon as possible
(within 1 hour of the reaction) and again at 2 and 8 hours (+ 1 hour window each) after the 
1st sample. The Day 1 predose samples will only be analyzed for participants with a reported 
suspected hypersensitivity reaction at any time following the first dose. If the participant is 
not in the clinic, these samples do not need to be collected and suspected hypersensitivity 
reaction will be reported as an AE only. If the suspected hypersensitivity reaction persists 
beyond 8 hours, the CRU should contact the MM for guidance.
x
If a hypersensitivity reaction is suspected, the day of the dosing (table 3): hypersensitivity 
reaction labs (tryptase, IgE, C5b-9) as well as chemistry, hematology, and urinalysis 
samples should be collected as soon as possible (within 1 hour of the reaction) and again at 
2 and 8 hours (+ 1 hour window each) after the 1st sample. The Day 1 predose samples will 
only be analyzed for participants with a reported suspected hypersensitivity reaction at any 
time following the first dose.
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Administrative Change Letter #6
Date of Letter: 29 Jun 2022
Page 2 of 5
Alexion Confidential
Please file this letter and any IRB/EC correspondence with all copies of the protocol in the Investigator 
Site File and in all pertinent repositories in which the protocol is maintained. If there are any questions 
concerning these changes, please contact us. Applicable changes will also be captured in any future 
protocol amendment.
___________________________
Phone: 
Email: 
Cc:
eTMF
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Administrative Change Letter #6
Date of Letter: 29 Jun 2022
Table 1:
Schedule of Activities - Study Overview for the First Participant in Each Cohort
Assessments
Screening
Treatment Period
EoT/ED 
Assessment
FU/ EoS 
Assessment
s
Inpatient (I) or 
Outpatient (O)a
O
I/O
I
I
I/O
O
O
I/O
I
I
I/O
O
I/O
I
I
I/O
I
I
I/O
O
O
O
O
Study Day 
-56 to -2
-1
1
2
3
5
8
14
15
16
17
19
21
22
23
28
29
30
31
36
51
65
85
Hours postdoseb
24
48
96
168
24
48
96
24
24
48
168
Injection/
infusion site evaluationc
X
X
X
X
X
X
X
X
X
Hypersensitivity rxn labs 
(tryptase, IgE, C5b-9)d
←See footnote m Xn →
Chemistry, hematology, 
and urinalysis labs
← Xn→
b All postdose timepoints are relative to the start of the IV infusion/time of the SC injection (ie, Ttime 0) except the ECGvital signs measurements, and PK/ and PD 
samples, and infusion site evaluation performed/collected at the EoI (see Table 3).
Error! Reference source not found.
Injection/infusion site evaluations will be performed within 15 minutes (± 5 minutes) after injection/EoI and ± 15 
minutes of the rest of the timepoints. from Time 0h and every 15minutes (+ 5 minutes) until the 1st hr after the start of the injection/infusion. The rest of the 
timepoints have a window of ± 15 minutes (see Table 3).
d If the participant is in the clinic, collect the first sample ASAP (preferred) or within 1 hour of the suspected hypersensitivity reaction. The 2 subsequent samples 
also have a permitted + 1 hour window. If a hypersensitivity reaction is suspected, hypersensitivity reaction labs (tryptase, IgE, C5b-9) as well as chemistry, 
hematology, and urinalysis samples should be collected as soon as possible (within 1 hour of the reaction) and again at 2 and 8 hours (+ 1 hour window each) after 
the 1st sample. The Hypersensitivity rxn labs Day 1 predose samples will only be analyzed for participants with a reported suspected hypersensitivity reaction at 
any time following the first dose. If the participant is not in the clinic, these samples do not need to be collected and suspected hypersensitivity reaction will be 
reported as an AE only. If the suspected hypersensitivity reaction persists beyond 8 hours, the CRU should contact the MM for guidance.
Page 3 of 5
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Alexion Confidential
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Administrative Change Letter #6
Date of Letter: 29 Jun 2022
Table 2:
Schedule of Activities - Study Overview for Subsequent Participants in Each Cohort
Assessments
Screening
Treatment Period
EoT Assessments
FU/ EoS 
Assessments
Inpatient (I) or Outpatient (O)a
O
I/O
I
I
I/O
O
I/O
I
I
I/O
O
I/O
I
I
I/O
I
I
I/O
O
O
O
O
Study Day 
-56 to -2
-1
1
2
3
5
7
8
9
10
12
14
15
16
21
22
23
24
29
43
57
78
Hours postdoseb
24
48
96
24
48
96
24
24
48
168
Injection/infusion site evaluationc
X
X
X
X
X
X
X
X
Hypersensitivity rxn labs (tryptase, 
IgE, C5b-9)d
←See footnoted Xn →
Chemistry, hematology, and 
urinalysis labs
← Xn→
b All postdose timepoints are relative to the start of the IV infusion/time of the SC injection (ie, Ttime 0) except the ECGvital signs measurements, and PK/ PD 
samples, and infusion site evaluation performed/collected at the EoI (see Table 3).
cInjection/infusion site evaluations will be performed within 15 minutes (± 5 minutes) after injection/EoI and ± 15 minutes of the rest of the timepoints. from Time/0h 
and every 15minutes (+ 5 minutes) until the 1st hr after the start of the injection/infusion. The rest of the timepoints have a window of ± 15 minutes (see Table 3).
dIf the participant is in the clinic, collect the first sample ASAP (preferred) or within 1 hour of the suspected hypersensitivity reaction. The 2 subsequent samples 
also have a permitted + 1 hour window. If a hypersensitivity reaction is suspected, hypersensitivity reaction labs (tryptase, IgE, C5b-9) as well as chemistry, 
hematology, and urinalysis samples should be collected as soon as possible (within 1 hour of the reaction) and again at 2 and 8 hours (+ 1 hour window each) after 
the 1st sample. The Hypersensitivity rxn labs Day 1 predose samples will only be analyzed for participants with a reported suspected hypersensitivity reaction at 
any time following the first dose. If the participant is not in the clinic, these samples do not need to be collected and suspected hypersensitivity reaction will be 
reported as an AE only. If the suspected hypersensitivity reaction persists beyond 8 hours, the CRU should contact the MM for guidance.
Page 4 of 5
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Alexion Confidential
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Administrative Change Letter #6
Date of Letter: 29 Jun 2022
Table 3:
Schedule of Activities – Each Dosing Day for All Participants
Assessments
Each Dosing Day (Inpatient Visits)
Study Day (First Participant)
Days 1, 15, 22, 29
Study Day for (Subsequent Participants)
Days 1, 8, 15, 22
Day/Time
Day 1 
Only
Each Dosing Day
Predose
Dose
Postdosea
Predose
Per Window (if 
specified)
-0.5 hr
0 hr
EoI (IV 
Dose Only)
Every 15 min 
for 1st hr
2
6
12
Injection/infusion site evaluationg
X
X
X
X
X
X
Hypersensitivity reaction labs (tryptase, IgE, 
C5b-9, chemistry, hematology, and urinalysis)
X
← Xi→
Chemistry, hematology, and urinalysis labs
← Xi→
a All postdose timepoints are relative to the start of the IV infusion/time of the SC injection (ie, time 0 hr) except the ECG and PK/PD samples, and infusion site 
evaluation performed/collected at the EoI (see footnote d).
g Injection/infusion site evaluations will be performed during the infusion, after I/EoI, and then within 15 minutes from Time/0h and every 15minutes (+ 5 minutes) 
until the 1st hr after the start of the injection/infusion. The rest of the timepoints have a window of ± 15 minutes. 
i If a hypersensitivity reaction is suspected, hypersensitivity reaction labs (tryptase, IgE, C5b-9 as well as chemistry, hematology, and urinalysis samples should be 
collected as soon as possible (within 1 hour of the reaction) and again at 2 and 8 hours (+ 1 hour window each) after the 1st sample. The Hypersensitivity rxn labs
Day 1 predose samples will only be analyzed for participants with a reported suspected hypersensitivity reaction at any time following the first dose.
Page 5 of 5
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Alexion Confidential
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