Conditions: Phenylketonuria (PKU)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief summary:
This is a Phase 3 open-label extension study enrolling adult patients with PKU who were previously treated with pegvaliase in Studies PAL-003 (NCT00924703) or 165-302 (NCT02468570). The study is designed to evaluate the long-term safety and efficacy of pegvaliase administered at doses \> 40 mg/day to 60 mg/day.

Detailed description:
Pegvaliase dosing will continue without interruption from Parent Study 165-302 (NCT02468570) or Parent Study PAL-003 (NCT00924703). Beginning on Day 1, subjects will receive the same dose and regimen of pegvaliase they were receiving in either 165-302 or PAL-003. A subject who reduces to a dose of 40 mg/day or lower for 32 consecutive weeks will be discontinued from study drug and withdrawn from the study as they will have the option to transition to commercial drug. Dose reductions may be performed if warranted due to AEs or hypophenylalaninemia. Dose increases to up to 60 mg/day may be performed per investigator discretion in consultation with the sponsor's medical monitor. Dosing will continue for approximately 121 weeks.

Arms:
arm 1: Beginning on Day 1, subjects will receive the same dose and regimen of pegvaliase they were receiving in 165-302 or PAL-003 (pegvaliase dosing should continue without interruption from the previous study). Subsequent revisions to dosing regimens are allowed following consultation with the medical monitor.

Interventions: intervention 1: Pegvaliase
Intervention descriptions: intervention 1: 40-60mg/day

Protocol document:
Prot_000.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title:  An Open-label Extension Study to Evaluate the Safety and Efficacy of 
Subcutaneous Injections of Pegvaliase (> 40 mg/day Dose) in Adults with 
Phenylketonuria 
 
NCT Number: NCT03694353 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 30 July 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Proprietary and Confidential 
30 July 2019 
CLINICAL STUDY PROTOCOL 
Study Title: 
An Open-label Extension Study to Evaluate the Safety and 
Efficacy of Subcutaneous Injections of Pegvaliase (> 40 mg/day 
Dose) in Adults with Phenylketonuria 
Protocol Number: 
165-304 
Active Investigational Product: 
pegvaliase (formerly BMN 165) 
IND Number: 
IND 076269 
Indication: 
Phenylketonuria 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 3 
Responsible Medical Monitor: 
, RN, MS 
Reference Therapy: 
None 
Treatment Duration: 
Approximately 121 weeks 
Doses of Investigational 
Product: 
> 40 mg/day to 60 mg/day 
Study Population: 
,QGLYLGXDOVZLWKSKHQ\ONHWRQXULD3.8DJHG 18 years and 
 70 years who previously received pegvaliase in PAL-003 or 
165-302 (> 40 mg/day dose) 
Date of Original Protocol: 
11 April 2018 
Date of Amendment 1: 
30 July 2019 
 
 
 
 
 
 
Property of BioMarin 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin. 
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code of Federal 
Regulations and the International Conference on Harmonisation Guidelines, including the archiving of essential documents. 
BioMarin is a registered trademark of BioMarin Pharmaceutical Inc. 
 
DocuSign Envelope ID: D7A66402-315A-4939-8858-10F8915CA3E5
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(165-304 Amendment 1)  
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30 July 2019 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment: 1 
Date: 30 July 2019 
RATIONALE AND SUMMARY OF MAJOR CHANGES 
A summary of major changes covered by Amendment 1 to the 165-304 protocol is provided 
below.   
1. The study duration has been extended from approximately 61 weeks to 121 weeks. 
Rationale: The study is ongoing and extending the duration should ensure that all subjects 
on the study continue to have access to pegvaliase without involuntary drug holidays. 
2. Additional immunogenicity assays have been added. 
Rationale: Because patients in 165-304 will receive pegvaliase doses higher than the 
currently approved maximum dose of 40 mg/day, more drug may be available to potentially 
combine with antibodies to form circulating immune complexes (CICs), which could 
increase the risk of immune-mediated events. Therefore, additional immunogenicity 
evaluations have been added; the additional evaluations will be performed on samples 
already identified for collection in the protocol. No additional blood draws will be required. 
3. Changes were made to dosing exception language for 1 subject who had transitioned 
from PAL-003 to 165-304 on a higher dose. 
Rationale: In a parent study for PAL-003 (the phase 2 study PAL-002), dosing with 
pegvaliase was weight-based, and the maximum permitted dose early in the study was up to 
5.0 mg/kg/week. One subject who continued on 120 mg/day dosing in PAL-003 based on the 
maximum reported body weight of ~220 kg and the demonstrated efficacy of that dose, has 
transitioned from PAL-003 into 165-304. The protocol is amended to remove reference to 
previous weight-based dosing while still including a dosing exception (not to exceed 
120 mg/day dose) for this subject. In addition, the amendment sets the maximum dose 
increase that an investigator can request at “not to exceed 60 mg/day”, with the exception of 
the aforementioned patient. 
4. Study background information has been updated to reflect commercial approval of 
pegvaliase as an available treatment option for patients with PKU in the US and EU. 
5. Additional minor changes have been made for purposes of consistency and clarity. 
Specific changes included in this amendment, including the Synopsis, since the original 
protocol (dated 11 April 2018) are outlined in Section 24. 
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30 July 2019 
2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE OF STUDY: An Open-label Extension Study to Evaluate the Safety and Efficacy of 
Subcutaneous Injections of Pegvaliase (> 40 mg/day Dose) in Adults with Phenylketonuria 
PROTOCOL NUMBER: 165-304 
STUDY SITES: Up to 29 sites in the United States 
PHASE OF DEVELOPMENT: Phase 3 
STUDY RATIONALE: 
Study 165-304 is an open-label extension for subjects who participated in Studies PAL-003 and 
165-302 at doses > 40 mg/day. The objective is to evaluate long-term safety and efficacy in subjects 
treated at doses exceeding the approved pegvaliase labeled dose (the currently approved label 
specifies up to and including 40 mg/day dose only). 
Literature reports suggest the majority of adults with PKU cannot adhere to severe phenylalanine 
(Phe) intake restrictions. Even among adults reporting to adhere to severe Phe intake restrictions, the 
majority fail to maintain recommended blood Phe levels. Baseline blood Phe levels and diet from 
the literature and previous pegvaliase clinical studies confirm this finding among adult participants. 
Adults with PKU with poor metabolic control represent a patient population in great need of 
additional therapeutic options.  
OBJECTIVES: 
The primary objective of the study is: 
x 
To evaluate the long-term safety and efficacy of pegvaliase (> 40 mg/day dose) in adult 
patients with PKU 
The secondary objective of the study is: 
x 
To characterize dietary protein intake from medical food and from intact food during 
long-term treatment with pegvaliase (> 40 mg/day dose) in adult patients with PKU 
The exploratory objective of the study is: 
x 
To characterize the long-term immunogenicity profile of pegvaliase (> 40 mg/day dose) in 
adult patients with PKU 
STUDY DESIGN AND PLAN: 
This is a Phase 3 open-label extension study enrolling approximately 40 adult subjects with PKU 
who were previously treated with pegvaliase in Studies PAL-003 or 165-302. The study is designed 
to evaluate the long-term safety and efficacy of pegvaliase administered as prefilled syringe drug 
product at a dose of > 40 mg/day to 60 mg/day, inclusive. Dose regimens other than daily dosing at 
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Proprietary and Confidential 
30 July 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
> 40 mg/day to 60 mg/day (with the exception of 1 subject enrolled from the PAL-003 study who 
receives a pegvaliase dose not to exceed 120 mg/day) may be allowed provided the investigator 
consults with the medical monitor and obtains approval from the medical monitor prior to starting 
the alternative regimen. Subjects will continue their prior pegvaliase dose regimen on the 165-304 
study, including 1 subject enrolled from the PAL-003 study who receives a pegvaliase dose not to 
exceed 120 mg/day. A subject who dose reduces to a dose of 40 mg/day or lower for 32 consecutive 
weeks will be discontinued from study drug and withdrawn from the study as they will have the 
option to transition to commercial drug. Dose reductions may be performed if warranted due to 
adverse events (AEs) or hypophenylalaninemia. Dose increases to up to 60 mg/day may be 
performed per investigator discretion in consultation with the sponsor’s medical monitor. Dosing 
will continue for approximately 121 weeks. After providing informed consent, subjects undergo 
screening evaluations to determine study eligibility. Screening assessments must be performed 
within 28 days of the first 165-304 dose of pegvaliase on Day 1. Study PAL-003 or 165-302 Study 
Completion Visit assessments may be used for the purpose of screening, with Day 1 of 165-304 
taking place the same day. Pegvaliase dosing should continue without interruption from the previous 
study; beginning on Day 1, subjects will receive the same dose and regimen of pegvaliase they were 
receiving in 165-302 or PAL-003. Subsequent revisions to dosing regimens are allowed following 
consultation with the medical monitor. 
A subject (or a subject-designated caregiver) must have met predefined self-administration criteria 
in PAL-003 or 165-302 to qualify for pegvaliase self-administration, including demonstrated 
working knowledge of the signs and symptoms of a hypersensitivity reaction, including 
anaphylaxis, and what to do if a hypersensitivity reaction is suspected. Eligible subjects (or 
caregivers) have been trained to self-administer pegvaliase. 
A competent adult will observe the subject during pegvaliase administration and for a minimum of 
1 hour following pegvaliase administration upon reintroduction of pegvaliase after resolution of a 
Grade 3 or higher hypersensitivity adverse event (HAE), any dose interruption of  4 days, and for a 
dose increase to 60 mg/day; administration of pegvaliase may only be performed if this person is 
present. Observations should be performed for all doses administered for 1 week after reintroduction 
of pegvaliase or a dose increase to 60 mg/day. Information and training on how to recognize a 
possible reaction, the severity of the reaction, and instructions on what to do if a reaction occurs will 
be provided to any person designated to observe the subject during pegvaliase administration. 
)ROORZLQJDGRVHLQWHUUXSWLRQRI 4 doses that is not due to safety, the investigator should consult 
with the medical monitor and obtain approval from the medical monitor prior to the subject 
restarting pegvaliase. 
Subjects are given 2 epinephrine injectors and are instructed to carry 1 epinephrine injector with 
them at all times. Each subject is contacted weekly to monitor for self-administration problems 
and/or AEs. Premedication with H1 antagonist, H2 antagonist, and antipyretic (eg, acetaminophen) 
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Page 5 
 
Proprietary and Confidential 
30 July 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
should be administered approximately 2 to 3 hours prior to pegvaliase administration for 1 week 
upon reintroduction of pegvaliase after resolution of a grade 3 or higher HAE, following any dose 
LQWHUUXSWLRQRI 4 days, and for a dose increases to 60 mg/day. If a non-steroidal anti-inflammatory 
medication (NSAID) is administered as a premedication, it should be given with food. Subjects may 
also be pre-medicated at any time in the study at the discretion of the investigator. Subjects are 
provided with a workbook to document the date and time of pegvaliase injections, the injection site, 
and suspected AEs. 
A subject’s ability to maintain a consistent diet is essential for the success of the study by ensuring 
that the efficacy and safety end points are attributable to study treatment rather than to changes in 
dietary protein intake. A dietitian under investigator supervision will manage subject diet for the 
entire duration of the study. Subjects are provided 3-day diaries in which all dietary protein intake 
(including medical food and intact food) must be recorded for 3 consecutive days immediately prior 
to each scheduled clinic visit for review with a dietitian. All subjects will be provided the option of 
tyrosine supplementation (500 mg, 3 times per day with meals) at the discretion of the investigator. 
Subjects are instructed not to change their dietary protein intake during the study. 
Because the risks of taking pegvaliase during pregnancy and breastfeeding are unknown, subjects 
cannot take pegvaliase if they are trying to conceive, are pregnant, or are breastfeeding. Subjects 
must be willing to use 2 acceptable methods of contraception while participating in the study and 
until 4 weeks after the study. Male subjects who are planning to impregnate a female partner and 
female subjects who are trying to become pregnant during the study must be temporarily 
discontinued from pegvaliase for 4 weeks prior to trying to conceive. During that time, subjects 
must use 2 acceptable methods of contraception. Subjects who are planning to become pregnant 
(or impregnate a female partner) may modify their diet in consultation with the investigator and/or 
study dietitian. Subjects who are confirmed to be pregnant by a serum pregnancy test and are 
temporarily off pegvaliase are not required to perform the scheduled urine pregnancy tests. Subjects 
who are pregnant or are trying to conceive and have temporarily discontinued pegvaliase should not 
perform the scheduled pharmacokinetic (PK) assessments. Male subjects who have impregnated a 
female partner may re-start pegvaliase after conception following the investigator’s consultation 
with and approval by the medical monitor. Male subjects must use a barrier method for 
contraception prior to restarting pegvaliase. Female subjects who remain in the study after 
temporary discontinuation of pegvaliase due to pregnancy may restart pegvaliase dosing after a 
confirmed negative urine pregnancy test result, the birth (or termination of the pregnancy) has been 
reported, and breastfeeding has been completed (if applicable), or after the subject is no longer 
actively trying to conceive. Re-starting pegvaliase dosing requires prior consultation with the 
investigator and approval by the medical monitor. Female subjects must return to the 
protocol-required contraception use, which must include 1 barrier method, immediately after the 
birth (or termination of the pregnancy). 
DocuSign Envelope ID: D7A66402-315A-4939-8858-10F8915CA3E5


 
(165-304 Amendment 1)  
Page 6 
 
Proprietary and Confidential 
30 July 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Except for subjects transitioning to commercial drug, if pegvaliase is discontinued before study 
completion, every effort will be made to maintain the subject in the study and continue study visits 
and assessments, provided the subject’s health, safety, and welfare are not detrimentally affected. 
In addition to BioMarin, a Data Monitoring Committee (DMC) monitors the safety of study 
subjects. The DMC is an independent committee that acts in an advisory capacity to BioMarin. 
Response to Hypersensitivity Adverse Events 
Subjects are evaluated for safety throughout the study and are trained to recognize potential HAEs 
(including anaphylaxis) and how to respond. Subjects are instructed to contact the investigator for 
any suspected HAE. After a telephone assessment, the investigator may require further evaluation at 
the clinic. If a hypersensitivity reaction (eg, injection-site reaction, rash, joint pain, itching) occurs, 
the subject may be advised to premedicate with H1 antagonist, H2 antagonist, and antipyretic 
(eg, acetaminophen) approximately 2 to 3 hours prior to subsequent pegvaliase doses. If NSAIDs 
are administered as a premedication, they should be given with food. 
HAEs, including anaphylaxis, are expected with pegvaliase administration. In response to a 
suspected HAE, pegvaliase dosing may be modified or halted depending on the severity of the event 
and suspected pegvaliase causality. Severity for HAEs will be per National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) grades. 
Subjects who experience an injection-VLWHVNLQUHDFWLRQWKDWODVWV 14 days including reactions that 
could be potential vasculitis should be referred to a dermatologist for consultation and a skin biopsy. 
Individual Stopping Criteria 
Subjects who have an NCI-&7&$(JUDGH 3 anaphylaxis event that is, in the judgment of the 
investigator and the sponsor’s medical monitor, related to study drug and suspected to meet Brown’s 
criteria for severe (grade 3) hypersensitivity may be permanently discontinued from study drug. 
Dosing in Response to Hypersensitivity Adverse Events 
Dosing in response to an HAE depends on the NCI-CTCAE grade and suspected relationship to 
study drug. Dosing instructions are as follows and are regardless of previous occurrence: 
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(165-304 Amendment 1)  
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Proprietary and Confidential 
30 July 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
NCI-CTCAE 
Grade a 
Related to 
Study Drug 
Action with Study Drug 
Individual 
Stopping 
Criteria d 
HRV 
Assessment e 
Maintain b 
Reduce c 
Interrupt c 
1 
Yes or No 
X 
(X) 
Optional 
(X) 
Optional 
 
Investigator 
discretion 
2 
Yes or No 
X 
(X) 
Optional 
(X) 
Optional 
 
Investigator 
discretion 
3 
No 
X 
(X) 
Optional 
(X) 
Optional 
 
Investigator 
discretion 
3 
Yes 
X 
(X) 
Optional 
(X) 
Optional 
 
Yes (if within 
24 hours of 
onset) 
3 d 
Yes 
 
 
 
X 
Immediately 
consult with 
sponsor 
medical 
monitor 
Yes (if within 
24 hours of 
onset) 
4 d 
Yes or No 
 
 
 
X 
Immediately 
consult with 
sponsor 
medical 
monitor 
Yes (if within 
24 hours of 
onset) 
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events, version 5.0; HRV, Hypersensitivity 
Reaction Visit; NCI, National Cancer Institute. 
a NCI-CTCAE grade determination is performed by the investigator and may be done either via telephone or clinic visit. 
b The investigator will instruct the subject to maintain the pegvaliase dose at the time of AE onset until improvement to 
grade 1 or resolution (per investigator assessment in the clinic or via telephone). 
c The pegvaliase dose may be reduced or interrupted if necessary per investigator determination. 
d If a subject has an NCI-&7&$(JUDGH 3 anaphylaxis event that is related to study drug and is suspected to meet 
Brown’s criteria for severe (grade 3) hypersensitivity in the judgment of the investigator and the sponsor’s medical 
monitor, the subject may be permanently discontinued from study drug. 
e If the investigator determines that the NCI-&7&$(JUDGH 3 hypersensitivity reaction is related to administration with 
study drug, the subject will be asked to return to the clinic within 24 hours of event onset for a hypersensitivity reaction 
visit (HRV) assessment, including laboratory tests (chemistry, hematology, urinalysis, anti-pegvaliase IgE [sampling 
must be performed > 8 hours after event onset and before the next dose of study drug], urine albumin/creatinine ratio, 
urinary N-methyl histamine, CRP, C3, C4, and tryptase).  
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Proprietary and Confidential 
30 July 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Once an AE (other than anaphylaxis) improves to grade 1 or resolves, the pegvaliase dose may be 
increased, maintained, or reduced, at the discretion of the investigator. If reduced, the recommended 
pegvaliase dose reductions include: from 60 mg/day to 40 mg/day, from 50 mg/day to 20 mg/day, or 
from 40 mg/day to 20 mg/day, with reductions from intermediate doses at the discretion of the 
investigator. If dosing has been interrupted due to an AE (other than anaphylaxis) and the 
investigator determines it is safe for the subject to resume dosing, the first dose after improvement 
of the AE should be performed in the clinic.  
Additionally, the subject should be premedicated with H1 antagonist, H2 antagonist, and antipyretic 
(eg, acetaminophen) approximately 2 to 3 hours prior to each dose of pegvaliase for 1 week upon 
UHWXUQWRGRVLQJLIWKHGRVHLQWHUUXSWLRQLV 4 days. If NSAIDs are administered as a premedication, 
they should be given with food. Also, a competent adult should observe the subject during 
pegvaliase administration and for a minimum of 1 hour following pegvaliase administration for 
1 week upon return to dosing LIWKHGRVHLQWHUUXSWLRQLV 4 days; administration of pegvaliase may 
only be performed if this person is present. 
Response to Anaphylaxis 
If the investigator suspects that the event is anaphylaxis, the subject will be assessed in the clinic 
and the sponsor’s medical monitor should be immediately notified. Laboratory assessments for 
suspected anaphylaxis events should be performed prior to the next administration of pegvaliase 
(if applicable) and include anti-pegvaliase IgE (for optimal results, sampling must be performed 
> 8 hours after event onset) and tryptase (for optimal results, perform within 24 hours of event 
onset). If the investigator determines it is safe for the subject to resume dosing with pegvaliase 
following resolution of anaphylaxis, the dose level will be reduced as follows: 
Scheduled Dose at Time 
of Anaphylaxis Onset 
Dose Following Resolution 
of Anaphylaxis Event a 
50 mg/day 
20 mg/day 
60 mg/day 
40 mg/day 
a Dose may be lowered further per investigator discretion. Dose frequency should be the same as the dose regimen at the 
time of anaphylaxis onset; however, dose frequency may be revised per investigator discretion and in consultation with 
the sponsor’s medical monitor. 
The first dose administered after resolution of anaphylaxis is to be administered at the clinic with 
equipment for emergency resuscitation (including epinephrine) within easy access. Additionally, the 
subject should be premedicated with H1 antagonist, H2 antagonist, and antipyretic 
(eg, acetaminophen) approximately 2 to 3 hours prior to each dose of pegvaliase for 1 week upon 
return to dosing regardless of the duration of dose interruption. If NSAIDs are administered as a 
premedication, they should be given with food. Also, a competent adult should observe the subject 
during pegvaliase administration and for a minimum of 1 hour following pegvaliase administration 
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Proprietary and Confidential 
30 July 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
for 1 week upon return to dosing regardless of the duration of dose interruption; administration of 
pegvaliase may only be performed if this person is present. 
Study Stopping Criteria for Adverse Events during Treatment with Pegvaliase 
If an anaphylaxis event occurs and meets Brown’s criteria for severe (grade 3) hypersensitivity, the 
DMC chair and/or committee will be informed to review and advise the sponsor on potential 
changes to the study conduct. Clinically severe hypersensitivity (Brown’s criteria, severe [grade 3]) 
is defined as significant hypoxia, hypotension or neurologic compromise that is life-threatening or 
required treatment to prevent a life-threatening event: 
x 
Cyanosis or SpO2  
x 
Hypotension with SBP < 90 mm Hg (adults) 
x 
Neurologic alteration: confusion, loss of consciousness, collapse, or incontinence 
NUMBER OF SUBJECTS PLANNED: 
Approximately 40 subjects will be enrolled. 
DIAGNOSIS AND ENTRY CRITERIA: 
Individuals eligible to participate in this study must meet all of the following inclusion criteria: 
x 
Must be enrolled in PAL-003 or 165-302 Part 4 at the time of screening for 165-304 and 
most recently receiving pegvaliase at a dose > 40 mg/day 
x 
Is at least 18 years of age and no older than 70 years of age at the time of screening 
x 
Has identified a competent person or persons    18 years of age who can observe the subject 
during study drug administration and for a minimum of 1 hour following administration in 
situations required per protocol 
o A home healthcare nurse may perform the study drug observations. 
x 
For females with childbearing potential, must have a negative pregnancy test at screening 
and be willing to have additional pregnancy tests during the study. (Females are considered 
not to have childbearing potential if they have been in menopause for at least 2 years, have 
had a tubal ligation at least 1 year prior to screening, or have had a total hysterectomy.) 
x 
If sexually active and not planning to become pregnant (self or partner), must be willing to 
use 2 acceptable methods of contraception while participating in the study and for 4 weeks 
after the study: 
o Acceptable methods of contraception include: (1) primary forms: hormonal 
(combination hormone-containing pills, patch, vaginal ring, or intrauterine device) or 
non-hormonal (copper-containing intrauterine device, tubal sterilization); (2) secondary 
forms: includes barrier forms and other forms of birth control and must include 
spermicide (eg, male condom; female condom is not an acceptable secondary form). 
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Proprietary and Confidential 
30 July 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
o Males (including partners) post vasectomy for 2 years with no known pregnancies do 
not need to use any other forms of contraception during the study. 
o Females (including partners) who have been in menopause for at least 2 years, have had 
a tubal ligation at least 1 year prior to screening, or have had a total hysterectomy do not 
need to use any other forms of contraception during the study. 
x 
Is willing and able to provide written, signed informed consent after the nature of the study 
has been explained and prior to any research-related procedures; a legally authorized 
representative may provide written consent and assent may be requested 
x 
Is willing and able to comply with all study procedures 
x 
Is in generally good health, as evidenced by physical examination and/or clinical laboratory 
evaluations (hematology, chemistry, and urinalysis) 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
x 
Use of any investigational product (except pegvaliase) or investigational medical device 
within 30 days prior to screening or requirement for any investigational agent prior to 
completion of all scheduled study assessments 
x 
Use of any medication (except pegvaliase) intended to treat PKU, including the use of large 
neutral amino acids, within 2 days prior to the administration of pegvaliase (Day 1) 
x 
Use or planned use of any injectable drugs containing PEG (other than pegvaliase), including 
medroxyprogesterone injection, within 3 months prior to screening and during study 
participation 
x 
A history of organ transplantation or on chronic immunosuppressive therapy 
x 
A history of substance abuse (as defined by the American Psychiatric Association: 
Diagnostic and Statistical Manual of Mental Disorders [DSM]) in the past 12 months or 
current alcohol or drug abuse 
x 
Current participation in the Kuvan® registry study (PKU Demographics, Outcomes and 
Safety [PKUDOS]) 
x 
Concurrent disease or condition that would interfere with study participation or safety 
(eg, history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, 
hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological, 
oncologic, or psychiatric disease) 
x 
Any condition that, in the view of the investigator, places the subject at high risk of poor 
treatment compliance or terminating early from the study 
INVESTIGATIONAL PRODUCT, DOSE, ROUTE, AND REGIMEN: 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Pegvaliase is recombinant Anabaena variabilis phenylalanine ammonia lyase-PEG and is provided 
in prefilled syringes to subjects for subcutaneous self (or caregiver) administration. 
DURATION OF TREATMENT: 
Approximately 121 weeks 
STATISTICAL METHODS AND CRITERIA FOR EVALUATION: 
Sample Size: 
Subjects who were previously treated with pegvaliase (doses > 40 mg/day) in Studies PAL-003 or 
165-302 may be enrolled into this study. No formal sample size calculation was conducted for this 
study. Approximately 40 subjects are expected to be enrolled. 
Analysis Populations: 
The safety population will consist of all subjects who receive at least 1 dose of pegvaliase during the 
study. 
The efficacy population will consist of all subjects who receive at least 1 dose of pegvaliase during 
the study and have post-treatment blood Phe concentration measurements. 
The PK population will consist of all subjects with at least 1 PK measurement. 
Safety Analysis: All subjects who receive any amount of pegvaliase in this study will be included in 
the safety analyses. All AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of AEs will be summarized by system organ class, preferred term, 
relationship to study drug, and severity. A by-subject listing will be provided for those subjects who 
experience a serious AE (SAE), including death, or experience an AE associated with early 
withdrawal from the study or study drug. Hypersensitivity AEs and AEs that result in dosing 
interruption or dose level reduction and the percentage of subjects who report these AEs will be 
presented.  
Other Safety Variables: Clinical laboratory data will be summarized by the type of laboratory test. 
Frequency and percentage of subjects who experience abnormal (ie, outside of reference range) 
and/or clinically significant abnormalities after pegvaliase administration will be presented for each 
clinical laboratory test. For each clinical laboratory test, descriptive statistics will be provided for 
baseline and all subsequent visits. Changes from baseline to the post-baseline visits will also be 
provided. Descriptive statistics for vital signs, physical examination results, electrocardiogram 
(ECG) test results, and immunogenicity test results will also be provided. Additionally, antibody 
incidences and titers will be summarized at the scheduled time point. 
Efficacy Analysis: Data from all subjects who receive any amount of pegvaliase and who have any 
post-treatment efficacy data will be included in the efficacy analysis. 
Blood Phe concentration at each scheduled time point will be summarized using descriptive 
statistics (mean, standard deviation, median, minimum, and maximum). Change in blood Phe 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
pegvaliase (formerly BMN 165) 
NAME OF ACTIVE INGREDIENT: 
Recombinant Anabaena variabilis 
phenylalanine ammonia lyase (rAvPAL) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
Volume: 
Page:  
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
concentration from baseline (to be defined in the Statistical Analysis Plan [SAP]) to each scheduled 
time point will also be summarized. 
The relationship between dietary Phe and protein intake (per information reported on the subject 
diet diary) and blood Phe concentration will also be explored. 
Pharmacokinetics Analyses: Trough concentrations of pegvaliase will be evaluated to assess 
steady-state trough exposure. Pegvaliase trough concentrations will be summarized descriptively by 
study visit. 
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3 TABLE OF CONTENTS 
1 
TITLE PAGE...………………………………………………..………………………1 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY ............................................2 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS ...................................................................................................13 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................18 
5 ETHICS..............................................................................................................................21 
5.1 Institutional Review Board or Independent Ethics Committee ................................21 
5.2 Ethical Conduct of Study ..........................................................................................22 
5.3 Subject Information and Informed Consent ..............................................................22 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................24 
7 INTRODUCTION .............................................................................................................25 
7.1 Nonclinical Studies ...................................................................................................26 
7.1.1 
Pharmacology ..............................................................................................27 
7.1.2 
Pharmacokinetics .........................................................................................27 
7.1.3 
Toxicology ...................................................................................................27 
7.1.3.1 
Safety Factors for the Phase 3 Starting Dose Based on the 
Chronic Nonclinical NOAELs .....................................................28 
7.2 Previous Clinical Studies ..........................................................................................28 
7.3 Study Rationale .........................................................................................................29 
7.4 Summary of Overall Risks and Benefits ...................................................................29 
7.4.1 
Analysis of Condition ..................................................................................29 
7.4.2 
Unmet Medical Need and Current Treatment Options ...............................30 
7.4.3 
Clinical Benefit ............................................................................................31 
7.4.4 
Risk ..............................................................................................................33 
7.4.5 
Benefit-Risk Conclusions ............................................................................34 
8 STUDY OBJECTIVES ......................................................................................................36 
9 INVESTIGATIONAL PLAN ............................................................................................37 
9.1 Overall Study Design and Plan .................................................................................37 
9.1.1 
Response to Hypersensitivity Adverse Events ............................................42 
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9.1.1.1 
Individual Stopping Criteria ........................................................42 
9.1.1.2 
Dosing in Response to Hypersensitivity Adverse Events ............42 
9.1.1.3 
Response to Anaphylaxis .............................................................44 
9.1.2 
Study Stopping Criteria for Adverse Events during Treatment with 
Pegvaliase ....................................................................................................45 
9.2 Discussion of Study Design, Including Choice of Control Group ............................45 
9.3 Selection of Study Population ...................................................................................45 
9.3.1 
Inclusion Criteria .........................................................................................46 
9.3.2 
Exclusion Criteria ........................................................................................47 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................47 
9.3.4 
Subject Identification and Replacement of Subjects ...................................49 
9.3.5 
Duration of Subject Participation ................................................................49 
9.4 Treatments .................................................................................................................49 
9.4.1 
Treatments Administered ............................................................................49 
9.4.2 
Identity of Investigational Product ..............................................................49 
9.4.2.1 
Product Characteristics and Labeling ..........................................49 
9.4.3 
Storage .........................................................................................................49 
9.4.4 
Directions for Administration .....................................................................50 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................51 
9.4.6 
Selection of Doses Used in the Study .........................................................51 
9.4.6.1 
Selection of Timing of Dose for Each Subject ............................51 
9.4.7 
Blinding .......................................................................................................51 
9.4.8 
Prior and Concomitant Medication .............................................................51 
9.4.9 
Treatment Compliance ................................................................................52 
9.5 Investigational Product Accountability .....................................................................52 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................52 
9.6 Dietary or Other Protocol Restrictions......................................................................52 
9.7 Efficacy and Safety Variables ...................................................................................54 
9.7.1 
Efficacy and Safety Measurements Assessed .............................................54 
9.7.2 
Primary Efficacy Variable ...........................................................................54 
9.7.3 
Secondary Efficacy Variables .....................................................................54 
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9.7.3.1 
Dietary Protein Intake ..................................................................54 
9.7.3.2 
Pharmacokinetics and Pharmacodynamics ..................................54 
9.7.4 
Exploratory Sample Analyses .....................................................................55 
9.7.5 
Safety Variables ..........................................................................................55 
9.7.5.1 
Adverse Events ............................................................................55 
9.7.5.2 
Clinical Laboratory Assessments .................................................55 
9.7.5.3 
Vital Signs, Physical Examinations, and Other 
Observations Related to Safety ....................................................57 
9.7.5.4 
Pregnancy Testing ........................................................................58 
10 REPORTING ADVERSE EVENTS .................................................................................59 
10.1 Safety Parameters and Definitions ............................................................................59 
10.1.1 Adverse Events ............................................................................................59 
10.1.2 Serious Adverse Events ...............................................................................59 
10.1.3 Adverse Events of Special Interest (AESI) .................................................60 
10.2 Methods and Timing for Capturing and Assessing Safety Parameters .....................60 
10.2.1 Adverse Event Reporting Period .................................................................60 
10.2.2 Eliciting Adverse Events .............................................................................60 
10.2.3 Assessment of Seriousness, Severity, and Causality ...................................61 
10.2.3.1 
Seriousness ...................................................................................61 
10.2.3.2 
Severity ........................................................................................61 
10.2.3.3 
Causality ......................................................................................62 
10.3 Procedures for Recording Adverse Events ...............................................................63 
10.3.1 Recording Adverse Events on an eCRF ......................................................63 
10.3.1.1 
Diagnosis versus Signs and Symptoms........................................63 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events ...............63 
10.3.1.3 
Persistent or Recurrent Adverse Events .......................................63 
10.3.1.4 
Abnormal Laboratory Values ......................................................64 
10.3.1.5 
Pre-existing Conditions ................................................................64 
10.3.1.6 
General Physical Examination Findings ......................................65 
10.3.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery ..............65 
10.3.1.8 
Deaths ..........................................................................................65 
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10.3.1.9 
Pregnancy .....................................................................................65 
10.4 Reporting Requirements ...........................................................................................66 
10.4.1 Expedited Reporting Requirements .............................................................66 
10.4.2 IRB Reporting Requirements ......................................................................66 
10.5 Follow-up of Subjects after Adverse Events .............................................................67 
10.6 Post-Study Adverse Events .......................................................................................67 
10. BioMarin Pharmacovigilance Contact Information ..................................................67 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................69 
11.1 Blood Phe Concentration ..........................................................................................69 
11.2 Safety and Pharmacokinetics ....................................................................................69 
11.3 Diet Diary ..................................................................................................................69 
12 STUDY PROCEDURES ...................................................................................................70 
12.1 Pre-Study ...................................................................................................................70 
12.2 Screening Visit/Week 1, Day 1 (Days -28 to Day 1) ................................................70 
12.3 On Study Treatment and Assessments ......................................................................71 
12.3.1 Week 9 (Day 57) and Every 8 Weeks Thereafter (± 7 Days) .....................71 
12.3.2 Weekly Contacts (Week 2 Until Study Completion) ..................................72 
12.4 Hypersensitivity Reaction Visit ................................................................................72 
12.5 Study Completion or Early Termination Visit ..........................................................73 
13 DATA QUALITY ASSURANCE .....................................................................................75 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................76 
14.1 Procedures for Accounting for Missing, Unused, and Spurious Data ......................76 
14.2 Safety Analysis .........................................................................................................76 
14.2.1 Adverse Events ............................................................................................76 
14.2.2 Other Safety Variables ................................................................................76 
14.3 Primary Efficacy Analysis ........................................................................................77 
14.4 Secondary Efficacy Analysis ....................................................................................77 
14.5 Pharmacokinetics Analyses .......................................................................................77 
14.6 Determination of Sample Size ..................................................................................77 
14.7 Analysis Populations .................................................................................................77 
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................77 
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15 DATA MONITORING COMMITTEE .............................................................................79 
16 COMPENSATION, INSURANCE AND INDEMNITY ..................................................80 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................81 
18 STUDY MONITORING AND AUDITING .....................................................................83 
19 RETENTION OF RECORDS ...........................................................................................84 
20 USE OF INFORMATION AND PUBLICATION ...........................................................85 
21 REFERENCES ..................................................................................................................86 
22 INVESTIGATOR RESPONSIBILITIES ..........................................................................88 
22.1 Conduct of Study and Protection of Human Subjects...............................................88 
23 SIGNATURE PAGE .........................................................................................................89 
24 PROTOCOL AMENDMENT TEXT REVISIONS ..........................................................90 
 
LIST OF TABLES 
Table 9.1.1:  165-304 Schedule of Events ...............................................................................40 
Table 9.1.1.2.1:  Dosing after Hypersensitivity Adverse Event ..............................................43 
Table 9.1.1.3.1:  Dosing after Anaphylaxis Event ...................................................................44 
Table 9.1.2.1:  Severity Criteria (Brown, 2004) ......................................................................45 
Table 9.7.5.2.1:  Clinical Laboratory Tests .............................................................................56 
Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................61 
Table 10.2.3.3.1:  Categories Describing Relationship of Adverse Events to Study 
Drug ...............................................................................................................62 
 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACMG 
American College of Medical Genetics and Genomics 
ADHD-RS 
Attention Deficit Hyperactivity Disorder Rating Scale 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BH4 
tetrahydrobiopterin 
BPV 
BioMarin Pharmacovigilance 
C3 
complement component 3 
C4 
complement component 4 
CFR 
Code of Federal Regulations 
CIC 
circulating immune complex 
Cmax 
maximum observed plasma concentration 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRO 
contract research organization  
CRP 
C-reactive protein 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DSM 
American Psychiatric Association: Diagnostic and Statistical Manual of 
Mental Disorders 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ENU2 
BTBRPahenu2 mouse model 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAE 
hypersensitivity adverse event 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRV 
Hypersensitivity Reaction Visit 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgE 
immunoglobulin E 
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IgG 
immunoglobulin G 
IgG4 
immunoglobulin G4 
IgM 
immunoglobulin M 
IP 
investigational product 
IND 
investigational new drug 
IRB 
Institutional Review Board 
I/T/M 
induction and gradual up-titration to maintenance dosing regimen 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNT 
medical nutritional therapy 
NCI 
National Cancer Institute 
NIAID/FAAN 
National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network 
NIH 
National Institutes of Health 
NOAEL 
no observable adverse effect level 
NSAID 
non-steroidal anti-inflammatory medication 
PAH 
phenylalanine hydroxylase 
PAL 
phenylalanine ammonia lyase 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
Phe 
phenylalanine 
PK 
pharmacokinetics 
PKU 
phenylketonuria 
PKUDOS 
PKU Demographics, Outcomes and Safety 
rAvPAL-PEG 
recombinant Anabaena variabilis phenylalanine ammonia lyase-PEG 
RDA 
recommended dietary allowance 
RDT 
Randomization Discontinuation Treatment  
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SDV 
source data verified 
SGOT 
serum glutamic oxalo-acetic transaminase 
SGPT 
serum glutamic pyruvate transaminase 
SOI 
Statement of Investigator  
SpO2 
blood oxygen saturation 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
elimination half-life 
Tmax 
time to maximum concentration 
US 
United States 
 
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Definition of Terms:  
Investigational Product (IP): 
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation [ICH] of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6 R2]).  
The terms “IP”, “study drug”, and “pegvaliase” are used interchangeably in the protocol. 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist investigators with access to timely and accurate information and with 
assurance of prompt resolution of any queries. 
Prior to initiating the study, the investigator will obtain written confirmation that the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws, and local regulations. A copy of the confirmation from the IRB/EC/REB 
will be provided to BioMarin Pharmaceutical Inc. (BioMarin) or its designee. The 
investigator will provide the IRB/EC/REB with all appropriate material, including the 
protocol, Investigator’s Brochure (IB), the Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the subjects, 
including all ICFs translated for subjects who do not speak the local language at the clinical 
site. The study will not be initiated and investigational product (IP) supplies will not be 
shipped to the site until appropriate documents from the IRB/EC/REB confirming 
unconditional approval of the protocol, the ICF, and all subject recruitment materials are 
obtained in writing by the investigator and copies are received at BioMarin or its designee. 
The approval document should refer to the study by protocol title and BioMarin protocol 
number (if possible), identify the documents reviewed, and include the date of the review and 
approval. BioMarin will ensure that the appropriate reports on the progress of the study are 
made to the IRB/EC/REB and BioMarin by the investigator in accordance with applicable 
guidance documents and governmental regulations. 
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5.2 
Ethical Conduct of Study 
It is expected that investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to adverse event (AE) reporting, diagnostic, 
or other procedures as specified in the protocol; and assuring appropriate compliance with 
study treatment administration and accountability. 
This study will be conducted in accordance with the following: 
x European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
x US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
x ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6(R2) 
(ICH E6 R2) 
x The ethical principles established by the Declaration of Helsinki 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/EC and will be conducted by scientifically and medically qualified persons. The benefits 
of the study are in proportion to the risks. The rights and welfare of the subjects will be 
respected and the investigators conducting the study do not find the hazards to outweigh the 
potential benefits. Each subject, or his/her legally authorized representative, will provide 
written, informed consent before any study-related tests or evaluations are performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed informed consent form (ICF), in compliance with 
ICH E6 R2 (Section 4.8), United States Code of Federal Regulations (CFR) 21 CFR §50, 
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, and other applicable local regulations, will be obtained for each subject prior to 
entering the subject into the study. The investigator will prepare the ICF and provide the 
documents to BioMarin for approval prior to submission to the IRB/EC/REB approval. 
BioMarin and the IRB/EC/REB must approve the documents before they are implemented. 
A copy of the approved ICF and, if applicable, a copy of the approved subject information 
sheet and all ICFs translated to a language other than the native language of the clinical site 
must also be received by BioMarin or designee prior to any study-specific procedures being 
performed. 
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A subject with a legally authorized representative will provide written assent (if required), 
and his/her legally authorized representative (parent or legal guardian) will provide written 
informed consent. The investigator will provide copies of the signed ICF to each subject 
(or the legally authorized representative of the subject) and will maintain the original in the 
record file of the subject. 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Subjects who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the investigator at each site must provide to BioMarin or 
designee a fully executed and signed Statement of Investigator (SOI) form. A US Food and 
Drug Administration (FDA) Form FDA 1572 serves as an acceptable SOI form. If 
Form FDA 1572 may not be used in a particular region, the investigator must provide a fully 
executed SOI on the form provided by the sponsor. All investigators and sub-investigators 
must be listed on Form FDA 1572 or its equivalent SOI. Financial Disclosure Forms must 
also be completed for all investigators and sub-investigators listed on Form FDA 1572 or the 
SOI who will be directly involved in the treatment or evaluation of subjects in this study. 
The study will be administered and monitored by employees or representatives of BioMarin. 
Clinical research associates (CRAs) or trained designees will monitor each site on a periodic 
basis and perform verification of source documentation for each subject as well as other 
required review processes. BioMarin’s Pharmacovigilance Department (or designee) will be 
responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a coordinating investigator will be identified who will be responsible 
for study overview. The coordinating investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The coordinating investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the coordinating investigator and a list of all 
investigators participating in the study will be provided in the CSR. 
Home healthcare may be administered by a vendor that is provided by the sponsor or a study 
site. Training and oversight of home healthcare personnel will be provided by the sponsor. 
Pharmacokinetic tests and antibody tests will be performed by BioMarin or a contract 
research organization (CRO). Clinical laboratory tests will be analyzed and processed by a 
central laboratory, with the exception of urine pregnancy tests, which will be analyzed by a 
local laboratory. A central laboratory will also be used to perform analysis of blood 
phenylalanine (Phe) concentrations. 
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7 
INTRODUCTION 
Phenylketonuria (PKU, OMIM 261600) is a rare autosomal recessive genetic disorder that is 
characterized by an inability of the body to break down the amino acid, phenylalanine (Phe), 
and is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). The 
estimated prevalence of PKU is 1 in 15,000 births in the United States (NIHCDP, 2001). 
PAH catalyzes the conversion of the essential amino acid phenylalanine (Phe) to tyrosine, 
and this enzymatic activity is facilitated by tetrahydrobiopterin (BH4). PAH deficiency 
results in abnormally elevated concentrations of Phe. 
The pathophysiology of PKU is well understood. A substantial body of evidence confirms 
that elevated Phe is directly toxic to cells in the brain, where it causes inhibition of protein 
synthesis in humans and animals (Wall, 1990), affects the normal morphology of myelinating 
proteins (Dyer, 1996), and leads to arrested or delayed development of dendrites and 
synapses in the cerebral cortex (Huttenlocher, 2000). Neuropathology in PKU has been 
shown to derive from oxidative stress, impaired neurotransmitter metabolism, impaired 
protein synthesis and lipid metabolism, and brain energy metabolism alterations 
(Schuck, 2015). The neurotoxicity of elevated Phe is a direct effect of Phe itself 
(Kaufman, 1989); no abnormal Phe metabolites are observed in the PKU individual and 
normal Phe metabolites are toxic only at concentrations that are much higher than those 
reported in individuals with PKU. 
Without highly restricted Phe intake, individuals with PKU quickly reach and sustain toxic 
concentrations of blood Phe. Individuals with classic PKU may have a complete absence or 
profound deficiency of PAH and typically show very high elevations of blood Phe 
 1200 μmol/L). Uncontrolled blood Phe in adults is associated with executive dysfunction 
and significant behavioral and psychiatric problems, including depression and anxiety, and 
results in a negative impact on patient quality of life (Moyle, 2007; Pietz, 1997; Smith, 2000; 
Waisbren, 1999; Gassio, 2003). High blood Phe levels negatively affect mood and ability to 
sustain attention in adults with PKU (ten Hoedt, 2011). Studies have reported widespread 
correlations between improved cognitive performance in adults with PKU and control of 
blood Phe during their life span (Palermo, 2017; Romani, 2017). The prevalence of 
psychiatric and neurologic symptoms in adults with PKU is higher than the US National 
Institutes of Health estimates for disease prevalence in adults in the general population 
(NIMH, 2013). 
The American College of Medical Genetics and Genomics (ACMG) practice guidelines for 
PKU recommend life-long management and maintenance of metabolic control as essential to 
optimal functioning of individuals with PKU, with a goal of maintaining blood Phe 
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cRQFHQWUDWLRQVPRO/Vockley, 2014). Similar European guidelines for the 
PDQDJHPHQWRI3.8UHFRPPHQGWUHDWPHQWWDUJHW3KHOHYHOVRIPRO/IRUSDWLHQWV
older than 12 years (van Spronsen, 2017). 
Historically the only treatment option available for patients with PKU was medical 
nutritional therapy (MNT) with severe restriction of Phe intake, alone or as adjunct to 
Kuvan® (sapropterin 6R-tetrahydrobiopterin or 6R-BH4). Phe restriction with MNT involves 
consumption of semisynthetic medical foods that provide a source of Phe-free protein, 
modified low-protein foods, small amount of natural protein (to provide required amounts of 
Phe), and other supplements (eg, vitamins, minerals) to correct nutritional deficiencies that 
can result from Phe restriction. MNT with severe Phe restriction can help some patients 
control their blood Phe levels, although data show that even when PKU patients report 
adherence with MNT, many patients continue to have very high blood Phe levels of 
approximately 926 μmol/L (Koch, 2002), demonstrating that MNT is not an effective 
treatment option for many adults with PKU. For the majority of adults with PKU, chronic 
MNT with Phe restriction is not sustainable nor feasible as a treatment option (Walter, 2002; 
Burton, 2010).  
BioMarin has developed pegvaliase, a genetically modified phenylalanine ammonia lyase 
(PAL) enzyme product of the cyanobacterium Anabaena variabilis that is PEGylated to 
decrease immunogenicity and increase half-life, as a novel treatment for PKU.  
A brief review of pegvaliase (also referred to as rAvPAL-PEG or BMN 165) is provided 
below. A comprehensive review of pegvaliase is contained in the Investigator’s Brochure 
supplied by BioMarin. Investigators are to review this document prior to initiating this study. 
7.1 
Nonclinical Studies 
The nonclinical program was specifically designed to support the chronic use of pegvaliase 
for PKU patients 16 years of age and older. The studies completed were comprehensive and 
included single and repeat-dose pharmacodynamic (PD), safety pharmacology, toxicokinetic 
and toxicity evaluations in ENU2 mice, and normal rats and monkeys. Developmental and 
reproductive toxicity studies were conducted in rats and rabbits. The pharmacological 
activity of pegvaliase was demonstrated in a rodent model of PKU, the ENU2 mouse. ENU2 
mice exhibit hyperphenylalaninemia similar to PKU patients and were utilized to help 
determine initial dose levels of pegvaliase for clinical trials. All nonclinical studies used the 
subcutaneous (SC) route of administration, and the results from these studies were used to 
inform the starting clinical dose of pegvaliase. 
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7.1.1 Pharmacology 
Pharmacology was assessed in the BTBR Pahenu2 (ENU2) mouse model of PKU. The ENU2 
mouse model exhibits characteristics similar to those of PKU patients, including 
hyperphenylalaninemia (baseline plasma Phe concentrations of 1000 to 2000 PM) and 
hypopigmentation. The repeat-dose studies in the BTBRPahenu2 mouse demonstrated the 
pegvaliase-related pharmacological activity resulting in decreased plasma Phe levels. There 
were no pegvaliase-related effects on respiratory or central nervous system parameters after a 
single SC administration to rats or cardiovascular parameters after a single SC administration 
to monkeys. 
7.1.2 Pharmacokinetics 
The pharmacokinetics (PK) of pegvaliase in rats, rabbits, and monkeys were similar to 
humans with respect to a 1-compartment model with 1st order absorption and elimination. 
Time to maximum concentration (Tmax) and elimination half-life (t1/2) were 1 to 3 days, and 
there was evidence of accumulation in all species. AUC and maximum observed plasma 
concentration (Cmax) were approximately dose proportional, with a high inter-animal 
variability in pegvaliase plasma levels at a given dose. Pegvaliase exposure decreased with 
multiple dosing, likely attributable to anti-drug antibody responses; exposures returned to 
levels comparable to Week 1 after Week 4 in the rat. Inter-animal variability in anti-drug 
antibody response and accumulation were high after repeat pegvaliase administration. 
7.1.3 Toxicology 
The nonclinical safety program for pegvaliase included single-dose and repeat-dose toxicity 
studies in rats and monkeys in order to characterize the potential toxicity and exaggerated 
pharmacology of pegvaliase. Developmental and reproductive toxicity studies were also 
conducted in rats and rabbits. The studies included toxicological endpoints as well as 
toxicokinetic and immunogenicity parameters. Plasma Phe levels were also assessed as a 
primary PD endpoint. The main pegvaliase safety-related findings identified from nonclinical 
studies were: (1) dose-dependent polyethylene glycol (PEG)-related findings, including 
vacuolation of renal tubule cells and histiocytic cells, in the repeat-dose rat toxicity studies, 
(2) dose-dependent, pegvaliase-related arterial inflammation in small arteries and arterioles 
in cynomolgus monkeys, and (3) dose-dependent reductions in body weight gain and 
maternal and fetal toxicity attributed to sustained reduction of Phe levels to below normal in 
wild-type animals. These findings were dose and time dependent, and resolved or partially 
resolved after a recovery period. The identified hazards from the nonclinical studies helped 
inform safety monitoring in clinical trials with pegvaliase. 
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7.1.3.1 
Safety Factors for the Phase 3 Starting Dose Based on the Chronic 
Nonclinical NOAELs 
Safety factors were derived from no observable adverse effect level (NOAEL) PK data 
obtained following the first SC dose in the 26-week rat and 39-week monkey studies and the 
first 2.5 mg (0.03 mg/kg) SC dose in the Phase 1 (PAL-001) clinical study. The predicted 
Cmax and AUC0-inf in humans at the Phase 3 starting dose level of 2.5 mg/week in naïve 
patients are, respectively, 298 ng/mL (Cmax) and 50,658 ng-hr/mL (AUC0-inf). A challenge 
with the safety factor determination was the high variability in exposure following repeat 
dosing in both animals and humans, believed to be due to the generation of anti-drug 
antibodies that bind to and rapidly reduce pegvaliase exposure. This initial reduction 
followed by a later increase in exposure has made obtaining a robust steady-state plasma 
drug level challenging. A conservative method was used to estimate the safety factors using 
PK data following the first dose (up to 72 hours post-dose), where anti-drug antibody effect 
was negligible, and plasma drug levels were high. 
Given the nonclinical PK data and expected Phase 3 exposure in humans based on PAL-001, 
safety factors calculated for peak exposure (Cmax) are 4.4-fold and 78.6-fold higher than 
anticipated human exposure based on rat and monkey data, respectively. On a systemic 
exposure basis, safety factors calculated from AUC0-72hr are 1.3-fold (rat) and 18.3-fold 
(monkey) higher than anticipated human exposure. 
7.2 
Previous Clinical Studies 
The pegvaliase clinical development program has included 8 clinical studies, representing the 
largest development program conducted to date in adults with PKU: a single-dose Phase 1 
study (PAL-001); 3 multi-dose Phase 2 studies (PAL-002, PAL-004, and 165-205) that were 
followed by the Phase 2 long-term open-label study (PAL-003); and 3 Phase 3 studies 
(165-301, 165-302, and the 165-302 substudy 165-303). The Phase 2 long-term open-label 
study PAL-003 and Part 4 open-label extension of Phase 3 Study 165-302 are ongoing to 
assess long-term efficacy and safety. 
Pegvaliase clinical studies included adult patients with a PKU diagnosis and blood Phe 
concentration > 600 μmol/L at screening and over the past 6 months. Baseline characteristics 
and demographics demonstrate that the studied population in pegvaliase clinical trials is 
representative of the general adult PKU population, including the high mean blood Phe 
values demonstrating significant need for effective treatment options to control blood Phe. 
Results from these studies have shown that pegvaliase is well tolerated and reduces blood 
Phe levels. Refer to the Investigator’s Brochure for detailed results from previous clinical 
studies. 
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7.3 
Study Rationale 
Study 165-304 is an open-label extension for subjects who participated in Studies PAL-003 
and 165-302 at doses > 40 mg/day. The objective is to evaluate long-term safety and efficacy 
in subjects treated at doses exceeding the currently approved pegvaliase label (the label 
specifies up to and including 40 mg/day dose only). 
Literature reports suggest the majority of adults with PKU cannot adhere to severe Phe intake 
restrictions (Cunningham, 2012). Even among adults reporting to adhere to severe Phe intake 
restrictions, the majority fail to maintain recommended blood Phe levels 
(Modan-Moses, 2007). Baseline blood Phe levels and diet from previous pegvaliase clinical 
studies confirm this finding among adult participants. Adults with PKU with poor metabolic 
control represent a patient population in great need of additional therapeutic options. 
7.4 
Summary of Overall Risks and Benefits 
7.4.1 Analysis of Condition 
Phenylketonuria is a serious inherited metabolic disorder in which Phe accumulates to 
abnormally high levels in the blood and brain, resulting in significant negative effects on 
neurocognitive, neuropsychological, and executive function performance in adults with PKU. 
Phenylketonuria is estimated to occur in 1 in 15,000 newborns in the United States. As a 
result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all 
individuals with PKU or PAH deficiency under the age of 40 are diagnosed at birth and 
treatment is implemented soon thereafter. 
Adult PKU patients often have untreated blood Phe levels > ȝPRO/+LVWRULFDOO\WKHUH
were 2 treatment options available for patients with PKU: medical nutritional therapy (MNT) 
with Phe restriction, and sapropterin dihydrochloride (Kuvan) as adjunct to MNT and Phe 
restriction. Most PKU patients require lifelong stringent Phe restriction and MNT to control 
blood Phe levels and to help prevent complications associated with high Phe levels in the 
brain. 
Uncontrolled blood Phe in adulthood is associated with impairment of neuropsychiatric, 
neurocognitive, and executive function, a heterogeneous variety of behavioral and psychiatric 
problems including depression and anxiety, and negatively affects patient quality of life 
(Moyle, 2007; Pietz, 1997; Smith, 2000; Waisbren, 1999; Gassio, 2003). High blood Phe 
levels also negatively affect mood and the ability to sustain attention in adults with PKU 
(ten Hoedt, 2011). Several interventional studies of restricted Phe intake to control blood Phe 
in adult PKU patients have shown improvements on neuropsychiatric and executive function 
domains when subjects are at lower blood Phe levels (Bilder, 2016). These findings suggest 
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that neuropsychiatric and executive functioning deficits are reversible in adults with PKU. 
Other recently published studies have reported widespread correlations between cognitive 
performance in adults with PKU and control of Phe during their lifespan, suggesting that it is 
important to maintain low blood Phe through life in order to provide optimal neurocognitive 
function (Palermo, 2017; Romani, 2017). 
The American College of Medical Genetics and Genomics (ACMG) practice guidelines 
recommend lifelong management of PKU, with a goal of maintaining blood Phe 
concentrations PRO/Vockley, 2014). Similar European guidelines for the 
PDQDJHPHQWRI3.8UHFRPPHQGWUHDWPHQWWDUJHW3KHOHYHOVRIPRO/IRUSDWLHQWV
older than 12 years of age (van Spronsen, 2017). 
7.4.2 Unmet Medical Need and Current Treatment Options 
There is a significant unmet need for patients with PKU because lifelong control of blood 
Phe levels with Phe restriction and MNT alone is unachievable for most patients, and 
addition of Kuvan to treatment is only effective in a sub-population of patients with less 
severe PKU (Blau, 2015). 
Medical Nutritional Therapy (MNT) 
Although strict adherence to Phe restriction and MNT can be effective in lowering blood Phe 
levels and preventing the severe neurological consequences of high blood Phe levels, most 
adult PKU patients are unable to maintain target blood Phe levels with restriction in protein 
intake alone, as lifelong restriction of natural protein and adherence to MNT imposes such a 
personal and social burden that it becomes practically impossible to sustain for the vast 
majority of subjects. For the majority of adults with PKU, chronic MNT with Phe restrictions 
is not sustainable nor feasible as a treatment option as most foods contain protein 
(Walter, 2002; Burton, 2010). In a study monitoring adherence to a loZ3KHGLHWRIWKH
adult PKU population were not maintaining nutritional low-Phe restrictions (Walter, 2002). 
The stringent MNT with onerous Phe-restriction proscribes consumption of natural protein 
such as meat, fish, chicken, eggs, nuts, beans, milk, and other dairy products as well as many 
higher protein grains and starches, thus significantly limiting food choices. In addition, PKU 
patients require concomitant administration of unpalatable synthetic Phe-free amino acid 
supplements to ensure adequate nutritional intake of protein. The stringent MNT has been 
found to cause nutritional deficiencies (eg, in vitamin B12 and other B vitamins, vitamin D, 
folate, calcium, and iron with associated health consequences), as well as social isolation 
related to the important role of food in our social interactions, the time burden of planning, 
assessing, calculating, and recording food intake, and the very limited number of natural 
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foods that can be eaten (MacDonald, 2016). PKU patients also suffer the impact of 
significant risk factors for non-PKU morbidity related to MNT, such as obesity, bone disease 
and dietary deficiencies, which result from a lifetime of attempted and increasingly 
unachievable control of Phe intake. 
In addition, chronically elevated blood Phe levels can, by compromising the neurocognitive 
functions needed to maintain adherence to MNT, potentially create a negative cycle of 
worsening disease control. Tasks such as monitoring dietary Phe intake, menu planning, 
avoiding prohibited foods, remembering to order MNT and low protein foods, and attending 
clinical appointments and routine blood testing visits may all be compromised by the effects 
of chronically elevated blood Phe levels. 
Sapropterin Dihydrochloride (Kuvan) 
Sapropterin dihydrochloride (Kuvan) is a synthetic oral formulation of BH4, which works by 
increasing PAH activity in PKU patients with some residual enzyme function (Blau, 2015). 
Kuvan is an approved pharmacological treatment for children and adults for the treatment of 
BH4-responsive PKU in the US. Approval of Kuvan was based on demonstrating blood Phe 
reduction in clinical trials and is indicated for use in conjunction with Phe-restricted intake to 
ORZHUEORRG3KHFRQFHQWUDWLRQV+RZHYHURQO\DSSUR[LPDWHO\WRRI3.8SDWLHQWV
respond to sapropterin therapy.  
Pegvaliase (Palynziq®) 
Pegvaliase was approved in the United States on 24 May 2018 under the name Palynziq for 
maintenance dosages up to 40 mg/day to reduce blood Phe concentrations in adult patients 
with PKU who have uncontrolled blood Phe concentrations  > 600 μmol/L on existing 
management, addressing a substantial unmet medical need for the adult PKU patient 
population. On 3 May 2019, pegvaliase was also approved in the EU to reduce blood Phe in 
patients with PKU aged 16 years and older who have inadequate blood Phe control (defined 
DVEORRG3KHOHYHOVJUHDWHUWKDQȝPRO/GHVSLWHSULRUPDQDJHPHQWZLWKDYDLODEOH
treatment options. 
7.4.3 Clinical Benefit 
Treatment of PKU by replacement of the PAH enzyme is not technically feasible because of 
its poor stability and the requirement for sapropterin co-factor co-generation, which only 
occurs in hepatocytes. Therefore, a search was undertaken for a BH4 independent enzyme 
that would be active in plasma. 
Substantial Reduction in Blood Phenylalanine 
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Phase 3 placebo-controlled and Phase 2 and Phase 3 long-term extension studies of 
pegvaliase for the treatment of adult subjects with PKU have shown evidence of blood Phe 
lowering effectiveness in adults with PKU with uncontrolled blood Phe > 600 ȝPRO/ZLWK
existing treatment. Substantial and sustained blood Phe reductions were observed throughout 
the pegvaliase clinical program. 
The first phase 3 study (165-301) characterized the safety and tolerability of the 
recommended low dose induction and gradual up-titration to maintenance (I/T/M) dosing 
regimen to a target dose of pegvaliase 20 mg or 40 mg/day of self-administered SC 
injections, using either a vial and syringe presentation or the proposed prefilled syringe (PFS) 
marketing presentation, to achieve a stable, pre-VSHFLILHGUHGXFWLRQLQEORRG3KHRI 
from pre-treatment baseline prior entry to the Randomization Discontinuation Treatment 
(RDT) phase (Part 2) of pivotal study 165-6XEMHFWVZKRDFKLHYHG EORRG3KH
reduction entered the RDT and were randomized to either continue pegvaliase treatment or 
start placebo for 8 weeks. 
Subjects enrolled in 165-301 had a mean blood Phe level of ~1200 μmol/L at pre-treatment 
baseline, suggesting poor metabolic control. In the 8-week RDT portion of 165-302, 
pegvaliase-treated subjects maintained mean blood Phe levels at 527.2 μmol/L compared to 
their RDT baseline of 503.9 μmol/L. In the placebo-treated group, mean blood Phe levels 
increased to 1385.7 μmol/L compared to their RDT baseline of 536.0 μmol/L. Study 165-302 
met its primary endpoint of change in blood Phe compared to each placebo group (p < 
0.0001). This beneficial treatment HIIHFWUHSUHVHQWVDLPSURYHPHQWLQEORRG3KH
compared to placebo. 
Among subjects in the I/T/M Population (all dose levels) who completed 1 year of treatment, 
DFKLHYHGEORRG3KHUHGXFWLRQDFKLHYHGEORRG3KHUHGXFWLRQWR
 360 μmol/L, DQGDFKLHYHGEORRG3KHUHGXFWLRQWRPRO/ZLWKLQWKH\HDU
A higher proportion of subjects met lower Phe reduction thresholds by 24 months of 
WUHDWPHQWDFKLHYHGEORRG3KHUHGXFWLRQDFKLHYHGEORRG3KHUHGXFWLRQ
WR 360 μmol/DQGDFKLHYHGEORRG3KHUHGXFWLRQWR 120 μmol/L. These findings 
are clinically meaningful in the context of current ACMG management guidelines for the 
WUHDWPHQWRI3.8UHFRPPHQGLQJWKDWVHUXP3KHEHPDLQWDLQHGDWȝPRO/WKURXJKRXW
life for optimal clinical outcomes (Vockley, 2014).  
These substantial and sustained reductions in blood Phe were achieved in adult PKU patients 
WUHDWHGZLWKSHJYDOLDVHGHVSLWHDPDMRULW\RISDWLHQWV!QRWDGKHULQJWR017DW
baseline and consuming significant amounts of protein from natural foods (mean intake 
39 grams/day). Full Phe restriction for PKU patients typically allows minimal natural protein 
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intake outside of MNT, but a majority of the subjects in the pivotal study were estimated to 
EHHDWLQJDSSUR[LPDWHO\RIWKHGDLO\-recommended allowance for protein for a healthy 
adult as natural intact protein. 
7.4.4 Risk 
The safety of pegvaliase was evaluated in 6 multiple dose studies in adult PKU patients 
totaling 579.6 patient-years of exposure with the recommended I/T/M dosing regimen for 
pegvaliase, including 403.4 patient-years of exposure with the to-be-marketed PFS 
presentation. Thus, important identified and potential risks associated with pegvaliase use 
have been sufficiently characterized to inform benefit-risk decisions by adult PKU patients 
and their treating physicians. 
The most commonly reported treatment-HPHUJHQW$(VZHUHDUWKUDOJLDLQMHFWLRQVLWH
UHDFWLRQKHDGDFKHDQGLQMHFWLRQVLWHHU\WKHPD,QWKHI/T/M 
population K\SHUVHQVLWLYLW\DGYHUVHHYHQWV+$(VZHUHYHU\FRPPRQDQGLQFOXGHG
DUWKUDOJLDUDVK SUXULWXVXUWLFDULDS\UH[LDDQGLQMHFWLRQ
VLWHUDVK7KHKLJKHVW+$(VHYHULW\ZDV*UDGHIRURIVXEMHFWVRU*UDGHIRU
VXEMHFWV0RVW+$(VGLGQRWUHTXLUHSHJYDOLDVHGRVHPRGLILFDWLRQDQG
RI+$(s resolved. The mechanism of HAEs, including anaphylaxis, is Type III 
immune complex-mediated hypersensitivity, with the highest frequency of HAEs occurring 
during the first 6 months of pegvaliase dosing when early antibody responses – PEG IgM, 
PEG IgG and PAL IgM – and circulating immune complexes (CICs) are highest, and mean 
C3 and C4 complement levels are lowest. A reduction in the incidence and event rate of 
HAEs was observed after 6 months, as the anti-PEG IgG and IgM antibodies declined to 
baseline levels and CIC and C3/C4 levels returned towards baseline. 
Type III, non-IgE-mediated anaphylaxis was the most clinically important identified risk in 
the pegvaliase development program. An independent allergist/immunologist assessed that 
RIWKe I/T/M study population experienced signs/symptoms consistent with a 
clinical diagnosis of anaphylaxis based on published diagnostic criteria (Sampson, 2006); 
RIWKHDQDSK\OD[LVFDVHVZHUHDVVHVVHGDVVHYHUHEDVHGRQSXEOLVKHGVHYHULW\
grading criteria specific to generalized hypersensitivity (Brown, 2004).  
Signs and symptoms associated with anaphylaxis per sponsor’s assessment against National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
(NIAID/FAAN) criteria were reported with higher rates in the first year 
(0.06 events/person-year in first 6 months and 0.08 events/person-year in the second 
6 PRQWKVLQWKH,70VWXG\SRSXODWLRQ2IQRWHVXEMHFWVZKRH[SHULHQFHGDQ
initial anaphylaxis event continued pegvaliase treatment and 4 subjects did not have 
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recurrence of anaphylaxis. These observations and paucity of IgE detection support that the 
mechanism of anaphylaxis is Type III IC-mediated hypersensitivity rather than Type I 
hypersensitivity, which is associated with an immediate exaggerated response upon 
re-exposure to an allergen. 
The incidence of severe anaphylaxis was reduced with pre-medication prior to pegvaliase 
injections, and all occurrences of anaphylaxis were managed successfully and resolved 
without sequelae. 
While Type III HAEs and laboratory findings such as reduced complement levels have 
occurred with pegvaliase administration, there have been no reported events suggestive of 
pegvaliase induced ongoing immune complex-mediated end-organ damage. 
7.4.5 Benefit-Risk Conclusions 
Pegvaliase is a novel enzyme substitution therapy, indicated to reduce blood Phe in adult 
patients with PKU who have uncontrolled (> 600 μmol/L) blood Phe with existing 
management. A comprehensive clinical development program has demonstrated that 
prolonged exposure to pegvaliase is well tolerated and effective in reducing blood Phe 
concentration in adult patients with PKU. 
A majority of adult PKU subjects completed induction and titration and continued to the 
maintenance phase of pegvaliase treatment with daily self-administered SC injections of 
pegvaliase, and experienced substantial and sustained reductions in blood Phe levels to 
within recommended treatment guidelines for PKU management. Significant blood Phe 
reductions were achieved in subjects consuming nearly the daily recommended allowance for 
protein as intact protein from natural foods. In addition, blood Phe reduction was associated 
with improvements in neurocognitive benefit as evidenced by long-term data on 
neurocognitive endpoints like the Attention Deficit Hyperactivity Disorder Rating Scale 
(ADHD RS)-IV in open label extension. 
Type III, non-IgE-mediated anaphylaxis was the most clinically important identified risk in 
the pegvaliase development program, occurriQJLQRIWKH,70VWXG\SRSXODWLRQ
All occurrences of anaphylaxis were managed successfully with the safe use conditions 
implemented in the clinical studies. 
Pegvaliase treatment at doses up to 40 mg/day demonstrated a positive benefit-risk balance in 
adults with PKU, with long-term treatment at doses greater than 40 mg/day up to 60 mg/day 
dose, inclusive, to be further evaluated in the 165-304 open-label extension study. 
Pegvaliase can address an unmet medical need for adult PKU patients who have uncontrolled 
blood Phe despite the current treatment options of chronic stringent Phe restriction and 
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MNT with or without the addition of Kuvan treatment, and has the potential to have a 
meaningful impact on the lives of adult PKU patients. 
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8 
STUDY OBJECTIVES 
The primary objective of the study is: 
x To evaluate the long-term safety and efficacy of pegvaliase (> 40 mg/day dose) in 
adult patients with PKU 
The secondary objective of the study is: 
x To characterize dietary protein intake from medical food and from intact food during 
long-term treatment with pegvaliase (> 40 mg/day dose) in adult patients with PKU 
The exploratory objective of the study is: 
x To characterize the long-term immunogenicity profile of pegvaliase (> 40 mg/day 
dose) in adult patients with PKU 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a Phase 3 open-label extension study enrolling approximately 40 adult subjects with 
PKU who were previously treated with pegvaliase in Studies PAL-003 or 165-302. The study 
is designed to evaluate the long-term safety and efficacy of pegvaliase administered as 
prefilled syringe drug product at a dose of > 40 mg/day to 60 mg/day, inclusive. Dose 
regimens other than daily dosing at > 40 mg/day to 60 mg/day (with the exception of 
1 subject enrolled from the PAL-003 study who receives a pegvaliase dose not to exceed 
120 mg/day) may be allowed provided the investigator consults with the medical monitor and 
obtains approval from the medical monitor prior to starting the alternative regimen. Subjects 
will continue their prior pegvaliase dose regimen on the 165-304 study, including 1 subject 
enrolled from the PAL-003 study who receives a pegvaliase dose not to exceed 120 mg/day. 
A subject who dose reduces to a dose of 40 mg/day or lower for 32 consecutive weeks will 
be discontinued from study drug and withdrawn from the study as they will have the option 
to transition to commercial drug. Dose reductions may be performed if warranted due to AEs 
or hypophenylalaninemia. Dose increases to up to 60 mg/day may be performed per 
investigator discretion in consultation with the sponsor’s medical monitor. Dosing will 
continue for approximately 121 weeks. 
After providing informed consent, subjects undergo screening evaluations to determine study 
eligibility. Screening assessments must be performed within 28 days of the first 165-304 dose 
of pegvaliase on Day 1. Study PAL-003 or 165-302 Study Completion Visit assessments may 
be used for the purpose of screening, with Day 1 of 165-304 taking place the same day. 
Pegvaliase dosing should continue without interruption from the previous study; beginning 
on Day 1, subjects will receive the same dose and regimen of pegvaliase they were receiving 
in 165-302 or PAL-003. Subsequent revisions to dosing regimens are allowed following 
consultation with the medical monitor. Subjects on temporary pegvaliase hold due to 
pregnancy planning in PAL-003 or 165-302 (and who received pegvaliase doses > 40 mg/day 
dose and up to 60 mg/day dose, inclusive) will be screened and enrolled in 165-304; 
however, they will not receive pegvaliase until consultation with the medical monitor 
(temporary hold released). 
A subject (or a subject-designated caregiver) must have met predefined self-administration 
criteria in PAL-003 or 165-302 to qualify for pegvaliase self-administration (refer to 
Section 9.4.4), including demonstrated working knowledge of the signs and symptoms of a 
hypersensitivity reaction, including anaphylaxis, and what to do if a hypersensitivity reaction 
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is suspected (refer to Section 9.1.1). Eligible subjects (or caregivers) have been trained to 
self-administer pegvaliase. 
A competent adult will observe the subject during pegvaliase administration and for a 
minimum of 1 hour following pegvaliase administration upon reintroduction of pegvaliase 
after resolution of a Grade 3 or higher HAE, any dose interruption of  4 days, and for a dose 
increase to 60 mg/day; administration of pegvaliase may only be performed if this person is 
present. Observations should be performed for all doses administered for 1 week after 
reintroduction of pegvaliase or a dose increase to 60 mg/day. Information and training on 
how to recognize a possible reaction, the severity of the reaction, and instructions on what to 
do if a reaction occurs will be provided to any person designated to observe the subject 
during pegvaliase administration. 
)ROORZLQJDGRVHLQWHUUXSWLRQRI 4 doses that is not due to safety, the investigator should 
consult with the medical monitor and obtain approval from the medical monitor prior to the 
subject restarting pegvaliase. 
Subjects are given 2 epinephrine injectors and are instructed to carry 1 epinephrine injector 
with them at all times. Each subject is contacted weekly to monitor for self-administration 
problems and/or AEs. Premedication with H1 antagonist, H2 antagonist, and antipyretic 
(eg, acetaminophen) should be administered approximately 2 to 3 hours prior to pegvaliase 
administration for 1 week upon reintroduction of pegvaliase after resolution of a grade 3 or 
KLJKHU+$(IROORZLQJDQ\GRVHLQWHUUXSWLRQRI 4 days, and for a dose increases to 
60 mg/day. If a non-steroidal anti-inflammatory medication (NSAID) is administered as a 
premedication, it should be given with food. Subjects may also be pre-medicated at any time 
in the study at the discretion of the investigator. Subjects are provided with a workbook to 
document the date and time of pegvaliase injections, the injection site, and suspected AEs. 
A subject’s ability to maintain a consistent diet is essential for the success of the study by 
ensuring that the efficacy and safety end points are attributable to study treatment rather than 
to changes in dietary protein intake. A dietitian under investigator supervision will manage 
subject diet for the entire duration of the study. Subjects are provided 3-day diaries in which 
all dietary protein intake (including medical food and intact food) must be recorded for 
3 consecutive days immediately prior to each scheduled clinic visit for review with a 
dietitian. All subjects will be provided the option of tyrosine supplementation (500 mg, 
3 times per day with meals) at the discretion of the investigator. Subjects are instructed not to 
change their dietary protein intake during the study. 
Because the risks of taking pegvaliase during pregnancy and breastfeeding are unknown, 
subjects cannot take pegvaliase if they are trying to conceive, are pregnant, or are 
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breastfeeding. Subjects must be willing to use 2 acceptable methods of contraception while 
participating in the study and until 4 weeks after the study. Male subjects who are planning to 
impregnate a female partner and female subjects who are trying to become pregnant during 
the study must be temporarily discontinued from pegvaliase for 4 weeks prior to trying to 
conceive. During that time, subjects must use 2 acceptable methods of contraception (refer to 
Section 9.3.1). Subjects who are planning to become pregnant (or impregnate a female 
partner) may modify their diet in consultation with the investigator and/or study dietitian. 
Subjects who are confirmed to be pregnant by a serum pregnancy test and are temporarily off 
pegvaliase are not required to perform the scheduled urine pregnancy tests. Subjects who are 
pregnant or are trying to conceive and have temporarily discontinued pegvaliase should not 
perform the scheduled PK assessments. Male subjects who have impregnated a female 
partner may re-start pegvaliase after conception following the investigator’s consultation 
with and approval by the medical monitor. Male subjects must use a barrier method for 
contraception prior to restarting pegvaliase. Female subjects who remain in the study after 
temporary discontinuation of pegvaliase due to pregnancy may restart pegvaliase dosing after 
a confirmed negative urine pregnancy test result, the birth (or termination of the pregnancy) 
has been reported, and breastfeeding has been completed (if applicable), or after the subject 
is no longer actively trying to conceive. Re-starting pegvaliase dosing requires prior 
consultation with the investigator and approval by the medical monitor. Female subjects must 
return to the protocol-required contraception use, which must include 1 barrier method, 
immediately after the birth (or termination of the pregnancy). 
Except for subjects transitioning to commercial drug, if pegvaliase is discontinued before 
study completion, every effort will be made to maintain the subject in the study and continue 
study visits and assessments, provided the subject’s health, safety, and welfare are not 
detrimentally affected. 
In addition to BioMarin, a Data Monitoring Committee (DMC) monitors the safety of study 
subjects. The DMC is an independent committee that acts in an advisory capacity to 
BioMarin. 
The assessments to be performed throughout the study are presented in Table 9.1.1. 
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Table 9.1.1:  165-304 Schedule of Events 
Event or Assessment a 
Screening/ 
Day 1 b 
Weekly 
Contact c 
Week 9 
(Day 57) 
and Every 
8 Weeks 
Thereafter 
 (±7 days) 
Hypersensitivity 
Reaction Visit d 
Early 
Termination/ 
Study 
Completion 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
12 lead ECG 
X 
 
 
 
X 
Physical examination 
X 
 
X 
X 
X 
Vital signs 
X 
 
X 
X 
X 
Weight 
X 
 
X 
 
X 
Clinical laboratory tests e 
X 
 
X 
X 
X 
C-reactive protein 
X 
 
X 
X 
X 
Complements C3 and C4 
X 
 
X 
X 
X 
Tryptase 
 
 
 
X 
 
Urine albumin/creatinine ratio f 
X 
 
X 
X 
X 
Urinalysis for N-methyl histamine 
 
 
 
X 
 
Urine pregnancy test g 
X 
 
X 
 
X 
Diet diary h 
X 
 
X 
 
X 
PK (plasma pegvaliase) i 
X j 
 
X 
 
X 
Plasma Phe, tyrosine j 
X 
 
X 
 
X 
Immunogenicity assessments k 
X 
 
X 
X 
(anti-pegvaliase 
IgE only) 
X 
Adverse events l 
X 
X 
X 
X 
X 
Concomitant medication l 
X 
X 
X 
X 
X 
Administer pegvaliase m 
X n 
X 
X 
 
 
ECG, electrocardiogram; PK, pharmacokinetics  
a Events or assessments are pre-dose unless otherwise specified. 
b Screening assessments must be performed during the 28 days prior to and including Day 1. Assessments performed at the 
Study Completion Visit and prior visits for 165-302 or PAL-003 may be used for establishing 165-304 eligibility provided 
they meet this time constraint and the ICF for 165-304 is signed and dated prior to those assessments. 
c Between scheduled clinic visits, the clinic staff will contact the subject weekly to monitor if the subject is experiencing 
problems with self-administration, to ask about any AEs or concomitant medications, and to answer questions. 
d If an NCI-CTCAE grade 3 (or higher) hypersensitivity reaction is suspected, the investigator may request further 
evaluation between 8 and 24 hours following event onset, including urinalysis for N-methyl histamine. Subjects who 
experience an injection-VLWHVNLQUHDFWLRQWKDWODVWV 14 days including reactions that could be potential vasculitis should 
be referred to a dermatologist for consultation and a skin biopsy. Refer to Section 12.4 for additional details regarding this 
visit. 
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e It is recommended that urine samples be obtained as a first or second morning void. In the event of elevated urinary 
protein on a test result, a repeat urinalysis should be performed no later than the next scheduled visit. This repeat urine 
sample must be performed in the morning at the first or second morning void to allow for accurate test results and may be 
performed by a home healthcare nurse. 
f It is recommended that urine samples be obtained as a first or second morning void. Subjects with a confirmed 
XULQHDOEXPLQFUHDWLQLQHUDWLRRI 100 mg/g should be referred to a nephrologist for consultation if results were within 
normal range at baseline. Subjects who had elevated results at baseline followed by a confirmed subsequent increase of 
 100 mg/g from baseline should also be referred to a nephrologist for consultation. For subjects previously enrolled in 
PAL-003, blood for baseline urine/albumin creatinine ratio listed under Screening/Day 1 will be drawn pre-dose on Day 1 
of 165-304. 
g To be performed locally (if applicable). If urine pregnancy test is positive or equivocal, perform serum pregnancy test 
(central laboratory). Subjects who are confirmed to be pregnant per a serum pregnancy test and are temporarily off 
pegvaliase are not required to perform the scheduled urine pregnancy tests. Also refer to Section 9.1. 
h Subjects should record at home all food, beverages, special low-protein foods, and medical foods consumed during the 
3 consecutive days preceding a study visit. 
i Blood is collected for PK at the same time as draw for plasma Phe and tyrosine. For subjects previously enrolled in 
165-302, blood for baseline PK listed under Screening/Day 1 will be drawn pre-dose on Day 1 of 165-304. 
j Blood is collected for plasma Phe after fasting 2.5 to 5 hours. Subjects who are pregnant or are trying to conceive and have 
temporarily discontinued pegvaliase should not perform the scheduled PK assessments. 
k Immunogenicity assays include (but are not limited to) total anti-pegvaliase, anti-rAvPAL IgG, anti-rAvPAL IgM, anti-
PEG IgG, anti-PEG IgM, anti-pegvaliase IgG4, and neutralizing antibodies; additional assays include IgG-C3d and IgM-
C3d circulating immune complexes (CICs); anti-pegvaliase IgE is determined when appropriate (hypersensitivity or other 
safety concern). 
l Subjects must be assessed for AEs and concomitant medications whenever assessed by study personnel beginning with the 
first dose of pegvaliase on Day 1. After pegvaliase initiation, all AEs and SAEs will be recorded until 4 weeks after either 
the last administration of pegvaliase or the Study Completion Visit/Early Termination Visit, whichever occurs last. If there 
LVDVNLQUHDFWLRQWKDWODVWV 14 days, the Skin Reaction electronic case report form (eCRF) should be completed. Subjects 
who experience an injection-VLWHVNLQUHDFWLRQWKDWODVWV 14 days including reactions that could be potential vasculitis 
should be referred to a dermatologist for consultation and a skin biopsy. It is recommended that a photograph of the skin 
reaction be taken by the subject or the site to help assess the event; photographs may be collected by the sponsor. 
m Subjects self-administer pegvaliase. During weekly contacts, subjects are asked about pegvaliase self-administration. 
n Following completion of the 165-302 or PAL-003 Study Completion Visit and confirmation of eligibility for 165-304, 
subjects may be dosed on the same day, designated 165-304 Day 1. 
 
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9.1.1 Response to Hypersensitivity Adverse Events 
Subjects are evaluated for safety throughout all parts of the study and are trained to recognize 
potential HAEs (including a serious anaphylaxis) and how to respond. Subjects are instructed 
to contact the investigator for any suspected HAE. After a telephone assessment, the 
investigator may require further evaluation at the clinic. If a hypersensitivity reaction 
(eg, injection-site reaction, rash, joint pain, itching) occurs, the subject may be advised to 
premedicate with H1 antagonist, H2 antagonist, and antipyretic (eg, acetaminophen) 
approximately 2 to 3 hours prior to subsequent pegvaliase doses. If NSAIDs are administered 
as a premedication, they should be given with food. 
Hypersensitivity AEs, including anaphylaxis, are expected with pegvaliase administration. 
Pegvaliase dosing in response to a suspected HAE may be modified or temporarily halted 
depending on the severity of the event and suspected pegvaliase causality. Severity for HAEs 
will be per National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) grades (refer to Section 10.1). 
Subjects who experience an injection-VLWHVNLQUHDFWLRQWKDWODVWV 14 days including 
reactions that could be potential vasculitis should be referred to a dermatologist for 
consultation and a skin biopsy. 
9.1.1.1 
Individual Stopping Criteria 
Subjects who have an NCI-&7&$(JUDGH 3 anaphylaxis event that is, in the judgment of 
the investigator and the sponsor’s medical monitor, related to study drug and suspected to 
meet Brown’s criteria (Brown, 2004) for severe (grade 3) hypersensitivity may be 
permanently discontinued from study drug. The sponsor’s medical monitor should be 
immediately notified when a subject experiences an NCI-&7&$(JUDGH 3 anaphylaxis 
event that is judged by the investigator to be related to pegvaliase and/or is suspected to meet 
Brown’s criteria (Brown, 2004) for severe (grade 3) hypersensitivity. 
9.1.1.2 
Dosing in Response to Hypersensitivity Adverse Events 
Dosing in response to an HAE depends on the NCI-CTCAE grade and suspected relationship 
to pegvaliase. Dosing instructions are presented in Table 9.1.1.2.1 and are regardless of 
previous occurrence. 
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Table 9.1.1.2.1:  Dosing after Hypersensitivity Adverse Event 
NCI-
CTCAE 
Grade a 
Related to 
Study Drug 
Action with Study Drug 
Individual 
Stopping Criteria d 
HRV  
Assessment e 
Maintain b Reduce c 
Interrupt c 
1 
Yes or No 
X 
(X) 
Optional 
(X) 
Optional 
 
Investigator  
discretion 
2 
Yes or No 
X 
(X) 
Optional 
(X) 
Optional 
 
Investigator  
discretion 
3 
No 
X 
(X) 
Optional 
(X) 
Optional 
 
Investigator 
discretion 
3 
Yes 
X 
(X) 
Optional 
(X) 
Optional 
 
Yes  
(if within 24 hours 
of onset) 
3 d 
Yes 
 
 
 
X 
Immediately consult 
with sponsor 
medical monitor 
Yes 
(if within 24 hours 
of onset) 
4 d 
Yes or No 
 
 
 
X 
Immediately consult 
with sponsor 
medical monitor 
Yes 
(if within 24 hours 
of onset) 
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events, version 5.0; HRV, Hypersensitivity 
Reaction Visit; NCI, National Cancer Institute. 
a NCI-CTCAE grade determination is performed by the investigator and may be done either via telephone or clinic visit. 
b The investigator will instruct the subject to maintain the pegvaliase dose at the time of AE onset until improvement to 
grade 1 or resolution (per investigator assessment in the clinic or via telephone). 
c The pegvaliase dose may be reduced or interrupted if necessary per investigator determination. 
d If a subject has an NCI-&7&$(JUDGH 3 anaphylaxis event that is related to study drug and is suspected to meet Brown’s 
criteria for severe (grade 3) hypersensitivity in the judgment of the investigator and the sponsor’s medical monitor, the 
subject may be permanently discontinued from study drug. 
e If the investigator determines that the NCI-&7&$(JUDGH 3 hypersensitivity reaction is related to administration with 
study drug, the subject will be asked to return to the clinic within 24 hours of event onset for a hypersensitivity reaction 
visit (HRV) assessment, including laboratory tests (chemistry, hematology, urinalysis, anti-pegvaliase IgE [sampling must 
be performed > 8 hours after event onset and before the next dose of study drug], urine albumin/creatinine ratio, urinary 
N-methyl histamine, CRP, C3, C4, and tryptase).  
 
Once an AE (other than anaphylaxis) improves to grade 1 or resolves, the pegvaliase dose 
may be increased, maintained, or reduced, at the discretion of the investigator. If reduced, the 
recommended pegvaliase dose reductions include: from 60 mg/day to 40 mg/day, from 
50 mg/day to 20 mg/day, or from 40 mg/day to 20 mg/day, with reductions from intermediate 
doses at the discretion of the investigator. If dosing has been interrupted due to an AE (other 
than anaphylaxis) and the investigator determines it is safe for the subject to resume dosing, 
the first dose after improvement of the AE should be performed in the clinic. 
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Additionally, the subject should be premedicated with H1 antagonist, H2 antagonist, and 
antipyretic (eg, acetaminophen) approximately 2 to 3 hours prior to each dose of pegvaliase 
IRUZHHNXSRQUHWXUQWRGRVLQJLIWKHGRVHLQWHUUXSWLRQLV 4 days. If NSAIDs are 
administered as a premedication, they should be given with food. Also, a competent adult 
should observe the subject during pegvaliase administration and for a minimum of 1 hour 
following pegvaliase administration for 1 week upon return to dosing if the dose interruption 
LV 4 days; administration of pegvaliase may only be performed if this person is present. 
9.1.1.3 
Response to Anaphylaxis 
If the investigator suspects that the event is anaphylaxis, the subject will be assessed in the 
clinic and the sponsor’s medical monitor should be immediately notified. Refer to 
Section 10.1.2 for safety reporting instructions for anaphylaxis events (serious or nonserious 
and irrespective of severity). Laboratory assessments for suspected anaphylaxis events 
should be performed prior to the next administration of pegvaliase (if applicable) and include 
anti-pegvaliase IgE (for optimal results, sampling must be performed > 8 hours after event 
onset) and tryptase (for optimal results, perform within 24 hours of event onset). If the 
investigator determines it is safe for the subject to resume dosing with pegvaliase following 
resolution of anaphylaxis, the dose level will be as presented in Table 9.1.1.3.1. 
Table 9.1.1.3.1:  Dosing after Anaphylaxis Event 
Scheduled Dose at Time 
of Anaphylaxis Onset 
Dose Following Resolution  
of Anaphylaxis Event a 
50 mg/day 
20 mg/day 
60 mg/day 
40 mg/day 
a Dose may be lowered further per investigator discretion. Dose frequency should be the same as the dose regimen at the 
time of anaphylaxis onset; however, dose frequency may be revised per investigator discretion and in consultation with the 
sponsor’s medical monitor. 
 
The first dose administered after resolution of anaphylaxis is to be administered at the clinic 
with equipment for emergency resuscitation (including epinephrine) within easy access. 
Additionally, the subject should be premedicated with H1 antagonist, H2 antagonist, and 
antipyretic (eg, acetaminophen) approximately 2 to 3 hours prior to each dose of pegvaliase 
for 1 week upon return to dosing regardless of the duration of dose interruption. If NSAIDs 
are administered as a premedication, they should be given with food. Also, a competent adult 
should observe the subject during pegvaliase administration and for a minimum of 1 hour 
following pegvaliase administration for 1 week upon return to dosing regardless of the 
duration of dose interruption; administration of pegvaliase may only be performed if this 
person is present. 
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9.1.2 Study Stopping Criteria for Adverse Events during Treatment with Pegvaliase 
If an anaphylaxis event occurs and meets Brown’s criteria (Brown, 2004) for severe 
(grade 3) hypersensitivity, the DMC chair and/or committee will be informed to review and 
advise the sponsor on potential changes to the study conduct. Clinically severe 
hypersensitivity (Brown’s criteria, severe [grade 3]) is defined as significant hypoxia, 
hypotension or neurologic compromise that is life-threatening or required treatment to 
prevent a life-threatening event: 
x Cyanosis or SpO2  
x Hypotension with SBP < 90 mm Hg (adults) 
x Neurologic alteration: confusion, loss of consciousness, collapse, or incontinence 
Brown’s severity criteria are presented in Table 9.1.2.1. 
Table 9.1.2.1:  Severity Criteria (Brown, 2004) 
Brown’s Criteria for 
Hypersensitivity Reactions 
Definition 
Mild (1) 
skin and subcutaneous tissue 
Generalized erythema, urticaria, periorbital edema, or 
angioedema 
Moderate (2) 
features suggested respiratory, cardiovascular, or 
gastrointestinal involvement 
Dyspnea, stridor, wheeze, nausea, vomiting, dizziness 
(pre-syncope), diaphoresis, chest or throat tightness, or 
abdominal pain 
Severe (3) 
hypoxia or neurologic compromise 
Cyanosis or SpO2 DWDQ\VWDJHK\SRWHQVLRQ
(SBP < 90 mm Hg in adults), confusion, collapse, loss of 
consciousness, or incontinence 
SBP, systolic blood pressure; SpO2, blood oxygen saturation. 
 
9.2 
Discussion of Study Design, Including Choice of Control Group 
This is an open-label extension study with no control group. Refer to Section 7.3 for the 
study rationale. 
9.3 
Selection of Study Population 
,QGLYLGXDOVZLWK3.8DJHG \HDUVDQG 70 years who previously received pegvaliase in 
PAL-003 or 165-302 (> 40 mg/day dose up to 60 mg/day dose, inclusive) are candidates for 
participation in the study. The rationale for selection of these subjects for study participation 
is provided in Section 7.3. Additional criteria for study participation are presented in 
Section 9.3.1 and Section 9.3.2. 
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9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following inclusion 
criteria: 
x Must be enrolled in PAL-003 or 165-302 Part 4 at the time of screening for 165-304 
and most recently receiving pegvaliase at a dose > 40 mg/day 
x Is at least 18 years of age and no older than 70 years of age at the time of screening 
x Has identified a competent person or persons    18 years of age who can observe the 
subject during study drug administration and for a minimum of 1 hour following 
administration in situations required per protocol 
o A home healthcare nurse may perform the study drug observations. 
x For females with childbearing potential, must have a negative pregnancy test at 
screening and be willing to have additional pregnancy tests during the study. 
(Females are considered not to have childbearing potential if they have been in 
menopause for at least 2 years, have had a tubal ligation at least 1 year prior to 
screening, or have had a total hysterectomy.) 
x If sexually active and not planning to become pregnant (self or partner), must be 
willing to use 2 acceptable methods of contraception while participating in the study 
and for 4 weeks after the study: 
o Acceptable methods of contraception include: (1) primary forms: 
hormonal (combination hormone-containing pills, patch, vaginal ring, or 
intrauterine device) or non-hormonal (copper-containing intrauterine 
device, tubal sterilization); (2) secondary forms: includes barrier forms 
and other forms of birth control and must include spermicide (e.g., male 
condom; female condom is not an acceptable secondary form). 
o Males (including partners) post vasectomy for 2 years with no known 
pregnancies do not need to use any other forms of contraception during the 
study. 
o Females (including partners) who have been in menopause for at least 
2 years, have had a tubal ligation at least 1 year prior to screening, or have 
had a total hysterectomy do not need to use any other forms of 
contraception during the study. 
x Is willing and able to provide written, signed informed consent after the nature of the 
study has been explained and prior to any research-related procedures; a legally 
authorized representative may provide written consent and assent may be requested 
x Is willing and able to comply with all study procedures 
x Is in generally good health, as evidenced by physical examination and/or clinical 
laboratory evaluations (hematology, chemistry, and urinalysis) 
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9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
x Use of any investigational product (except pegvaliase) or investigational medical 
device within 30 days prior to screening or requirement for any investigational agent 
prior to completion of all scheduled study assessments 
x Use of any medication (except pegvaliase) intended to treat PKU, including the use of 
large neutral amino acids, within 2 days prior to the administration of pegvaliase 
(Day 1) 
x Use or planned use of any injectable drugs containing PEG (other than pegvaliase), 
including medroxyprogesterone injection, within 3 months prior to screening and 
during study participation 
x A history of organ transplantation or on chronic immunosuppressive therapy 
x A history of substance abuse (as defined by the American Psychiatric Association: 
Diagnostic and Statistical Manual of Mental Disorders [DSM]) in the past 12 months 
or current alcohol or drug abuse 
x Current participation in the Kuvan® registry study (PKU Demographics, Outcomes 
and Safety [PKUDOS]) 
x Concurrent disease or condition that would interfere with study participation or safety 
(eg, history or presence of clinically significant cardiovascular, pulmonary, hepatic, 
renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, 
neurological, oncologic, or psychiatric disease) 
x Any condition that, in the view of the investigator, places the subject at high risk of 
poor treatment compliance or terminating early from the study 
9.3.3 Removal of Subjects from Treatment or Assessment 
Subjects (or their legally authorized representative) may withdraw their consent to participate 
in the study at any time without prejudice. The investigator must withdraw from the study 
any subject who requests to be withdrawn. A subject’s participation in the study may be 
discontinued at any time at the discretion of the investigator and in accordance with his/her 
clinical judgment. When possible, the tests and evaluations listed for the termination visit 
should be carried out (refer to Section 12.5). BioMarin must be notified of all subject 
withdrawals as soon as possible. 
BioMarin reserves the right to discontinue the study at any time. Premature termination of 
the study may occur because of regulatory authority decision, a change in the opinion of the 
IRB/IEC/REB, clinical or safety reasons, or at the discretion of the sponsor. The sponsor 
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reserves the right to discontinue the development of pegvaliase at any time, or to discontinue 
participation by an individual investigator or site for poor enrollment or noncompliance. 
Any  decision to terminate the study will be promptly communicated to investigators, 
regulatory authorities, and IRB/IEC/REB. The investigator is responsible for communicating 
any decision to terminate a study to hospital staff involved in the conduct of the study and the 
participating subjects (and their families). 
Reasons for which the investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following: 
x Subject experiences a serious or intolerable AE 
x Subject develops a clinically significant laboratory abnormality 
x Subject requires medication or medical procedure prohibited by the protocol 
x Subject does not adhere to study requirements specified in the protocol 
x Subject was erroneously admitted into the study or does not meet entry criteria 
x Subject is lost to follow-up 
Subjects who have an NCI-&7&$(JUDGH 3 anaphylaxis event that is, in the judgment of 
the investigator and the sponsor’s medical monitor, related to study drug and suspected to 
meet Brown’s criteria (Brown, 2004) for severe (grade 3) hypersensitivity may be 
permanently discontinued from study drug. The sponsor’s medical monitor should be 
immediately notified when a subject experiences an NCI-&7&$(JUDGH 3 anaphylaxis 
event that is possibly or probably related to pegvaliase and/or is suspected to meet Brown’s 
criteria (Brown, 2004) for severe (grade 3) hypersensitivity. 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject (or the subject’s legally authorized representative, if appropriate) 
requesting contact with the investigator. This information should be recorded in the study 
records. 
The investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study sponsor, regulatory agencies, and IRB/ECREB. It is 
the investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as HIPAA in the US, from each 
subject or, if appropriate, the subject’s legally authorized representative. If permission to use 
protected health information is withdrawn, it is the investigator’s responsibility to obtain a 
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written request to ensure that no further data will be collected from the subject and the 
subject will be removed from the study. 
9.3.4 Subject Identification and Replacement of Subjects 
Subjects will not be replaced in this study. Each subject will retain the unique subject 
identifier assigned in their previous study. This unique identifier will be on all case report 
form (CRF) pages. 
9.3.5 Duration of Subject Participation 
Following a screening period of up to 28 days, subjects receive pegvaliase for approximately 
121 weeks or until study closure. 
9.4 
Treatments 
9.4.1 Treatments Administered 
Pegvaliase is administered SC via open-label pre-filled syringe. 
9.4.2 Identity of Investigational Product 
The investigational product is pegvaliase (recombinant Anabaena variabilis phenylalanine 
ammonia lyase-PEG). For subcutaneous self (or caregiver) administration, subjects are 
supplied with prefilled syringes in 3 sizes. Sizes are 2.5 mg (0.5 mL of 5 mg/mL protein 
concentration), 10 mg (0.5 mL of 20 mg/mL protein concentration), and 20 mg (1.0 mL of 
20 mg/mL protein concentration). 
The excipients in this drug product are tromethamine, tromethamine-hydrochloride, 
sodium chloride, L-phenylalanine, and water for injection. 
9.4.2.1 
Product Characteristics and Labeling 
Drug product packaging is identified with lot and identification numbers and provided in a 
box labeled with the study number.  
9.4.3 Storage 
At the study site, all study drug must be stored at 5 r3°C (41 r5°F), under the conditions 
specified in the Investigator’s Brochure, and in a secure area accessible only to the 
designated pharmacists and clinical site personnel. All study drug must be stored and 
inventoried, and the inventories must be carefully and accurately documented according to 
applicable state, federal, and local regulations; ICH GCP, and study procedures. Information 
regarding storage of study drug in subjects’ homes is provided in the subject 
self-administration training materials in the Study Reference Manual (refer to Section 9.4.4). 
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9.4.4 Directions for Administration 
The injection sites for administration of pegvaliase should alternate between doses. Injection 
sites should not be near an open wound or mole. 
Subjects (or a subject-designated caregiver) must meet all of the following criteria to be 
eligible to self-administer the drug: 
x Has no known cognitive impairments that may increase the safety risk per 
investigator assessment 
x Has no medical history or current medications that may compromise 
self-administration of pegvaliase per investigator assessment 
x Has completed all required self-administration training and has demonstrated 
self-administration competency per investigator assessment, including how to prepare 
pegvaliase for administration and safely perform the injection 
Refer to Section 9.1.1 for study drug administration requirements regarding the presence of a 
competent adult and premedication requirements. 
)ROORZLQJDGRVHLQWHUUXSWLRQRI 4 doses that is not due to safety, the investigator should 
consult with the medical monitor and obtain approval from the medical monitor prior to the 
subject restarting pegvaliase. Dose regimens may be revised provided the investigator 
consults with the sponsor’s medical monitor and obtains approval from the medical monitor 
prior to starting an alternative dose regimen. 
If a subject has an NCI-CTCAE grade 3 or higher AE during the study, the subject’s 
suitability for self-administration of pegvaliase will be re-assessed by the investigator. In 
addition, the suitability for self-administration of pegvaliase will be re-assessed by the 
investigator if a subject experiences any issues with self-administration. 
Between scheduled clinic visits, the clinic staff will contact the subject weekly to monitor if 
the subject is experiencing problems with self-administration, for any AEs, and to answer 
questions throughout the duration of the study. The subject must perform the scheduled 
assessments and procedures in the clinic as outlined in 9.1.1 and Section 12. All subjects 
were trained in previous studies. Training materials and other information specific to the 
study site personnel are provided in the Study Reference Manual, which includes 
self-administration training materials and instruction on the following: 
x How to prepare and perform the injections of pegvaliase safely 
x How to receive, store, and return both used and unused pegvaliase 
x How to safely use and dispose of prefilled syringes used for injections of pegvaliase 
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x How to use a prefilled syringe every time drug is administered 
x How to care for the injection site after an injection of pegvaliase 
x How to document each pegvaliase injection 
x How to identify an AE and how to report this to the study site 
x How and when to use epinephrine 
x Whom to contact at the study site in case of an emergency 
Subjects will be provided with a workbook to document the date and time of pegvaliase 
injections, injection site, any suspected AEs, and other relevant information. Dosing in 
response to an AE should be determined by the investigator (refer to Section 9.1.1). 
9.4.5 Method of Assigning Subjects to Treatment Groups 
This is an open-label study. 
9.4.6 Selection of Doses Used in the Study 
The rationale for the selected dose (> PJGD\GRVHXSWR 60 mg/day dose, inclusive) is 
provided in Section 7.3. Subjects will begin Study 165-304 on the same dose and dosing 
regimens they were on at the end of the previous study (165-302 or PAL-003). 
9.4.6.1 
Selection of Timing of Dose for Each Subject 
Subjects are encouraged to administer study drug at approximately the same time each day to 
minimize diurnal variation in blood Phe and tyrosine. 
9.4.7 Blinding 
Subjects will receive open-label pegvaliase. 
9.4.8 Prior and Concomitant Medication 
All prescription and over-the-counter medication taken by a subject for 30 days before 
screening are recorded on the designated eCRF. 
The investigator may prescribe additional medications during the study as long as the 
prescribed medication is not prohibited by the protocol (refer to Section 9.3.2). In the event 
of an emergency, any needed medications may be prescribed without prior approval but the 
medical monitor must be notified of the use of any contraindicated medication immediately 
thereafter. Any concomitant medication added or discontinued during the study should be 
recorded on the appropriate eCRF. 
For instruction regarding premedication, refer to Section 9.1. 
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9.4.9 Treatment Compliance 
The date, time, and quantity of each dose of study drug administered to each subject must be 
recorded by the subject in a workbook provided for the study. The site staff will collect the 
workbook at scheduled 8 week clinic visits and transcribe this information to the appropriate 
eCRF. These data will be used to assess compliance and will be reviewed by CRAs (refer to 
Section 11). 
9.5 
Investigational Product Accountability 
The investigator (or designee) is responsible for maintaining accurate records (including 
dates and quantities) of IP received, subjects to whom IP is dispensed (subject-by-subject 
dose-specific accounting), IP returned, and IP lost or accidentally or deliberately destroyed. 
The investigator (or designee) must retain all unused or expired study drug syringes until the 
study monitor (on-site CRA) confirms accountability data. Used prefilled syringes are not 
retained; accountability is based on syringe label stickers in subject study workbook. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin’s designated Drug 
Destruction Facility upon request. The return of study drug or study drug materials must be 
accounted for on a Study Drug Return Form provided by BioMarin. 
Subjects are provided instructions for returning unused study drug prefilled syringes and for 
proper disposal of used study drug prefilled syringes or study drug materials. 
All study drug should be stored, inventoried, reconciled, and destroyed or returned according 
to applicable state and federal regulations and study procedures. 
9.6 
Dietary or Other Protocol Restrictions 
Diet will be assessed for its role in blood Phe reduction relative to pegvaliase dosing. 
A dietitian will be involved with reviewing, counseling, analyzing, and managing subject diet 
throughout the study. 
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A 3-day diet diary and a nutrient analysis software program (Metabolic Pro®) will be used to 
establish baseline Phe and protein intake levels prior to Day 1. Protein from medical foods 
(Phe-free amino acid fortified food sources) and protein from intact foods (any other food 
sources containing Phe) are collectively referred to as dietary protein. 
Baseline measurements will be used as the comparator for subsequent 3-day diet diary 
entries. Subjects will be required to maintain dietary protein intake levels that are consistent 
with their baseline levels for the entire study, with a consistent diet defined as one in which 
the intact protein changes are < IURPEDVHOLQHDQGWKHPHGLFDOIRRGSURWHLQFKDQJHV
< IURPEDVHline. Subjects who are planning to become pregnant (or impregnate a female 
partner) may modify their diet in consultation with the investigator and/or study dietitian. 
The dietitian will perform additional counseling with a subject for any intact protein and/or 
PHGLFDOIRRGSURWHLQLQWDNHFKDQJHVWKDWDUH IURPEDVHOLQH 
Further corrective actions will be implemented when the intact protein and/or medical food 
SURWHLQLV ± IURPEDVHOLQH$IWHUWKHVXEMHFWGHPRQVWUDWHV FKDQJHIURPEDVHOLQH
intake of intact protein and/or medical food protein, the dietitian will counsel the subject to 
resume their baseline diet and may perform another 3-day diet record and blood Phe 
FRQFHQWUDWLRQDVVHVVPHQWLQZHHNV,IWKHVXEMHFWGHPRQVWUDWHV ± change in intake of 
intact protein and/or medical food protein at the next scheduled study visit (8 weeks), a 
discussion with the medical monitor may be required to discuss further actions related to 
non-adherence with consistent dietary protein intake throughout the study, at the discretion of 
the investigator. 
The 3-day diet diary should reflect the 3 consecutive days prior to the scheduled study visit. 
If dietary protein intake is determined to be inconsistent with baseline values, it is 
recommended that the dietitian counsel the subject on how to return to baseline values by 
modifying intake of intact protein and/or medical food protein. If diet changes have been 
implemented, a blood Phe concentration assessment and 3-day diet record should be 
collected 2 weeks after implementation, in addition to all regularly scheduled assessments. 
Any changes must also be documented on the appropriate eCRF. 
x ,IEORRG3KHOHYHOVGHFUHDVHWR ȝPRO/DQGLWLVGHWHUPLQHGWKDWDVXEMHFWLV
consuming less than their recommended dietary allowance (RDA) for intact protein 
(RDAs for intact protein: men 18 years of age: 52 JGD\PHQ 19 years of age: 
56 g/day; women 18 years of age: 46 JGD\ZRPHQ 19 years of age: 46 g/day), the 
dietitian may instruct the subject to increase their intact protein by 10 grams and 
decrease their medical food protein by 5 grams. This increased intake will now be the 
new reference baseline for dietary protein intake for future dietary assessments. 
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x ,IEORRG3KHOHYHOVGHFUHDVHWR ȝPRO/DQd it is determined that a subject is 
consuming more than his or her RDA but less than 2x his or her RDA for intact 
SURWHLQWKHGLHWLWLDQPD\LQVWUXFWWKHVXEMHFWWRLQFUHDVHLQWDFWSURWHLQLQWDNHE\
and decrease medical food protein intake by 5 grams compared to his or her current 
dietary intake. This increased intake becomes the new reference baseline for dietary 
protein intake for the subject’s future dietary assessments. 
x ,IEORRG3KHOHYHOVGHFUHDVHWR ȝPRO/DQGLWLVGHWHUPLQHGWKDWDVXEMHFW is 
FRQVXPLQJ 2x his or her RDA for intact protein, the dietitian may instruct the 
subject to maintain his or her current intact protein intake and medical food protein 
intake. The subject will continue to use the same reference baseline for dietary protein 
intake for future dietary assessments. 
Any dietary changes must be documented in the subject’s 3-day diet diary and on the 
appropriate eCRF. 
9.7 
Efficacy and Safety Variables 
9.7.1 
Efficacy and Safety Measurements Assessed 
The Schedule of Events (Table 9.1.1) outlines the timing of required events and assessments. 
9.7.2 Primary Efficacy Variable 
Blood samples for Phe concentration are taken after fasting for 2.5 to 5 hours as indicated in 
Table 9.1.1 and analyzed by a central laboratory. 
9.7.3 Secondary Efficacy Variables 
9.7.3.1 
Dietary Protein Intake 
A subject’s diet is monitored using a 3-day diet diary. The 3-day dietary record (diet diary) is 
completed by subjects, brought to clinic visits for review, and maintained with the study 
source documents. Subjects record all food, beverages, special low-protein foods, and 
medical foods consumed for 3 consecutive days prior to the scheduled clinic visit. Data are 
analyzed by the nutritional software (Metabolic Pro®) for total kcals, protein, Phe, tyrosine, 
and the percentage of daily recommended intake provided for protein, Phe, tyrosine, 
vitamins, and minerals (refer to Section 9.6). 
9.7.3.2 
Pharmacokinetics and Pharmacodynamics 
Blood samples for PK (plasma pegvaliase) and PD (plasma Phe) analysis are drawn 
according to the Schedule of Events (9.1.1). Analysis of pegvaliase plasma concentrations 
will be performed by BioMarin or a contract research organization. 
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9.7.4 Exploratory Sample Analyses 
Blood and urine samples may be analyzed to evaluate biochemical, molecular, cellular and 
genetic/genomic aspects of PKU and to develop the assays used for these evaluations. For 
each portion of the blood and urine samples reserved for protocol-specified analyses, there 
may be multiple sample aliquots. The unused aliquots may be used during the study for assay 
development or other purposes stated in Section 9.7.4.   
9.7.5 Safety Variables 
Safety in this study will be determined from evaluations of AEs, clinical laboratory 
assessments, vital signs, physical examinations, electrocardiogram (ECG) results, and 
immunogenicity tests. 
9.7.5.1 
Adverse Events 
The occurrence of AEs will be assessed continuously commencing with the first dose of 
study drug on Day 1. The determination, evaluation, and reporting of AEs will be performed 
as outlined in Section 10. Assessments of AEs will occur at the time points outlined in 
Section 9.1.1. 
9.7.5.2 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are outlined in 
Section 9.1.1. The scheduled clinical laboratory tests are listed in Table 9.7.5.2.1. Refer to 
the Lab Manual for instructions on obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the investigator should be 
repeated (at the investigator’s discretion) until the cause of the abnormality is determined, the 
value returns to baseline or to within normal limits, or the investigator determines that the 
abnormal value is no longer clinically significant. 
The investigator should assess all abnormal clinical results and include a comment on 
whether or not the result is clinically significant. Each clinically significant laboratory result 
should be recorded as an AE. 
In the event of elevated urinary protein on a test result, a repeat urinalysis should be 
performed. This repeat urine sample must be performed in the morning at the first or second 
morning void to allow for accurate test results and may be performed by a home healthcare 
nurse. Subjects with a confirmed urine/albumin creatinine UDWLRRI 100 mg/g should be 
referred to a nephrologist for consultation if results were within normal range at baseline. 
Subjects who had elevated results at baseline followed by a confirmed subsequent increase of 
 100 mg/g from baseline should also be referred to a nephrologist for consultation. 
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The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the investigator will be recorded on the AE eCRF. 
Table 9.7.5.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Hematology 
Urine Tests 
Albumin 
Hemoglobin 
Appearance 
Alkaline phosphatase 
Hematocrit 
Color 
ALT (SGPT) 
White blood cell count 
pH 
AST (SGOT) 
Red blood cell count 
Specific gravity 
Total bilirubin 
Platelet count 
Ketones 
Blood urea nitrogen 
Differential cell count 
Protein a 
Creatinine 
 
Glucose 
Gamma-glutamyltransferase 
 
Bilirubin 
Total protein 
 
Nitrite 
Calcium 
 
Urobilinogen 
Sodium 
 
Hemoglobin 
Potassium 
 
Urinary albumin/creatinine ratio b 
Glucose 
 
Urinary microscopy 
Uric acid 
 
Urinary N-methyl histamine 
Chloride 
Complement Panel 
Other 
Creatine phosphokinase 
C3 
Pregnancy test, if applicable c 
LDH 
C4 
Phenylalanine 
Bicarbonate 
 
Tyrosine 
 
 
CRP 
 
 
Serum tryptase level 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; C3, C4, complement components 3, 4; CRP, C-reactive 
protein; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase 
a It is recommended that urine samples are obtained as a first or second morning void. In the event of elevated urinary 
protein on a test result, a repeat urinalysis should be performed. This repeat urine sample must performed in the morning at 
the first or second morning void to allow for accurate test results and may be performed by a home healthcare nurse. 
b It is recommended that urine samples are obtained as a first or second morning void. Subjects with a confirmed 
XULQHDOEXPLQFUHDWLQLQHUDWLRRI 100 mg/g should be referred to a nephrologist for consultation if results were within 
normal range at baseline. Subjects who had elevated results at baseline followed by a confirmed subsequent increase of 
 100 mg/g from baseline should also be referred to a nephrologist for consultation. 
c Urine pregnancy test performed by local laboratory. If urine pregnancy test is positive or equivocal, perform serum 
pregnancy test by central laboratory.  
 
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9.7.5.3 
Vital Signs, Physical Examinations, and Other Observations Related to 
Safety 
9.7.5.3.1 Vital Sign Measurements 
Vital signs should be measured after resting for 5 minutes and include seated systolic blood 
pressure and diastolic blood pressure measured in mm Hg, heart rate in beats/minute, 
respiration rate in breaths/minute, and temperature in °C. Weight (kg) will also be measured. 
Assessments will occur at the time points outlined in Section 9.1.1. 
9.7.5.3.2 Physical Examination Findings 
Physical examination will include assessment of general appearance, head, eyes, ears, nose, 
throat, and the following body systems: cardiovascular, dermatologic, lymphatic, respiratory, 
gastrointestinal, musculoskeletal, and neurological/psychological. Other body systems may 
be examined, and findings should be noted on the appropriate eCRF. Clinically significant 
changes from screening should be recorded as AEs (refer to Section 10). Assessments will 
occur at the time points outlined in Section 9.1.1. 
9.7.5.3.3 Electrocardiography 
A standard 12-lead ECG will be recorded, while the subject is resting, at the time points 
outlined in Table 9.1.1. 
9.7.5.3.4 Other Laboratory Assessments 
Immunogenicity will be assessed with immunogenicity assays including, but not limited to, 
the following: 
x Total anti-pegvaliase antibodies (TAb) 
x Anti-rAvPAL IgG antibodies 
x Anti-rAvPAL IgM antibodies 
x Anti-PEG IgG antibodies 
x Anti-PEG IgM antibodies 
x Anti-pegvaliase IgG4 antibodies 
x Neutralizing antibodies (NAb) 
x Anti-pegvaliase IgE 
x IgG-C3d and IgM-C3d Circulating Immune Complexes (CICs) 
Samples will be collected for immunogenicity assays at the time points indicated in the 
Schedule of Events (Section 9.1.1). 
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Antibody tests will be analyzed by BioMarin and/or CROs (refer to Section 6). 
9.7.5.4 
Pregnancy Testing 
Female subjects with childbearing potential will have a urine pregnancy test performed at the 
time points specified in the Schedule of Events (Section 9.1.1). Subjects who are confirmed 
to be pregnant by a serum pregnancy test and are temporarily off study drug are not required 
to perform the scheduled urine pregnancy tests. 
Additional pregnancy tests will be performed at any visit when pregnancy status is in 
question. Serum pregnancy tests must be performed in the event of a positive or equivocal 
urine pregnancy test result. 
Refer to Section 10.3.1.9 for details on the reporting procedures in the event of pregnancy. 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable AE is any untoward medical occurrence (eg, sign, symptom, 
illness, disease, or injury) in a subject administered the study drug or other protocol-imposed 
intervention, regardless of attribution. This includes the following: 
x AEs not previously observed in the subject that emerge during the course of the 
study. 
x Pre-existing medical conditions judged by the investigator to have worsened in 
severity or frequency or changed in character during the study. 
x Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures, medication washout, or no-treatment 
run-in). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the study 
drug caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the study drug and the AE. 
For this study, a medical device is defined as the prefilled syringe and all of the component 
parts. Adverse events assessed by the investigator as related to the device, including 
malfunction, injury, or medication error, will be captured as AEs. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
10.1.2 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence at any dose that meets 
1 or more of the following criteria: 
x Is fatal 
x Is life threatening 
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Note: Life-threatening refers to an event that places the patient at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
x Requires or prolongs in-patient hospitalization.  
x Results in persistent or significant disability or incapacity 
x Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
x Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the patient or require intervention to prevent one of the above 
consequences (eg, anaphylaxis) 
All AEs that do not meet any of the criteria for SAEs should be regarded as non-serious AEs. 
10.1.3 Adverse Events of Special Interest (AESI) 
For this protocol, anaphylaxis per NIAID/FAAN criteria for the clinical diagnosis of 
anaphylaxis is designated an AESI (serious or nonserious and irrespective of severity) to 
facilitate rapid reporting and sponsor review. All occurrences of anaphylaxis per 
NIAID/FAAN criteria will be reported to the sponsor within 24 hours of the site becoming 
aware of the event using the SAE form. Severity and serious criteria (if applicable) should be 
reported on the SAE form. 
10.2 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.2.1 Adverse Event Reporting Period 
After informed consent is obtained and the first administration of study drug, all non-serious 
AEs, AESI, SAEs, and pregnancies are reported until 4 weeks following either the last 
administration of study drug or the early termination visit, whichever period is longer (refer 
to Section 12.5). The criteria for determining SAEs is provided in Section 10.1.2. 
For this study, a medical device is defined as the prefilled syringe and all of the component 
parts. The reporting period for device-related events begins with the first dose administered 
and ends with the last dose administered. 
10.2.2 Eliciting Adverse Events 
Investigators will seek information on AEs, SAEs, and AESI at each subject contact by 
specific questioning and, as appropriate, by examination. Information on all AEs, SAEs, and 
AESI should be recorded in the subject’s medical record and on the AE eCRF. 
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10.2.3 Assessment of Seriousness, Severity, and Causality 
The investigator responsible for the care of the subject or qualified medical designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.1.2 
for SAE definitions). These assessments should be made by a study clinician with the 
training and authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse 
practitioner, or DDS). 
10.2.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.1.2. Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.2.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on patient/event  outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning. The severity of each will be assessed using the 
defined categories in Table 10.2.3.2.1. 
The investigator will determine the severity of each AE, SAE, and AESI using the 
NCI-CTCAE v5.0. Adverse events that do not have a corresponding CTCAE term will be 
assessed according to the general guidelines for grading used in the CTCAE v5.0 as stated 
below. 
Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL) a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL b 
4 
Life threatening or debilitating: consequences; urgent 
intervention indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the telephone, 
managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, taking 
medications, not bedridden. 
 
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10.2.3.3 
Causality 
The investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE eCRF. To ensure consistency of causality assessments, 
investigators should apply the guidance in Table 10.2.3.3.1. 
Table 10.2.3.3.1:  Categories Describing Relationship of Adverse Events to Study Drug 
Relationship 
Description 
Not Related 
Exposure to the IP has not occurred 
OR 
The administration of the IP and the occurrence of the AE are not reasonably related in 
time 
OR 
The AE is considered likely to be related to an etiology other than the use of the IP; 
that is, there are no facts [evidence] or arguments to suggest a causal relationship to the 
IP. 
Related 
The administration of the IP and the occurrence of the AE are reasonably related in 
time 
AND 
The AE could be explained equally well by factors or causes other than exposure to the 
IP 
OR 
The administration of IP and the occurrence of the AE are reasonably related in time 
AND 
The AE is more likely explained by exposure to the IP than by other factors or causes. 
IP, investigational product 
 
Factors suggestive of a causal relationship could include (but are not limited to): 
x Plausible temporal relationship 
x Absence of alternative explanations 
x Rarity of event in a given patient or disease state 
x Absence of event prior to study drug exposure 
x Consistency with study product pharmacology 
x Known relationship to underlying mechanism of study drug action 
x Similarity to adverse reactions seen with related drug products 
x Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process. Regardless of the investigator’s assessment of causality for 
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individual AE reports, the sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.3 
Procedures for Recording Adverse Events 
10.3.1 Recording Adverse Events on an eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on an 
eCRF. Avoid colloquialisms and abbreviations. 
Record only 1 diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the sponsor to the 
original terms entered on the eCRF, using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. 
10.3.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known). If not known, enter 
sign(s) and/or symptom(s). If a diagnosis subsequently becomes available, then this diagnosis 
should be entered on the AE form, replacing the original entries where appropriate. 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause. For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the eCRF. However, 
medically important events that may be linked and/or separated in time should be recorded as 
independent events on the eCRF. For example, if severe hemorrhage leads to renal failure, 
both events should be recorded separately on the eCRF. 
10.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points. Such an event should be recorded only once on the eCRF unless its 
severity increases or decreases (in which case it should be recorded again on the AE eCRF). 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs. Each recurrence of the AE should be individually recorded as a 
separate event on the AE eCRF. 
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10.3.1.4 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the eCRF. 
A clinical laboratory abnormality should be documented as an AE if it is not otherwise 
refuted by a repeat test to confirm the abnormality and any 1 or more of the following 
conditions is met: 
x Accompanied by clinical symptoms 
x Leading to a change in study medication (eg, dose modification, interruption or 
permanent discontinuation) 
x Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
x The abnormality suggests a disease and/or organ toxicity 
x The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported. 
10.3.1.5 
Pre-existing Conditions 
A pre-existing condition is one that is present at the start of the study. Such conditions should 
be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period. It is 
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important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.3.1.6 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.3.1.5). During the study, any new clinically significant findings 
and/or abnormalities discovered on physical examination that meet the definition of an AE 
(or an SAE) must be recorded and documented as an AE or SAE on the AE eCRF. 
10.3.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE except as described below. There are some hospitalization scenarios 
that do not require reporting as an SAE when there is no occurrence of an AE. These 
scenarios include planned hospitalizations or prolonged hospitalizations to: 
x Perform a protocol-mandated efficacy measurement 
x Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
x Receive scheduled therapy (study drug or otherwise) for the study indication 
x Routine hospitalization for childbirth, including planned caesarean section 
10.3.1.8 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.2.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the sponsor as an 
SAE within 24 hours. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF. If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the eCRF. If the death is attributed to progression of the 
disease or condition being studies, record “-” as the SAE term on the eCRF. 
10.3.1.9 
Pregnancy 
Pregnancy in either a subject or the partner of a subject who has taken study drug should be 
reported within 24 hours of the site becoming aware of the pregnancy. The pregnancy should 
be reported by faxing the Pregnancy Form in the study reference materials to BioMarin 
Pharmacovigilance (BPV) and completing the pregnancy eCRF in the electronic data capture 
(EDC) system. The investigator must make every effort to follow the subject through 
resolution of the pregnancy (delivery or termination) and to report the resolution on the 
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Pregnancy Follow-up Form in the study reference materials. The pregnancy follow-up eCRF 
must also be completed and reported to BPV within 24 hours. In the event of pregnancy in 
the partner of a study subject, the investigator should make every reasonable attempt to 
obtain the woman’s consent for release of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
sponsor considers these to be medically significant), recorded on the eCRF, and 
expeditiously reported to the sponsor as an SAE. 
10.4 
Reporting Requirements 
The sponsor is responsible for identifying, preparing, and reporting all suspected unexpected 
serious adverse reactions (SUSARs) to the relevant competent authorities, ethics committees, 
and investigators in accordance with requirements identified in the clinical trials regulations. 
10.4.1 Expedited Reporting Requirements 
All SAEs and AESI that occur during the course of the AE Reporting Period (refer to 
Section 10.2.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF and completing the SAE report form. The SAE report form 
must be submitted to BPV within 24 hours of the site becoming aware of the event. Each 
SAE must also be reported on the appropriate eCRF. Investigators should not wait to collect 
information that fully documents the event before notifying BPV of an SAE. BioMarin may 
be required to report certain SAEs to regulatory authorities within 7 calendar days of being 
notified about the event; therefore, it is important that investigators submit any information 
requested by BioMarin as soon as it becomes available. 
Adverse events assessed by the investigator as related to the device (ie, prefilled syringe), 
including malfunction, injury, or medication error, will be captured in in the EDC system. 
All serious events related to the device will be reported to BPV within 24 hours using the 
device-related event report form. 
The reporting period for SAEs begins after the first dose of study drug in the 165-304 study 
and continues until 4 weeks following either the last administration of study drug or study 
discontinuation/termination, whichever is longer. 
10.4.2 IRB Reporting Requirements 
Reporting of SAEs to the IRB will be done in compliance with the standard operating 
procedures and policies of the IRB and with applicable regulatory requirements. Adequate 
documentation must be obtained by BioMarin showing that the IRB was properly and 
promptly notified as required. 
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10.5 
Follow-up of Subjects after Adverse Events 
The investigator should follow all unresolved AEs, unless the subject is lost to follow-up, or 
it has been determined that the study treatment or participation was not the cause of the AE  
The outcome of AEs should be documented on the AE eCRF and in the subject’s medical 
record to facilitate source data verification. 
The investigator should follow all unresolved SAEs to resolution, unless the subject is lost to 
follow up, or it has been determined that the study treatment or participation was not the 
cause of the SAE.  Resolution of the SAE (with dates) should be documented on the AE 
eCRF and the SAE report form, as well as the subject's medical record to facilitate source 
data verification. 
For some SAEs, the sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.6 
Post-Study Adverse Events 
At the last scheduled visit, the investigator should instruct each subject to report, to the 
investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment. 
The investigator should notify the study sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the investigator believes 
that the death or SAE may have been related to prior study treatment. The sponsor should 
also be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study. 
10. 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
Novato, CA 94949 
Phone: 
(415) 506-6179
Fax: 
(415) 532-3144
E-mail:
drugsafety@bmrn.com
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The investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
, RN, MS 
Address: 
105 Digital Drive 
 
 
Novato, CA 94949 USA 
Phone:  
 
Fax: 
 
  
E-mail: 
 
 
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11 
APPROPRIATENESS OF MEASUREMENTS 
11.1 
Blood Phe Concentration 
Blood Phe concentration is an appropriate measure for efficacy as several studies have shown 
a correlation between blood Phe levels and clinical symptoms in patients with PKU 
(Vockley, 2014). In addition, the National Institutes of Health (NIH) guidelines on the 
treatment of PKU are based on assessments of blood Phe levels (NIH, 2000). A discussion of 
blood Phe concentration and its relationship with PKU is provided in Section 7. 
11.2 
Safety and Pharmacokinetics 
Safety and PK assessments in this study are recognized as reliable, accurate, and relevant. 
11.3 
Diet Diary 
Refer to Section 9.6 and Section 9.7.3.1 for information about the 3-day diet diary. 
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12 
STUDY PROCEDURES 
12.1 
Pre-Study 
An ICF must be signed and dated by the subject (or legally authorized representative when 
appropriate), investigator (or designee), and witness before any study-related procedures are 
performed. 
12.2 
Screening Visit/Week 1, Day 1 (Days -28 to Day 1) 
After subjects provide informed consent for this study, assessments and procedures must be 
completed within the 28 days prior to and including Day 1. Any required assessment or 
procedure completed for Study PAL-003 or 165-302 may be used for screening purposes 
provided it was performed within 28 days of Day 1 in this study and the ICF for this study 
was signed before the assessment in the prior study was performed. Following completion of 
the 165-302 or PAL-003 Study Completion Visit and confirmation of eligibility for 165-304, 
subjects may be dosed on the same day, designated 165-304 Day 1. 
The following study activities will be performed at the Screening/Week 1, Day 1 visit: 
x Demographics 
x Medical history 
x 12-lead ECG 
x Physical examination 
x Vital signs 
x Weight 
x Clinical laboratory tests 
x C-reactive protein (CRP) 
x Complements C3 and C4 
x Urine albumin/creatinine ratio. For subjects previously enrolled in PAL-003, blood 
for baseline urine/albumin creatinine ratio listed under Screening will be drawn 
pre-dose on Day 1 of 165-304. 
x Urine pregnancy test, if applicable. A serum pregnancy test must be performed in the 
event of any positive or equivocal urine pregnancy test result. 
x Diet diary issued to subject for use in reporting at Week 9 visit 
x PK (plasma pegvaliase). For subjects previously enrolled in 165-302, blood for 
baseline PK listed under Screening will be drawn pre-dose on Day 1 of 165-304. 
x Plasma Phe, tyrosine 
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x Immunogenicity assessments 
x AEs 
x Concomitant medications 
x Pegvaliase injection (after eligibility for 165-304 is established) 
12.3 
On Study Treatment and Assessments 
Events and assessments should be performed pre-dose unless otherwise specified. 
All scheduled assessments and procedures must be performed in the clinic or by a home 
healthcare nurse with the exception of administration of study drug, which may be done 
outside of the clinic. A home healthcare nurse may be made available to perform the 
following study assessments: 
x Injection training and education visits 
x Study drug administration 
x Observation of subject for 1 hour post-dose 
x Collection and/or preparation and shipment of blood and/or urine samples 
Assessment of AEs and concomitant medications should be performed whenever the subject 
is seen by site staff or a home healthcare professional. 
,IWKHUHLVDVNLQUHDFWLRQWKDWODVWV 14 days including reactions that could be potential 
vasculitis, the Skin Reaction eCRF should be completed and the subject should be referred to 
a dermatologist for consultation and a skin biopsy. It is recommended that a photograph of 
the skin reaction be taken by the subject or the site to help assess the event; photographs may 
be collected by the sponsor. Subjects who discontinue from study drug early will be asked to 
continue to perform the visit assessments until study completion (refer to Section 9.3.3). 
12.3.1 Week 9 (Day 57) and Every 8 Weeks Thereafter (± 7 Days) 
The following study activities are performed in the study clinic: 
x Physical examination 
x Vital signs 
x Weight 
x Clinical laboratory tests. It is recommended that urine samples are obtained as a first 
or second morning void. 
x C-reactive protein (CRP) 
x Complements C3 and C4 
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x Urine albumin/creatinine ratio 
x Urine pregnancy test, if applicable. A serum pregnancy test must be performed in the 
event of any positive or equivocal urine pregnancy test result. 
x Diet diary review with dietitian 
x PK (plasma pegvaliase) 
x Plasma Phe, tyrosine 
x Immunogenicity assessments 
x AEs 
x Concomitant medications 
x Pegvaliase injection 
12.3.2 Weekly Contacts (Week 2 Until Study Completion) 
In the weeks when subjects do not have a scheduled clinic visit, the following study activities 
are performed via telephone, email or other mode of communication: 
x Clinic staff asks whether there are any problems with self-administration of study 
drug and answers any questions. 
x Assessment of AEs 
x Concomitant medications 
12.4 
Hypersensitivity Reaction Visit 
Subjects with an NCI-CTCAE grade 3 or 4 suspected hypersensitivity reaction assessed by 
the investigator as related to study drug should return to the clinic between 8 and 24 hours 
following event onset for the following HRV evaluations: 
x Physical examination 
x Vital signs 
x Clinical laboratory tests. It is recommended that urine samples are obtained as a first 
or second morning void. 
x C-reactive protein (CRP) 
x Complements C3 and C4 
x Tryptase 
x Urine albumin/creatinine ratio 
x Urinalysis for N-methyl histamine 
x Immunogenicity assessment (anti-pegvaliase IgE only) 
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x Assessment of AEs  
x Concomitant medications 
Subjects who experience an injection-VLWHVNLQUHDFWLRQWKDWODVWV 14 days including 
reactions that could be potential vasculitis should be referred to a dermatologist for 
consultation and a skin biopsy. 
12.5 
Study Completion or Early Termination Visit 
Subjects should perform the Study Completion Visit 4 weeks after the last dose of study drug 
or after completion of study participation, whichever occurs last. 
For subjects who terminate from the study early, the Early Termination visit should occur 
within 4 weeks after the last study drug dose or after withdrawal from study participation, 
whichever occurs last. If study drug is discontinued before study completion, the investigator 
will ask the subject to remain in the study to continue study visits and assessments, provided 
the subject’s health, safety, and welfare would not be detrimentally affected (refer to 
Section 9.3.3). 
Any unresolved SAE, AE that caused a subject to withdraw from the study, or clinically 
significant abnormal laboratory value or vital sign measurement identified at this visit will be 
followed by the investigator until resolution. Every reasonable effort should be made to 
contact any subject who is lost to follow-up (refer to Section 9.3.3). 
The following study activities will be performed in the study clinic at the Study Completion 
or Early Termination visit: 
x 12-lead ECG 
x Physical examination 
x Vital signs 
x Weight 
x Clinical laboratory tests. It is recommended that urine samples are obtained as a first 
or second morning void. 
x C-reactive protein (CRP) 
x Complements C3 and C4 
x Urine albumin/creatinine ratio 
x Urine pregnancy test, if applicable. A serum pregnancy test must be performed in the 
event of any positive or equivocal urine pregnancy test result. 
x Diet diary for review with dietitian 
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x PK (plasma pegvaliase) 
x Plasma Phe, tyrosine 
x Immunogenicity assessments 
x AEs 
x Concomitant medications 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, source document requirements, CRFs, monitoring requirements, and 
procedures for reporting AEs, including SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, SAE reporting, and drug accountability 
records. 
Sites will enter study data into eCRFs in the study EDC system. Data Quality Control will be 
performed by BioMarin Clinical Data Management or designee through implementation of 
quality control checks specified in the study data management plan and edit check 
specifications. 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
The Statistical Analysis Plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS version 9.2. 
14.1 
Procedures for Accounting for Missing, Unused, and Spurious Data 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort will be made to ensure complete, accurate, and timely data collection 
and, therefore, avoid missing data. If study drug is discontinued before study completion, the 
investigator will ask the subject to remain in the study to continue study visits and 
assessments, provided the subject’s health, safety, and welfare are not detrimentally affected. 
For AEs and concomitant medications, partially missing dates will be imputed 
conservatively. 
14.2 
Safety Analysis 
14.2.1 Adverse Events 
The most current version of the Medical Dictionary for Regulatory Activities terminology 
(MedDRA) will be used by the sponsor to assign system organ class and preferred term 
classification to events and diseases based on the original terms entered on the eCRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-subject listing will 
be provided for those subjects who experience an SAE, including death, or experience an AE 
associated with early withdrawal from the study or study drug. Hypersensitivity AEs and 
AEs that result in dosing interruption or dose level reduction, and the percentage of subjects 
who report these AEs will be presented. 
14.2.2 Other Safety Variables 
Clinical laboratory data will be summarized by the type of laboratory test. Frequency and 
percentage of subjects who experience abnormal (ie, outside of reference range) and/or 
clinically significant abnormalities after study drug administration will be presented for each 
clinical laboratory test by study drug group. For each clinical laboratory test, descriptive 
statistics will be provided for baseline and all subsequent visits. Changes from baseline to the 
post-baseline visits will also be provided. Descriptive statistics for vital signs, physical 
examination results, ECG test results, and immunogenicity test results will also be provided. 
Additionally, antibody incidences and titers will be summarized at the scheduled time point. 
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14.3 
Primary Efficacy Analysis 
Data from all subjects who receive at least 1 dose of study drug and who have any 
post-treatment efficacy data will be included in the efficacy analysis. 
Blood Phe concentration at each scheduled time point will be summarized using descriptive 
statistics (mean, standard deviation, median, minimum, and maximum). Change in blood Phe 
concentration from baseline (to be defined in the SAP) to each scheduled time point will also 
be summarized. 
14.4 
Secondary Efficacy Analysis 
Average of 3-day dietary record at each scheduled time point will be summarized using 
descriptive statistics (mean, standard deviation, median, minimum, and maximum). 
The relationship between dietary Phe and protein intake (per information reported on the 
subject diet diary) and blood Phe concentration will also be explored. 
14.5 
Pharmacokinetics Analyses 
Trough concentrations of pegvaliase will be evaluated to assess steady-state trough exposure 
of pegvaliase administered using prefilled syringe. 
14.6 
Determination of Sample Size 
Subjects who were previously treated with pegvaliase in Studies PAL-003 or 165-302 may 
be enrolled into this study. No formal sample size calculation was conducted for this study. 
Approximately 40 subjects are expected to be enrolled. 
14.7 
Analysis Populations 
The safety population will consist of all subjects who receive at least 1 dose of pegvaliase 
during the study. 
The efficacy population will consist of all subjects who receive at least 1 dose of pegvaliase 
during the study and have post-treatment blood Phe concentration measurements. 
The PK population will consist of all subjects with at least 1 PK measurement. 
14.8 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
investigator considers that subject safety is compromised without immediate action. In these 
circumstances, immediate approval by the chair of the IRB must be sought and the 
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investigator should inform BioMarin and the full IRB/IEC within 2 working days after the 
safety issue occurs. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the IRB/IEC, 
and all active subjects must again provide informed consent. 
If discrepancies exist between the text of the statistical analysis as planned in the protocol 
and the final SAP, a protocol amendment will not be issued and the SAP will prevail. 
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15 
DATA MONITORING COMMITTEE 
The Data Monitoring Committee (DMC) will act in an advisory capacity to BioMarin to 
monitor subject safety and the efficacy of pegvaliase in subjects who participate in 
Study 165-304. The DMC responsibilities may include the following: 
x Review the study protocol, Investigator’s Brochure, and plans for data monitoring 
x Evaluate subject risk/benefit and other factors that could affect individual study or 
program outcome based on efficacy and safety data from current studies as well as 
external evidence such as scientific or therapeutic developments 
x Assess data report quality, data monitoring timeliness, and protocol compliance; 
request additional information if warranted 
x Protect the safety of the study participants in accordance with the stopping rules as 
defined in the study protocol 
x Make recommendations to BioMarin concerning continuation or termination of the 
study or other modifications of the study based on their observations 
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16 
COMPENSATION, INSURANCE AND INDEMNITY 
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the reasonable cost of travel for study-related visits in 
accordance with BioMarin’s study-specific travel and reimbursement policy. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort related 
solely to the study subject’s disease. Costs associated with such hospitalizations, tests, and 
treatments should be billed and collected in the way that such costs are usually billed and 
collected outside the study. 
The investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the study drug or by procedures performed as part of the study. Any 
subject who experiences a study-related injury should be instructed by the investigator to 
seek immediate medical treatment at a pre-specified medical institution if possible, or at the 
closest medical treatment facility, if necessary. The subject should be given the name of a 
person to contact to seek further information about, and assistance with, treatment for 
study-related injuries. The treating physician should bill the subject’s health insurance 
company or other third party payer for the cost of this medical treatment. If the cost of the 
medical treatment is not covered by health insurance or another third party that usually pays 
these costs, then either BioMarin or the institution may pay for reasonable and necessary 
medical services to treat the injuries caused by the study drug or study procedures. In some 
jurisdictions, BioMarin is obligated by law to pay for study-related injuries without prior 
recourse to third party payer billing and/or regardless of fault. If this is the case, BioMarin 
will comply with the law. 
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CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each subject. The investigator must review 
and electronically sign the completed eCRF casebook to verify its accuracy. 
eCRFs must be completed using a validated web-based application. Study site personnel will 
be trained on the application and will enter the clinical data from source documentation. 
Unless explicitly allowed in the CRF instructions, blank data fields are not acceptable. 
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with 21 CFR Part 11, the system will require the personnel making 
the correction to enter a reason for changing the value. The documented audit trail will 
include the reason for the change, the original value, the new value, the time of the correction 
and the identity of the operator. 
BioMarin’s policy is that study data on the eCRFs must be verifiable to the source data, 
which necessitates access to all original recordings, laboratory reports, and subject records. 
In addition, all source data should be attributable (signed and dated). The investigator must 
therefore agree to allow direct access to all source data. Subjects (or their legally authorized 
representative) must also allow access to their medical records, and subjects will be informed 
of this and will confirm their agreement when giving informed consent. If direct source 
document verification of study data by the site monitor is prohibited by institutional policy or 
local law, then the investigator must make available facilities and/or personnel to allow 
GCP-compliant source verification to occur. Examples of such methods include certified 
copies of records which have study data visible but sensitive information redacted, or other 
GCP-compliant means agreed between the investigator and the sponsor. 
A CRA designated by BioMarin will compare the eCRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed. 
Before a subject’s eCRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified. The Data Manager, or designee, will then set the status of the forms, 
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visits, and the entire casebook to Locked. The investigator will then electronically sign the 
casebook, specifying that the information on the eCRFs is accurate and complete. 
Upon completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 
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STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. 
The investigator and staff are responsible for being present or available for consultation 
during routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the investigator should notify BioMarin 
immediately. The investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 
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RETENTION OF RECORDS 
The investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The investigator/institution must take 
measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the US or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The investigator/institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution, or private practice, but not less than 15 years. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by a BioMarin agreement. BioMarin must be notified 
and will assist with retention should investigator/institution be unable to continue 
maintenance of subject files for the full 15 years. It is the responsibility of BioMarin to 
inform the investigator/institution as to when these documents no longer need to be retained. 
 
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USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the investigator/institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) (http://www.icmje.org/about-
icmje/faqs/icmje-recommendations/) and good publication practices (GPP). 
 
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21 
REFERENCES 
American Psychiatric Association. American Psychiatric Association: Diagnostic and Statistical Manual of 
Mental Disorders. In: American Psychiatric Association, editor. Washington, DC: 2000: 85-93. 
Bilder DA, Noel JK, Baker ER, et al. Systematic review and meta-analysis of neuropsychiatric symptoms and 
executive functioning in adults with phenylketonuria. Developmental Neuropsychology. 2016. 
Blau, N, Longo, N. Alternative therapies to address the unmet medical needs of patients with phenylketonuria. 
Expert Opin Pharmacother 16[6], 791-800. 2015. 
Brown, SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 114[2], 371-376. 
2004. 
Burton, BK, Bausell, H, Katz, R et al. Sapropterin therapy increases stability of blood phenylalanine levels in 
patients with BH4-responsive phenylketonuria (PKU) Mol Genet Metab, doi:10.1016/j.ymgme.2010.06.015. 
2010. 
Cunningham, A, Bausell, H, Brown, M, Chapman, M et. al. Recommendations for the use of sapropterin in 
phenylketonuria. Mol Genet Metab 106[3], 269-276. 2012. 
Dyer, CA, Kendler, A, Philbotte, T, et al. Evidence for central nervous system glial cell plasticity in 
phenylketonuria. J Neuropathol Exp Neurol 55[7], 795-814. 1996. 
Gassio R, Campistol J, Vilaseca MA, et al. Do adults with phenylketonuria improve their quality of life after 
introduction/resumption of a phenylalanine-restricted diet? Acta Paediatr 92[12], 1474-1478. 2003. 
Huttenlocher, P. The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr 159 [Suppl 
2], S102-S106. 2000. 
Kaufman, S. An evaluation of the possible neurotoxicity of metabolites of phenylalanine. J Pediatr 114[5], 895-
900. 1989.  
Koch R, Burton B, Hoganson G, et al. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis 
25, 333-46. 2002. 
MacDonald, A, Smith, TA, de Silva, S, et al. The personal burden for caregivers of children with 
phenylketonuria: a cross-sectional study investigating time burden and costs in the UK. Molecular Genetics and 
Metabolism Reports 9, 1–5. 2016. 
Modan-Moses, D, Vered, I, Schwartz, G, Anikster, Y, et al. Peak bone mass in patients with phenylketonuria. J 
Inherit Metab Dis 30[2], 202-208. 2007. 
Moyle, JJ, Fox, AM, Arthur, M, Bynevelt, M et. al. Meta-analysis of neuropsychological symptoms of 
adolescents and adults with PKU. Neuropsychol Rev 17[2], 91-101. 2007.  
NIH. Phenylketonuria (PKU): screening and management. NIH Consensus Statement 17[3], 1-33. 2000. 
NIHCDP (National Institutes of Health Consensus Development Panel). National Institutes of Health consensus 
development conference statement: phenylketonuria: screening and management. October 16-18, 2000. 
Pediatrics 108(4), 972-983. 2001. 
NIMH. The Numbers Count: Mental Disorders in America. NIH 1-8. 2013. 
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Palermo, L, Geberhiwot, T, MacDonald, A, et al. Cognitive outcomes in early-treated adults with 
phenylketonuria (PKU): a comprehensive picture across domains. Neuropsychology 31[3], 255–267. 2017. 
Pietz, J, Fatkenheuer, B, Burgard, P, Armbruster, M, et al. Psychiatric disorders in adult patients with early-
treated phenylketonuria. Pediatrics 99[3], 345-350. 1997. 
Romani, C, Palermo, L, MacDonald, A, et al. The impact of phenylalanine levels on cognitive outcomes in 
adults with phenylketonuria: effects across tasks and developmental stages. Neuropsychology, Vol. 31[3], 242–
254. 2017. 
Sampson, HA, Munoz-Furlong, A, Campbell, RL, Adkinson, NF, Jr, et al. Second symposium on the definition 
and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 117[2], 391-397. 2006.  
Schuck, PF, Malgarin, F, Cararo, JH, et al. Phenylketonuria pathophysiology: on the role of metabolic 
alterations. Aging and Disease 6[5], 390-99. 2015. 
Smith, I, Knowles, J. Behaviour in early treated phenylketonuria: a systematic review. Eur J Pediatr 159 Suppl 
2, S89-S93. 2000.  
Ten Hoedt AE, de Sonneville LM, Francois B, et al. High phenylalanine levels directly affect mood and 
sustained attention in adults with phenylketonuria: a randomised, double-blind, placebo-controlled, crossover 
trial. J Inherit Metab Dis 34(1), 165-171. 2011. 
van Spronsen, FJ, van Wegberg, AMJ, Ahring, K, et al. Key European guidelines for the diagnosis and 
management of patients with phenylketonuria. www.thelancet.com/diabetes-endocrinology. 2017.  
Vockley, J, Andersson, HC, Antshel, KM, et al. Phenylalanine hydroxylase deficiency: diagnosis and 
management guideline. Genet Med 16[2],188-200. 2014. 
Waisbren. Handbook of Neurodevelopmental and Genetic Disorders in Children. In: Goldstein S, Reynolds CR, 
editors. New York: Guildford Publications, 1999: 433-458. 
Wall, KM, Pardridge, WM. Decreases in brain protein synthesis elicited by moderate increases in plasma 
phenylalanine. Biochemical and Biophysical Research Communications 168[3], 1177-1183. 1990. 
Walter, JH, White, FJ, Hall, SK, MacDonald, A, et al. How practical are recommendations for dietary control in 
phenylketonuria? Lancet 360[9326], 55-57. 2002. 
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INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Subjects  
In accordance with FDA Form 1572 and/or principles of ICH E6 R2 GCP, the investigator 
will ensure that: 
x He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
x He or she will personally conduct or supervise the study. 
x He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes, and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and/or 
ICH E6 R2 Sections 2.9 and 4.8 are met. As well, he or she will ensure that IRB/IEC 
review and approval in 21 CFR Part 56 and/or ICH E6 R2 Section 2.6 are met. 
x He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 R2 Section 4.11. 
x He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
x His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
x Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 R2 
Section 4.9 are kept, and those records are available for inspection in accordance with 
21 CFR 312.68 and/or ICH E6 R2 Section 4.9.7. 
x The IRB/EC/REB complies with the requirements of 21 CFR Part 56, ICH 
Section 3.0, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human subjects or others are 
reported to the IRB/EC/REB. Additionally, he or she will not make any changes in 
the research without IRB/EC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human subjects. 
x He or she agrees to comply with all other requirements regarding the obligations of 
clinical investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6 R2. 
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SIGNATURE PAGE 
Protocol Title:  
An Open-label Extension Study to Evaluate the Safety and Efficacy of 
Subcutaneous Injections of Pegvaliase (> 40 mg/day Dose) in Adults 
with Phenylketonuria 
Protocol Number:  165-304 Amendment 1 
Protocol Date:  
30 July 2019 
 
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
ICH E6 R2, as stated in the protocol, and other information supplied to me. 
 
 
 
Investigator Signature 
 
Date 
Printed name: 
 
Accepted for the Sponsor: 
 
 
Medical Monitor Signature 
 
Date 
Printed name: 
 
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PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See page 2).  
Text that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font. 
Section No./Title 
Revision 
Rationale 
Synopsis (Study 
Rationale) 
Study 165-304 is an open-label extension for subjects who participated in Studies PAL-003 and 165-302 at doses > 40 
mg/day. The objective is to evaluate long-term safety and efficacy in subjects treated at doses exceeding the 
proposedapproved pegvaliase labellabeled dose (the currently approved label specifies up to and including 40 mg/day dose 
only). 
4 
Synopsis (Study 
Design and Plan) 
This is a Phase 3 open-label extension study enrolling approximately 40 adult subjects with PKU who were previously 
treated with pegvaliase in Studies PAL-003 or 165-302. The study is designed to evaluate the long-term safety and efficacy 
of pegvaliase administered as prefilled syringe drug product at a dose of > 40 mg/day to 60 mg/day, inclusive. Dose 
regimens other than daily dosing at > 40 mg/day to 60 mg/day (up to 5.0 mg/week butwith the exception of 1 subject 
enrolled from the PAL-003 study who receives a pegvaliase dose not to exceed 120 mg/day) may be allowed provided the 
investigator consults with the medical monitor and obtains approval from the medical monitor prior to starting the 
alternative regimen. Subjects will continue their prior pegvaliase dose regimen on the 165-304 study, including 1 subject 
enrolled from the PAL-003 study who receives a pegvaliase weekly dose upnot to 5.0exceed 120 mg/kg.day.  A subject who 
dose reduces to a dose of 40 mg/day or lower for 32 consecutive weeks will be discontinued from study drug and withdrawn 
from the study as they will have the option to transition to commercial drug. Dose reductions may be performed if 
warranted due to adverse events (AEs) or hypophenylalaninemia. Dose increases to up to 60 mg/day may be performed per 
investigator discretion in consultation with the sponsor’s medical monitor. Dosing will continue for approximately 61121 
weeks. 
1, 3 
Synopsis 
(Duration of 
Treatment) 
Approximately 61121 weeks 
1 
7/Introduction 
CurrentlyHistorically the only treatment option available for patients with PKU iswas medical nutritional therapy (MNT) 
with severe restriction of Phe intake, alone or as adjunct to Kuvan® (sapropterin 6R-tetrahydrobiopterin or 6R-BH4). 
4 
7.3/Study 
Rationale 
Study 165-304 is an open-label extension for subjects who participated in Studies PAL-003 and 165-302 at doses > 40 
mg/day. The objective is to evaluate long-term safety and efficacy in subjects treated at doses exceeding the 
proposedcurrently approved pegvaliase label (the label specifies up to and including 40 mg/day dose only). 
4 
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Section No./Title 
Revision 
Rationale 
7.4.1/Analysis of 
Condition 
Adult PKU patients often have untreated blood Phe levels > ȝPRO/CurrentlyHistorically, there arewere 2 treatment 
options available for patients with PKU: medical nutritional therapy (MNT) with Phe restriction, and sapropterin 
dihydrochloride (Kuvan) as adjunct to MNT and Phe restriction. 
4 
7.4.2/Unmet 
Medical Need and 
Current Treatment 
Options 
Sapropterin dihydrochloride (Kuvan) is a synthetic oral formulation of BH4, which works by increasing PAH activity in 
PKU patients with some residual enzyme function (Blau, 2015). Kuvan is approved for children and adults in the United 
States for the treatment of BH4-responsive PKU in conjunction with Phe-restricted intake, and in the European Union for 
BH4-responsive PKU and BH4 deficiency. 
,QWKHSLYRWDOFOLQLFDOVWXGLHVRI.XYDQRQO\DSSUR[LPDWHO\WRRISHGLDWULFDQGDGXOW3.8SDWLHQWVUHDFKHGD
PLQLPXPUHGXFWLRQLQEORRG3KHIURPEDVHOLQHDIWHUWUHDWPHQWZLWK.XYDQDWHLWKHUDPJNJRUPJ/kg dose 
(Kuvan package insert; Blau 2015). 
Kuvan is an approved pharmacological treatment for children and adults for the treatment of BH4-responsive PKU in the 
US. Approval of Kuvan was based on demonstrating blood Phe reduction in clinical trials and is indicated for use in 
conjunction with Phe-UHVWULFWHGLQWDNHWRORZHUEORRG3KHFRQFHQWUDWLRQV+RZHYHURQO\DSSUR[LPDWHO\WRRI
PKU patients respond to sapropterin therapy.  
Pegvaliase (Palynziq®) 
Pegvaliase was approved in the United States on 24 May 2018 under the name Palynziq for maintenance dosages up to 
40 mg/day to reduce blood Phe concentrations in adult patients with PKU who have uncontrolled blood Phe 
concentrations  > 600 μmol/L on existing management, addressing a substantial unmet medical need for the adult PKU 
patient population. On 3 May 2019, pegvaliase was also approved in the EU to reduce blood Phe in patients with PKU aged 
16 years and older who have inadequate blood Phe control (dHILQHGDVEORRG3KHOHYHOVJUHDWHUWKDQȝPRO/GHVSLWH
prior management with available treatment options. 
4 
7.4.4/Risk 
The safety of pegvaliase was evaluated in 6 multiple dose studies in adult PKU patients totaling 473.4579.6 patient-years of 
exposure with the recommended I/T/M dosing regimen for pegvaliase, including 298.6403.4 patient-years of exposure with 
the to-be-marketed PFS presentation. Thus, important identified and potential risks associated with pegvaliase use have 
been sufficiently characterized to inform benefit-risk decisions by adult PKU patients and their treating physicians. 
5 
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Section No./Title 
Revision 
Rationale 
The most commonly reported treatment-emergent AEs were arthralgia (7072.6LQMHFWLRQVLWHUHDFWLRQ6564.9
headache (5251.2DQGLQMHFWLRQVLWHHU\WKHPD4350.2,QWKHmultiple-dose studies of pegvaliase,I/T/M population  
hypersensitivity adverse events (HAEs) were very common (93.594DQGLQFOXGHGDUWKUDOJLD69.571UDVK40.238
pruritus (31.4XUWLFDULDVHUXPVLFNQHVVS\UH[LD and angioedema (0.4injection site rash 
(217KHKLJKHVW+$(VHYHULW\ZDV*UDGHIRU22.618.2RIVXEMHFWVRU*UDGHIRU58.962.5VXEMHFWV0RVW.6
HAEs did not require pegvaliase dose modification, and 97.5RI+$(VUHVROYHG 
9.1/Overall Study 
Design and Plan 
This is a Phase 3 open-label extension study enrolling approximately 40 adult subjects with PKU who were previously 
treated with pegvaliase in Studies PAL-003 or 165-302. The study is designed to evaluate the long-term safety and efficacy 
of pegvaliase administered as prefilled syringe drug product at a dose of > 40 mg/day to 60 mg/day, inclusive. Dose 
regimens other than daily dosing at > 40 mg/day to 60 mg/day (up to 5.0 mg/week butwith the exception of 1 subject 
enrolled from the PAL-003 study who receives a pegvaliase dose not to exceed 120 mg/day) may be allowed provided the 
investigator consults with the medical monitor and obtains approval from the medical monitor prior to starting the 
alternative regimen. Subjects will continue their prior pegvaliase dose regimen on the 165-304 study, including 1 subject 
enrolled from the PAL-003 study who receives a pegvaliase weekly dose upnot to 5.0exceed 120 mg/kgday. A subject who 
dose reduces to a dose of 40 mg/day or lower for 32 consecutive weeks will be discontinued from study drug and withdrawn 
from the study as they will have the option to transition to commercial drug. Dose reductions may be performed if 
warranted due to AEs or hypophenylalaninemia. Dose increases to up to 60 mg/day may be performed per investigator 
discretion in consultation with the sponsor’s medical monitor. Dosing will continue for approximately 61121 weeks. 
1, 3 
Table 9.1.1/SOE 
(footnotes) 
k Immunogenicity assays include (but are not limited to) total anti-pegvaliase, anti-rAvPAL IgG, anti-rAvPAL IgM, anti-
PEG IgG, anti-PEG IgM, anti-pegvaliase IgG4, and neutralizing antibodies; additional assays include IgG-C3d and IgM-
C3d circulating immune complexes (CICs); anti-pegvaliase IgE is determined when appropriate (hypersensitivity or other 
safety concern). 
2 
Table 
9.1.1.2.1/Dosing 
After HAE 
(footnotes) 
c The pegvaliase dose may be reduced or interrupted if necessary per investigator determination. The investigator should 
consult with the sponsor’s medical monitor prior to performing dose reductions during Part 2... 
5 
9.3.5/Duration of 
Subject 
Participation 
Following a screening period of up to 28 days, subjects receive pegvaliase for approximately 61121 weeks or until study 
closure. 
1 
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Section No./Title 
Revision 
Rationale 
9.7.4/Exploratory 
Sample Analysis 
Blood and urine samples may be analyzed to evaluate biochemical, molecular, cellular and genetic/genomic aspects of PKU 
and to develop the assays used for these evaluations. For each portion of the blood and urine samples reserved for protocol-
specified analyses, there may be multiple sample aliquots. Once samples have been successfully analyzed during the study 
per protocol,The unused sample portionsaliquots may be used during the study and afterwards to evaluate the biochemical, 
molecular, cellular, and genetic/genomic aspects of PKU and to develop the assays used for these evaluations.for assay 
development or other purposes stated in Section 9.7.4.   
5 
9.7.5.3.4/Other 
Laboratory 
Assessments 
Immunogenicity will be assessed by determining antibody response with immunogenicity assays including, but not limited 
to, the following: 
x 
Anti-PEG IgG antibodies 
x 
Anti-PEG IgM antibodies 
x 
Anti-pegvaliase IgG4 antibodies 
x 
IgG-C3d and IgM-C3d Circulating Immune Complexes (CICs) 
2 
10.2.3/Assessment 
of Seriousness, 
Severity, and 
Causality 
The investigator responsible for the care of the subject or qualified medical designee will assess AEs for severity, 
relationship to study drug, and seriousness (refer to Section 10.1.2 for SAE definitions). 
5 
10.3.1.7/ 
Hospitalization, 
Prolonged 
Hospitalization, or 
Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE except as 
described below. There are some hospitalization scenarios that do not require reporting as an SAE when there is no 
occurrence of an AE. These scenarios include planned hospitalizations or prolonged hospitalizations to: 
x 
Routine hospitalization for childbirth, including planned caesarean section 
5 
10.5/Follow-Up 
after AEs 
The investigator should follow all unresolved AEs and SAEs until the events are resolved or have stabilized,, unless the 
subject is lost to follow-up, or it has been determined that the study treatment or participation was not the cause of the AE or 
SAE. Resolution The outcome of AEs and SAEs (with dates) should be documented on the AE eCRF and in the subject’s 
medical record to facilitate source data verification. 
The investigator should follow all unresolved SAEs to resolution, unless the subject is lost to follow up, or it has been 
determined that the study treatment or participation was not the cause of the SAE.  Resolution of the SAE (with dates) 
5 
DocuSign Envelope ID: D7A66402-315A-4939-8858-10F8915CA3E5


 
(165-304 Amendment 1)  
Page 94 
 
Proprietary and Confidential 
30 July 2019 
Section No./Title 
Revision 
Rationale 
should be documented on the AE eCRF and the SAE report form, as well as the subject's medical record to facilitate source 
data verification. 
 
DocuSign Envelope ID: D7A66402-315A-4939-8858-10F8915CA3E5

SAP_001.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title:  An Open-label Extension Study to Evaluate the Safety and Efficacy of 
Subcutaneous Injections of Pegvaliase (> 40 mg/day Dose) in Adults with 
Phenylketonuria 
 
 
NCT Number: NCT03694353 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date:  07 May 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study name: 
Overview 
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165-304
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Proprietary and Confidential 
 
 
105 Digital Drive 
Novato, CA 94949 
 
 
 
Statistical Analysis Plan 
 
Study 165-304 
 
07 May 2021 
 
 
 
 
 
 
 
The information in this document is considered privileged and confidential by BioMarin 
Pharmaceutical Inc. and may not be disclosed to others except to the extent necessary to obtain 
Institutional Review Board approval and informed consent, or as required by Federal and State Laws.  
Persons to whom this information is disclosed must be informed that this information is privileged 
and confidential and that it should not be further disclosed. 
 


 
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TABLE OF CONTENTS 
1 LIST OF ABBREVIATIONS ..............................................................................................4
2 INTRODUCTION ...............................................................................................................6
2.1 Objectives of Study .....................................................................................................6
2.2 Study Design ...............................................................................................................6
2.3 Study Population .........................................................................................................7
2.4 Study Dosage and Administration ..............................................................................7
2.5 Sample Size Determination .........................................................................................7
2.6 Blinding and Randomization Methods .......................................................................7
2.6.1
Blinding Method ............................................................................................7
2.6.2
Randomization Method .................................................................................8
2.7 Interim Analysis ..........................................................................................................8
3 GENERAL ANALYSIS CONSIDERATION .....................................................................9
3.1 Analysis Populations ...................................................................................................9
3.1.1
Efficacy .........................................................................................................9
3.1.2
Safety .............................................................................................................9
3.2 Treatment Group Presentation ....................................................................................9
3.3 Pooling of Data from Sites with Small Enrollment ....................................................9
3.4 Study Day Derivation ..................................................................................................9
3.4.1
Baseline Definition ......................................................................................10
3.5 Visit Window for Analysis .......................................................................................10
3.6 Handling of Dropouts and Missing Data ..................................................................11
4 SUBJECT DISPOSITION .................................................................................................12
5 DISCONTINUATION AND COMPLETION ..................................................................13
6 PROTOCOL DEVIATIONS .............................................................................................14
7 DEMOGRAPHICS AND BASELINE CHARACTERISTICS.........................................15
8 MEDICAL HISTORY .......................................................................................................16
9 PRIOR AND CONCOMITANT MEDICATIONS/PROCEDURES ................................17
10 STUDY DRUG USAGE....................................................................................................19
11 EXTENT OF EXPOSURE TO STUDY DRUG ...............................................................20


 
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12 EFFICACY EVALUATIONS ...........................................................................................21
12.1 Primary Efficacy Variables .......................................................................................21
12.2 Secondary Efficacy Variables ...................................................................................21
12.3 Pharmacokinetics ......................................................................................................21
13 SAFETY EVALUATIONS ...............................................................................................22
13.1 Adverse Events .........................................................................................................22
13.1.1 All Adverse Events ......................................................................................22
13.1.2 Low Blood Phe (Blood Phe ȝPRO/$QDO\VLV ...................................24
13.1.3 Other Adverse Event Analysis ....................................................................24
13.2 Clinical Laboratory Tests ..........................................................................................24
13.3 Vital Signs .................................................................................................................24
13.4 12-lead Electrocardiogram ........................................................................................24
13.5 Physical Examination ................................................................................................25
13.6 Immunogenicity Tests ...............................................................................................25
13.7 Pregnancy Test ..........................................................................................................25
14 APPENDICES ...................................................................................................................26
 
LIST OF TABLES 
Table 3.5.1:  Visit Time Windows for the Treatment Period ..................................................11
 
LIST OF APPENDICES 
Appendix 1:  Search Strategies for Adverse Event of Special Interest, and Sponsor 
Defined AEs of Clinical Significance ...........................................................26
 


 
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1 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
AUC 
area under the concentration-time curve 
BMI 
body mass index 
C3 
complement component 3 
C4 
complement component 4 
CRP 
C-reactive protein 
CRF 
Case Report Form 
CSR 
CTCAE 
clinical study report 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
electrocardiogram 
HAE 
hypersensitivity adverse event 
HI 
hyperactivity/impulsivity 
IA 
inattention 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
ITT 
intent-to-treat 
IWRS 
LOCF 
Interactive Web Response System 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
Nab 
neutralizing antibody 
NIAID/FAAN 
National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network 
NCA 
non-compartmental analysis 
NSAID 
non-steroidal anti-inflammatory drug 
PAL 
phenylalanine 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
Phe 
phenylalanine 


 
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Abbreviation 
Definition 
PK 
pharmacokinetics 
PKU 
phenylketonuria 
PT 
preferred term 
rAvPAL-PEG  
recombinant Anabaena variabilis phenylalanine ammonia lyase-PEG 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SMQ 
Standardized MedDRA Queries 
TEAE 
treatment-emergent adverse event 
t1/2 
elimination half-life 
TMD 
total mood disturbance 
V/F 
apparent volume of distribution 
Tab 
total antibody 
WHO Drug 
World Health Organization Drug Dictionary 


 
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2 
INTRODUCTION 
Study 165-304 is an open-label extension study to evaluate long-term safety and efficacy of 
VXEFXWDQHRXVLQMHFWLRQVRISHJYDOLDVH!PJGD\'RVHLQDGXOWVZLWKSKHQ\ONHWRQXULD
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RIPHWKRGVRIWKHGDWDDQDO\VHVRXWOLQHGLQWKHSURWRFRO-XO\ 
If discrepancies exist between the text of the statistical analysis as planned in the protocol 
and the final SAP, a protocol amendment will not be issued and the SAP will prevail. 
2.1 
Objectives of Study 
The primary objective of the study is: 
x To evaluate the long-WHUPVDIHW\DQGHIILFDF\RISHJYDOLDVH!PJGD\GRVHLQ
adult patients with PKU 
The secondary objective of the study is: 
x To characterize dietary protein intake from medical food and from intact food during 
long-WHUPWUHDWPHQWZLWKSHJYDOLDVH!PJGD\GRVHLQDGXOWSDWLHQWVZLWK3.8 
The exploratory objective of the study is: 
x To characterize the long-term immunogenicity profile of pegvaliase (> 40 mg/day 
GRVHLQDGXOWSDWLHQWVZLWK3.8 
2.2 
Study Design 
This is a Phase 3 open-label extension study enrolling approximately 40 adult subjects with 
PKU who were previously treated with pegvaliase in Studies PAL-003 or 165-302. The study 
is designed to evaluate the long-term safety and efficacy of pegvaliase administered as 
prefilled syringe drug product at a dose of > 40 mg/day to 60 mg/day, inclusive. Dose 
regimens other than daily dosing at > 40 mg/day to 60 mg/day (with the exception of 1 
subject enrolled from the PAL-003 study who receives a pegvaliase dose not to exceed 120 
PJGD\PD\EHDOORZHGSURYLGHGWKHLQYHVWLJDWRUFRQVXOWVZLWKWKHPHGLFDOPRQLWRUDQG
obtains approval from the medical monitor prior to starting the alternative regimen. Subjects 
will continue their prior pegvaliase dose regimen on the 165-304 study, including 1 subject 
enrolled from the PAL-003 study who receives a pegvaliase dose not to exceed 120 mg/day. 
A subject who dose reduces to a dose of 40 mg/day or lower for 32 consecutive weeks will 
be discontinued from study drug and withdrawn from the study as they will have the option 
to transition to commercial drug. Dose reductions may be performed if warranted due to AEs 
or hypophenylalaninemia. Dose increases to up to 60 mg/day may be performed per 


 
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investigator discretion in consultation with the sponsor’s medical monitor. Dosing will 
continue for approximately 121 weeks. 
After providing informed consent, subjects undergo screening evaluations to determine study 
eligibility. Screening assessments must be performed within 28 days of the first 165-304 dose 
of pegvaliase on Day 1. Study PAL-003 or 165-302 Study Completion Visit assessments may 
be used for the purpose of screening, with Day 1 of 165-304 taking place the same day. 
Pegvaliase dosing should continue without interruption from the previous study; beginning 
on Day 1, subjects will receive the same dose and regimen of pegvaliase they were receiving 
in 165-302 or PAL-003. Subsequent revisions to dosing regimens are allowed following 
consultation with the medical monitor. Subjects on temporary pegvaliase hold due to 
pregnancy planning in PAL-003 or 165-302 (and who received pegvaliase doses > 40 mg/day 
dose and up to 60 mg/day dose, inFOXVLYHZLOOEHVFUHHQHGDQGHQUROOHGLQ-304; 
however, they will not receive pegvaliase until consultation with the medical monitor 
WHPSRUDU\KROGUHOHDVHG 
2.3 
Study Population 
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PAL-003 or 165-!PJGD\GRVHXSWRPJGD\GRVHLQFOXVLYHDUHFDQGLGDWHVIRU
participation in the study. Additional criteria for study participation are presented in Protocol 
165-304 Section 9.3.1 and Section 9.3.2. 
2.4 
Study Dosage and Administration 
Subject will begin the study on the same dose and dosing regimens they were on at the 
completion of the previous study. Subjects will receive pegvaliase SC via pre-filled syringe 
at a dose of >40 mg/day to 60 mg/day, inclusive. Dose reductions may be performed if 
warranted due to AE or hypophenylalaninemia. Dose increases to up to 60 mg/day may be 
performed per investigator discretion in consultation with the sponsor’s medical monitor 
2.5 
Sample Size Determination 
Subjects who were previously treated with pegvaliase in Studies PAL-003 or 165-302 may 
be enrolled into this study. No formal sample size calculation was conducted for this study. 
Approximately 40 subjects are expected to be enrolled. 
2.6 
Blinding and Randomization Methods 
2.6.1 Blinding Method 
Subjects will receive open-label pegvaliase. 


 
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2.6.2 Randomization Method 
This is an open-label study. 
2.7 
Interim Analysis 
Not applicable. 


 
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3 
GENERAL ANALYSIS CONSIDERATION 
Descriptive summaries of continuous variables will include the mean, standard deviation 
6'PHGLDQPLQLPXPPD[LPXPDQGZKHUHDSSURSULDWHFRQILGHQFHLQWHUYDOIRUWKH
mean. Descriptive summaries of categorical variables will include n, frequency, and 
percentage.   
Baseline data and relevant dosing data from parent studies will be integrated together with 
data in Study 165-304 for long term safety and efficacy analyses, when appropriate. 
Additional analyses will be conducted as appropriate to evaluate the impact of the COVID19 
pandemic on the study conduct and results, especially for the treatment effect as estimated in 
the trial. 
3.1 
Analysis Populations 
3.1.1 Efficacy 
The efficacy population will consist of all subjects who receive at least one dose of 
pegvaliase during the study and have post-treatment blood Phe concentration measurement. 
The PK population will consist of all subjects with at least one PK measurement. 
3.1.2  Safety 
The safety population will consist of all subjects who receive at least one dose of pegvaliase 
during the study. 
3.2 
Treatment Group Presentation 
The following treatment groups will be considered in summary tables: 
x Daily dose at each Phe/safety assessment (<20mg, 20 to < 40 mg, 40 to <60 mg, 
൒60 PJDQG$Q\'RVH 
3.3 
Pooling of Data from Sites with Small Enrollment 
Since the enrollment for each site is expected to be small, the analyses will not be adjusted by 
site or pooled sites.   
3.4 
Study Day Derivation 
Study days will be derived as follows: 
x The drug start date in study 304 will be assigned as Study Day 1 
x For visit occurs on or after drug start date, Study day = visit date – day 1 date + 1 


 
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x For visit occurs before drug start date, Study day = visit date – day 1 date. There is no 
Study Day 0 
3.4.1 Baseline Definition 
7KHSDUHQWVWXG\EDVHOLQHQDwYHEDVHOLQHIRUDOOVDIHW\and efficacy endpoint is defined as 
the last non-missing measurement prior to the initiation of pegvaliase in the parent study. 
7KHVWXG\EDVHOLQHIRUDOOVDIHW\DQGHIILFDF\HQGSRLQWZKHQDSSOLFDEOHLVGHILQHGDV
the last non-missing measurement collected prior to first pegvaliase dose in study 304. 
3.5 
Visit Window for Analysis 
All efficacy and safety data will be summarized by study week of assessment. An assessment 
for a subject will be classified according to the study day of the assessment where it falls 
within a window. The windows are designated for each scheduled week of visit and centered 
on a target day. If there are two or more assessments within a designated window, the 
assessment that is closest to the target day will be used for analyses. If the two closest 
assessments to the target day are equidistant from the target day, then for numerical variable, 
the average of the two assessments will be used for analyses. For categorical variable, the 
worse of the 2 equidistant measurements, indicating less treatment effect, will be used.  
Table 3.5.1 lists the scheduled weeks of the assessments collected in this study and the 
corresponding range of trHDWPHQWGD\VZLQGRZGXULQJZKLFKDYLVLWPD\KDYHRFFXUUHG 
 
 


 
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Table 3.5.1:  Visit Time Windows for the Treatment Period  
Derived Visit 
Target Daya 
Windowb 
Screening/Day 1 
Day -1 
Day -28 to 1 
Week 9 
Day 57  
Day 2 to Day 84 
:HHN;;;;!HYHU\ZHHNV Day (XX- 
Day (XX-WR'D\;; 
a  Target days are relative to the first dosing day of study drug. 
b Visit day is calculated by (visit date – ILUVWGRVLQJGD\ 
3.6 
Handling of Dropouts and Missing Data 
Subjects who discontinued prematurely will not be replaced. To investigate the robustness of 
the primary analysis, last observation carried forward (LOCFLPSXWDWLRQDSSURDFKZLOOEH
used as sensitivity analysis.  


 
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4 
SUBJECT DISPOSITION 
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WKHQXPEHURIVXEMHFWVZKRFRPSOHWHGWKHVWXG\WKHQXPEHURIVXEMHFWVZKR
completed study treatment, and the number of subjects in each analysis population (efficacy, 
VDIHW\3.DVDSSURSULDWHZLOOEHVXPPDUL]HG 


 
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5 
DISCONTINUATION AND COMPLETION 
For subjects who prematurely discontinued study, the primary reason for discontinuation will 
be summarized by treatment group. A similar summary will be provided for subjects who 
discontinue study drug. A subject listing of completion and early termination from study will 
also be provided.  


 
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6 
PROTOCOL DEVIATIONS 
A major protocol deviation is defined as a departure from the approved study protocol that 
may impact the rights, safety, or welfare of the subjects or the integrity of the data, which 
will be summarized by deviation category.  
A minor or administrative protocol deviation is defined as a departure from the approved 
study protocol that has minimum or no impact on the rights, safety, or welfare of the subjects 
or the integrity of the data. Minor protocol deviations will also be summarized by deviation 
category. For details regarding the classification of the deviations, please refer to the Study 
Specific Guideline for Managing Protocol Deviations. 
All protocol deviations collected in 165-304 will be summarized. Subjects with protocol 
deviations will be provided in a listing. Subjects with inclusion or exclusion criteria 
deviations will also be provided in a separate listing. 


 
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7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Subject demographic information will be summarized for the efficacy analysis population as 
well as the safety population. Demographics, including age, age group, sex, race, and 
ethnicity, will be summarized by descriptive statistics. 
Subject characteristics at study 165-304 baseline as well as parent study baseline (naïve 
EDVHOLQHZLOOEHVXPPDUL]HGIRUWKHHIILFDF\DQalysis population and safety population. 
Baseline subject characteristics will include height, weight, BMI, blood Phe concentration, 
intake of protein and dietary Phe, three-day average dietary intake, percent of subjects on 
restricted diet, and antibody status.  


 
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8 
MEDICAL HISTORY 
Each subject’s chronic diseases, disorders, and surgeries in the past will be collected as 
general medical history. General medical history will be summarized by system organ class 
62&DQG3UHIHUUHG7HUP37E\GHVFHQGLQJRUGHURIIUHTXHQF\IRUDOOVXEMects enrolled in 
165-304. A by-subject listing of each subject’s medical history collected at the Screening 
Visit will also be provided.  


 
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9 
PRIOR AND CONCOMITANT MEDICATIONS/PROCEDURES 
Prior and concomitant medications will be summarized for all subjects entering 165-304. For 
analysis purposes, the following definitions will be used to determine prior and concomitant 
medications: 
x Prior medications: any medications taken within 30 days prior to screening and prior 
to the date of initial study drug administration in 165-304. 
x Concomitant medications: any medications initially taken on or after the date of 
initial study drug administration. 
x Prior and concomitant medications: any medications taken both prior to the date of 
initial study drug administration and on or after the date of initial study drug 
administration will be reported both as prior and concomitant medications. Therefore, 
any medications taken prior to the first dose date where the stop date is reported as 
“continuing” or missing will be considered both as prior and concomitant 
medications. 
In the event the start date of a medication is partial, the following imputation rules will be 
applied: 
x If only day is missing, then the start date will be imputed as the first day of the month, 
if the year and month is same or after the first dose year and month. If only day is 
missing, then the start date will be imputed as the last day of the month, if the year 
and month is prior to the first dose year and month. If month is the same as the month 
of first dose of study drug then the start date will be imputed as the first dose date.  
x If only year is non-missing, then the start date will be imputed as the first day of the 
year. If year is the same as the year of first dose of study drug then the start date will 
be imputed as the first dose date. 
In the event the stop date of a medication is partial, the following imputation rules will be 
applied: 
x If only day is missing, then the end date will be imputed as the last day of the month.  
x If only year is non-missing, then the end date will be imputed as the last day of the 
year.  
All medications will be coded using the current version of the World Health Organization 
'UXJ:+2'UXJGLFWLRQDU\6HSWHPEHU3ULRUDQGFRQFRPLWDQWPHGLFDWLRQXVHZLOO
be separately summarL]HGE\$QDWRPLFDO7KHUDSHXWLF&KHPLFDO$7&PHGLFDWLRQFODVV
(Level DQGSUHIHUUHGQDPHLHJHQHULFPHGLFDWLRQQDPH$VXEMHFWUHSRUWLQJWKHVDPH
medication more than once will be counted once when calculating the number and 


 
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percentage of subjects who received that medication. A subject listing of each subject’s prior 
and concomitant medications will be provided. 


 
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10 
STUDY DRUG USAGE 
Study drug usage rate will be calculated based on the drug exposure records captured in 
eCRFs and dispensed drug amount capWXUHGLQWKH,QWHUDFWLYHZHEUHVSRQVHV\VWHP,:56 
The overall study drug usage rate will be derived from the total amount of study drug intake 
divided by the total dispensed study drug amount over the study period and multiplied by 
 


 
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11 
EXTENT OF EXPOSURE TO STUDY DRUG 
7RWDOQXPEHURIGD\VRQGUXJWRWDODPRXQWRIVWXG\GUXJPJDQGPHDQGDLO\GRVHPJ
will be presented using summary statistics such as n, mean, SD, median, minimum, and 
maximum for the following variables: 
x $YHUDJHRIGDLO\GRVHVPJUeceived 
x 7RWDO'RVHVPJUHFHLYHG 
x Total duration of treatment 
Any dose interruption longer than 28 days will be excluded from the total exposure duration 
calculation. 
The extent of exposure will be summarized using observed data collected on the exposure 
CRF only.  
A by-subject listing of each subject’s extent of exposure and compliance will be provided. 


 
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12 
EFFICACY EVALUATIONS 
Unless specified otherwise, efficacy analyses will be based on the efficacy population.  
12.1 
Primary Efficacy Variables 
The primary efficacy variable is phe concentration, the following will be summarized: 
x Observed values, change and percent change from parent study baseline in blood Phe 
concentration at each visit 
x 3HUFHQWRIVXEMHFWVZLWKEORRG3KH ȝPRO/DWHDFKYLVLWGXULQJVWXG\ 
x 3HUFHQWRIVXEMHFWVZLWKEORRG3KH ȝPRO/DWHDFKYLVLWGXULQJVWXG\ 
x 3HUFHQWRIVXEMHFWVZLWKEORRG3KH ȝPRO/DWHDFKYLVLWGXULQJVWXG\ 
The efficacy variable will be summarized by 8-week cycle for blood Phe. Plots for mean 
blood Phe concentration, change from baseline and percentage change from baseline in blood 
Phe concentration will be generated for both observed values and values after LOCF 
imputation. A subject listing of blood Phe concentration will be provided. 
12.2 
Secondary Efficacy Variables 
The parameters of interest for dietary intake include: 
x Protein intake from medical food 
x Protein intake from intact food 
x Total protein intake 
x Total calorie intake 
x Total tyrosine intake 
x Total phenylalanine intake 
The observed values, change and percent change from naïve baseline at parent studies for all 
parameters at each visit will be summarized for the efficacy population. The values collected 
on the three-day diet diary will be averaged for each parameter at each visit before being 
summarized. In addition, similar analysis will be performed for percentage of daily 
recommended intake provided for protein, Phe, tyrosine, vitamins and minerals. A subject 
listing will also be provided. 
12.3 
Pharmacokinetics 
Table summary and subject listing of plasma pegvaliase concentration by study visit will be 
provided. 


 
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13 
SAFETY EVALUATIONS 
Safety will be assessed by examining the incidence, exposure adjusted event rate, severity 
grade, and relationship to study drug of all treatment-emergent adverse eventV7($(V
reported during the study period. In addition, clinical laboratory results, vital signs, 
pregnancy test, physical exam and ECG values will be assessed.  
13.1 
Adverse Events 
$(VZLOOEHFRGHGLQDFFRUGDQFHZLWKWKH0HG'5$YHUVLRQ2QO\WUHDWPHQW-emergent 
DGYHUVHHYHQWV7($(VRFFXUULQJDQGUHSRUWHGGXULQJWKHVWXG\SHULRGZLOOEHLQFOXGHGLQ
the adverse event summaries. A TEAE is defined as any AE that newly appeared or 
worsened in severity following initiation of the study drug administration until 30 days after 
last dose of the study. If the onset date of an AE is missing, the AE will be considered 
treatment-emergent.   
13.1.1 All Adverse Events 
The incidence and frequency of all treatment-emergent AEs will be summarized by system 
RUJDQFODVV62&SUHIHUUHGWHUP37UHODWLRQVKLSWRVWXG\GUXJDQG1DWLRQDO&DQFHU
,QVWLWXWH1&,&RPPRQ7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV&7&$(VHYHULW\JUDGHV
For those AEs that occurred more than once during the study, the maximum severity will be 
used to summarize the AEs by severity. 
If the onset date or end date of an adverse event is partial, the same imputation rules 
described in Section 9 will be applied. 
The treatment-emergent AEs will be summarized in the following categories: 
x All AEs by SOC and PT 
x All AEs by SOC, PT and severity 
x AEs assessed by investigators as related to study drug by SOC and PT 
x AEs assessed by investigators as related to study drug by SOC, PT and severity 
x SHULRXV$(V6$(VE\62&DQG37 
x All AEs by PT in descending frequency order  
x All AEs by SOC and PT with exposure adjusted event rate 
x Neuropsychiatric AEs by SOC, PT and severity 
x AEs assessed by investigators as related to PFS/Device malfunction  
x AEs leading to withdrawal from study by SOC and PT 


 
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x AEs leading to study drug discontinuation by SOC and PT 
In addition to the standard summary tables and listings, the following information will also 
be summarized for AEs of special interest, and sponsor defined AEs of significance: 
x AE profile summary table, including: 
 Duration of the events during 165-304 
 5HFXUUHQFHRIWKHHYHQWVVXPPDU\IRUQXPEHURIHYHQWVSHUVXEMHFW 
 Actions related to study drug 
 Outcomes of the events 
x Pre-medication usage 
x Common treatment 
x Incidence rate over time 
The AEs of special interest include: 
x Anaphylaxis per NIAID/FAAN criteria 
x Acute systemic hypersensitivity reaction 
x Anaphylaxis per FDA criteria 
The sponsor defined AEs of Clinical clinical significance include:  
x Hypersensitivity Reaction  
x Angioedema 
x Serum sickness 
x Severe injection site reaction 
x +\SRSKHQ\ODODQHPLDVHHORZEORRG3KHOHYHOVEHORZ 
x *HQHUDOL]HGVNLQUHDFWLRQZLWKGD\GXUDWLRQ 
x ,QMHFWLRQVLWHVNLQUHDFWLRQZLWKGD\GXUDWLRQ 
x Persistent arthralgia (> 6 months duratLRQ 
The search strategy for AEs of special interest and sponsor defined AEs of significance is 
provided in Appendix 1.  
In addition to standard AE listings, by-subject listings of injection site reaction AEs, HAEs, 
and psychiatric AEs under each identification strategies will be provided. Study drug dose 


 
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level at onset date of each of the AE, and immunogenicity test results will be presented on 
the listings. AEs will be sorted by onset date, preferred term, and end date. 
13.1.2 /RZ%ORRG3KH%ORRG3KHȝPRO/$QDO\VLV 
Safety from subjects who experienced two coQVHFXWLYHORZEORRG3KHȝPRO/
measurements will be summarized. 
13.1.3 Other Adverse Event Analysis 
$OOODEDGYHUVHHYHQWVGHILQHGDV$(VZLWK62&HTXDOWR³,QYHVWLJDWLRQDO3URGXFW´WKDWDUH
NCI CTCAE grade >3 will be summarized. 
13.2 
Clinical Laboratory Tests 
Standard descriptive statistics will be presented for clinical laboratory tests, including 
hematology, chemistry and urinalysis, at each scheduled visit and for change in laboratory 
values from baseline. The proportion of subjects who experienced at least one laboratory test 
result outside the normal ranges will be presented for each measurement as appropriate. Shift 
table from baseline to most extreme post-baseline value based on normal range and based on 
&7&JUDGLQJZKHUHDYDLODEOHZLOODOVREHJHQHUDted for each parameter as appropriate. A 
subject listing of laboratory test results for hematology, chemistry, urinalysis, and other 
laboratory tests will be provided separately. Values with CTC grade as 3 or above will be 
flagged in the listings. 
A listinJRIODERUDWRU\WHVWUHVXOWVIRUVXEMHFWVZLWKDODQLQHWUDQVDPLQDVH$/7RUDODQLQH
DPLQRWUDQVIHUDVH$67[8/1DQGWRWDOELOLUXELQ[8/1ZLOODOVREHSURYLGHG 
13.3 
Vital Signs 
9LWDOVLJQVZLOOLQFOXGHV\VWROLFEORRGSUHVVXUH6%3DQGGLDVWROLFEORRGSUHVVXUH'%3
measured in millimeters of mercury (mm +JKHDUWUDWHLQEHDWVSHUPLQXWHUHVSLUDWLRQUDWH
LQEUHDWKVSHUPLQXWHDQGWHPSHUDWXUHLQGHJUHHV&HOVLXV& 
Summary statistics including n, mean, SD, median, minimum, and maximum will be 
provided for these parameters at each visit. A subject listing will also be provided.   
13.4 
12-lead Electrocardiogram 
The frequency of abnormalities and clinically significant abnormalities in 12-lead 
electrocardiogram will be summarized at each visit. A subject listing of ECG findings will be 
provided. 


 
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13.5 
Physical Examination 
Physical examinations will include assessments of general appearance; head, eyes, ears, nose, 
and throat; the cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, 
genitourinary, musculoskeletal, and neurologic/psychological systems. Other body systems 
may be examined. A subject listing for clinically significant findings at each visit will be 
provided.  
13.6 
Immunogenicity Tests 
Immunogenicity will be performed using validated immunogenicity assays. Blood samples 
for routine immunogenicity testing will be collected every 8 weeks or at an Early 
Termination visit. Routine immunogenicity testing will include assays for total anti-
SHJYDOLDVHDQWLERGLHV7$EDQWL-rAvPAL IgG, anti-rAvPAL IgM, anti-PEG IgG, anti-PEG 
,J0QHXWUDOL]LQJDQWLERGLHV1$EDQWL-pegvaliase IgG4, and circulating immune 
FRPSOH[HV,J*&,&DQG,J0&,&,QWKHHYHQWRID+\SHUVHQVLWLYLW\5HDFWLRQYLVLW+59
sampling and testing will be performed for anti-pegvaliase IgE, as well as other potentially-
related clinical laboratory tests, including CRP, complement C3 and C4, and tryptase.   
For immunogenicity analysis, an incidence table and titer summary statistics including mean, 
median, standard deviation, and minimum/maximum titer values at each study visit will be 
provided for each antibody analyte. Plots of mean titer and percent positivity over time will 
also be generated. A listing of anti-pegvaliase IgE test results will be provided by subject. 
Anti-drug antibody impact on safety will be evaluated. Plots and tables will be generated to 
explore the potential impact of anti-drug antibodies on HAE frequency and severity. A listing 
will be provided for each subject who has Hypersensitivity Reaction Visit, with the most 
proximal antibody test result listed for each analyte, and when available, CRP, complement 
C3 and C4, and tryptase at the time of the event. 
Anti-drug antibody impact on efficacy will be evaluated. Plots and tables may be generated 
to explore the potential impact of anti-drug antibodies on blood Phe levels. 
13.7 
Pregnancy Test 
A subject listing for pregnancy urine sample test at each visit will be provided.  


 
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14 
APPENDICES 
Appendix 1:  Search Strategies for Adverse Event of Special Interest, and Sponsor 
Defined AEs of Clinical Significance 
MedDRA version: most current version at program termination 
1: Anaphylaxis AEs per NIAID/FAAN criteria 
Anaphylaxis per NIAID/FAAN is defined using the NIAID/FAAN clinical diagnostic criteria 
through review on the potential anaphylaxis per NIAID/FAAN cases, which are identified 
using Broad algorithmic anaphylactic reaction SMQ: 
$OJRULWKP $RU%DQG&RU'DQG%RU& 
Name of Search 
Category 
Preferred Term 
Broad Algorithmic Anaphylactic Reaction 
SMQ 
A 
Anaphylactic reaction 
 
A 
Anaphylactic shock 
 
A 
Anaphylactic transfusion reaction 
 
A 
Anaphylactoid reaction 
 
A 
Anaphylactoid shock 
 
A 
Circulatory collapse 
 
A 
First use syndrome 
 
A 
Kounis syndrome 
 
A 
Shock 
 
A 
Type I hypersensitivity 
 
B 
Acute respiratory failure 
 
B 
Asthma 
 
B 
Bronchial oedema 
 
B 
Bronchospasm 
 
B 
Cardio-respiratory distress 
 
B 
Chest discomfort 
 
B 
Choking 
 
B 
Choking sensation 
 
B 
Circumoral oedema 
 
B 
Cough 
 
B 
Cyanosis 
 
B 
Dyspnoea 
 
B 
Hyperventilation 
 
B 
Laryngeal dyspnoea 


 
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Name of Search 
Category 
Preferred Term 
 
B 
Laryngeal oedema 
 
B 
Laryngospasm 
 
B 
Laryngotracheal oedema 
 
B 
Mouth swelling 
 
B 
Nasal obstruction 
 
B 
Oedema mouth 
 
B 
Oropharyngeal spasm 
 
B 
Oropharyngeal swelling 
 
B 
Respiratory arrest 
 
B 
Respiratory distress 
 
B 
Respiratory failure 
 
B 
Reversible airways obstruction 
 
B 
Sensation of foreign body 
 
B 
Sneezing 
 
B 
Stridor 
 
B 
Swollen tongue 
 
B 
Tachypnoea 
 
B 
Throat tightness 
 
B 
Tongue oedema 
 
B 
Tracheal obstruction 
 
B 
Tracheal oedema 
 
B 
Upper airway obstruction 
 
B 
Wheezing 
 
C 
Allergic oedema 
 
C 
Angioedema 
 
C 
Erythema 
 
C 
Eye oedema 
 
C 
Eye pruritus 
 
C 
Eye swelling 
 
C 
Eyelid oedema 
 
C 
Face oedema 
 
C 
Flushing 
 
C 
Generalised erythema 
 
C 
Injection site urticaria 
 
C 
Lip oedema 
 
C 
Lip swelling 


 
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Name of Search 
Category 
Preferred Term 
 
C 
Ocular hyperaemia 
 
C 
Oedema 
 
C 
Periorbital oedema 
 
C 
Pruritus 
 
C 
Pruritus allergic 
 
C 
Pruritus generalised 
 
C 
Rash 
 
C 
Rash erythematous 
 
C 
Rash generalised 
 
C 
Rash pruritic 
 
C 
Skin swelling 
 
C 
Swelling 
 
C 
Swelling face 
 
C 
Urticaria 
 
C 
Urticaria papular 
 
D 
Blood pressure decreased 
 
D 
Blood pressure diastolic decreased 
 
D 
Blood pressure systolic decreased 
 
D 
Cardiac arrest 
 
D 
Cardio-respiratory arrest 
 
D 
Cardiovascular insufficiency 
 
D 
Diastolic hypotension 
 
D 
Hypotension 
 
2: Acute systemic hypersensitivity reaction 
An anaphylaxis episode which meets the NIAID/FAAN criteria and is positively adjudicated 
by an independent expert allergist/immunologist as anaphylaxis according to the 
NIAID/FAAN criteria and based on clinical judgment of the significance of symptoms, is 
referred to as an acute systemic hypersensitivity reaction. 
3: Anaphylaxis per FDA criteria 
Anaphylaxis events defined according to the DPARP methodology are referred to as 
“anaphylaxis per FDA criteria”. The FDA’s assessment methodology includes individual 
case safety reports with any of the following characteristics:  


 
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x Clinical manifestations consistent with NIAID/FAAN Criterion 1 (skin involvement 
UHVSLUDWRU\RUFDUGLRYDVFXODUFRPSURPLVHDQG 
x Verbatim reports of anaphylaxis or anaphylactic reaction, even if NIAID/FAAN 
criteria were not met; and  
x Cases involving subject injection of epinephrine alone, even if subject did not 
experience signs/symptoms necessary to meet NIAID/FAAN criteria.  
Anaphylaxis episodes meeting these FDA criteria are the primary focus of the safety 
assessment. 
4: Hypersensitivity AEs  
Hypersensitivity AEs will be identified in two ways: 
%URDG$OJRULWKPLFDQDSK\ODFWLFUHDFWLRQ6WDQGDUGL]HG0HG'5$4XHULHV604 
$OJRULWKP $RU%DQG&RU'DQG%RU& 
Modified Hypersensitivity SMQ to include below additional preferred terms 
Name of Search 
Preferred Term 
Additional preferred terms for Modified 
Hypersensitivity SMQ 
Arthralgia 
 
Arthritis 
 
Eye inflammation 
 
Eye irritation 
 
Eye pain 
 
Joint stiffness 
 
Joint swelling 
 
Pyrexia 
 
Vision blurred 
 
Polyarthritis 
 
5: Hypersensitivity Reaction  
+\SHUVHQVLWLYLW\UHDFWLRQVDUHGHILQHGDVWKHPRGLILHGK\SHUVHQVLWLYLW\604QDUURZ604
or an anaphylaxis event as described in Appendix 1 – Listing 1 and adjudicated by 
BioMarin’s Pharmacovigilance group.  
7KHIROORZLQJWHUPVVKRXOGEHDGGHGWRWKH0RGLILHG+\SHUVHQVLWLYLW\1DUURZ604VHDUFK
criteria: 
x Dyspnoea 
x Pruritus 


 
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x Arthritis 
x Arthralgia 
The following terms should be excluded from the 0RGLILHG+\SHUVHQVLWLYLW\1DUURZ604
search criteria: 
x injection site rash  
x injection site urticaria 
 
6: Angioedema per sponsor criteria 
A 2-step process to identify angioedema per sponsor criteria, the following assessment was 
performed on the entire AE dataset:  
x Step 1: all reported ADRs suggestive of angioedema using the Angioedema MedDRA 
HLT search, which includes the following 21 PTs: angioedema, circumoral oedema, 
eyelid oedema, face oedema, Gleich’s syndrome, hereditary angioedema, idiopathic 
angioedema, intestinal angioedema, laryngeal oedema, laryngotracheal oedema, lip 
oedema, lip swelling, mouth swelling, oculorespiratory syndrome, oedema mouth, 
oropharyngeal swelling, periorbital oedema, pharyngeal oedema, swelling face, 
swollen tongue, and tongue oedema.  
x Step 2: BioMarin then clinically assessed the retrieved data identified from Step 1 to 
assign concurrent events into episodes and to exclude:  
o False positive ADR reports that have clear confounders which impact 
DVVHVVPHQWHJRQVHWRIHYHQWVGD\V after last dose or 
events/episodes with a very clear alternative etiology, such as throat 
VZHOOLQJVHFRQGDU\WRLQWXEDWLRQ&DVHVZHUHQRWH[FOXGHGZKHUHWKH
events have a long duration which may be atypical for angioedema, or 
where events occurred concurrent with other conditions which may have 
contributed to their development (eg, eye swelling reported during 
HSLVRGHVRIVHDVRQDODOOHUJ\ 
x Episodes which occurred as part of an acute systemic hypersensitivity reaction and, 
therefore, will already be included in the incidence for acute systemic hypersensitivity 
UHDFWLRQVWRDYRLGGXSOLFDWLRQ 
In the sponsor’s opinion, the methodology described above is more likely to be reflective of 
the true incidence of angioedema manifestations. 


 
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7: Serum Sickness 
Serum sickness-like reaction will be defined by including all preferred term of serum 
sickness, serum sickness-like reactions and Type III immune complex mediated reactions. 
8: Severe Injection-site reaction 
Severe injection site reaction will be identified as any injection site reaction report that is 
UHSRUWHGDV&RPPRQ7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV&7&$(*UDGHRUDERYH
LQVHYHULW\DQGPHHWLQJ0HG'5$KLJKOHYHOWHUP+/7IRU,QMHFWLRQVLWHUHDFWLRQRULV
reported as a Serious Adverse Reaction, irrespective of severity. 
9: Hypophenylalanemia 
+\SRSKHQ\ODODQLQHPLDLVGHILQHGDVDEORRGSKHQ\ODODQLQH3KHOHYHOPRO/IRUD
minimum of 2 consecutive values, with the start of the event defined as the first blood Phe 
assessment day with < 30 PRO/DQGWKHHQGRIWKHHYHQWGHILQHGDVWKHGD\SULRUWRWKHILUVW
EORRG3KHDVVHVVPHQWXPRO/ 
,QMHFWLRQVLWHVNLQUHDFWLRQZLWKGD\GXUDWLRQ 
,QMHFWLRQVLWHVNLQUHDFWLRQZLWKGD\GXUDWLRQZLOOEHLGHQWLILHGE\SUHIHUUHGWHUPVHDUFK
using the list below. To be included as injection site skin reaction, the duration of the event 
QHHGVWREHGD\V0XOWLSOH$(UHFRUGVZLWKVDPHSUHIHUUHGWHUPDQGGD\GLIIHUHQFH
EHWZHHQWKHVWDUWGDWHDQGHQGGDWHDUHFRQVLGHUHGDVVDPHHYHQW 
Name of Search 
Preferred Term 
Injection site skin reaction  
Injection site anaesthesia 
 
Injection site extravasation 
 
Injection site phlebitis 
 
Injection site movement impairment 
 
Injection site lymphadenopathy 
 
Injection site atrophy 
 
Injection site cyst 
 
Injection site erosion 
 
Injection site fibrosis 
 
Injection site granuloma 
 
Injection site induration 
 
Injection site mass 
 
Injection site necrosis 
 
Injection site oedema 
 
Injection site ulcer 


 
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Name of Search 
Preferred Term 
 
Injection site hypersensitivity 
 
Injection site irritation 
 
Injection site discomfort 
 
Injection site dysaesthesia 
 
Injection site hyperaesthesia 
 
Injection site hypoaesthesia 
 
Injection site swelling 
 
Injection site calcification 
 
Injection site pustule 
 
Injection site nodule 
 
Injection site scar 
 
Injection site bruising 
 
Injection site haematoma 
 
Injection site haemorrhage 
 
Injection site hypertrophy 
 
Injection site pain 
 
Injection site paraesthesia 
 
Injection site pruritus 
 
Injection site urticaria 
 
Injection site papule 
 
Injection site macule 
 
Injection site vasculitis 
 
Injection site plaque 
 
Injection site discolouration 
 
Injection site injury 
 
Injection site abscess 
 
Injection site abscess sterile 
 
Injection site dermatitis 
 
Injection site erythema 
 
Injection site infection 
 
Injection site inflammation 
 
Injection site rash 
 
Injection site reaction 
 
Injection site thrombosis 
 
Injection site vesicles 
 
Injection site ischaemia 
 
Injection site cellulitis 


 
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Name of Search 
Preferred Term 
 
Injection site discharge 
 
Injection site scab 
 
Injection site eczema 
 
Injection site recall reaction 
 
Injection site exfoliation 
 
*HQHUDOL]HGVNLQUHDFWLRQZLWKGD\GXUDWLRQ 
*HQHUDOL]HGVNLQUHDFWLRQZLWKGD\GXUDWLRQZLOOEHLGHQWLILHGLQIROORZLQJZD\V 
x Preferred term search using below listing, or 
x Broad vasculitis SMQ 
7REHLQFOXGHGDVJHQHUDOL]HGVNLQUHDFWLRQWKHGXUDWLRQRIWKHHYHQWQHHGVWREHGD\V
(MultiplH$(UHFRUGVZLWKVDPHSUHIHUUHGWHUPDQGGD\GLIIHUHQFHEHWZHHQWKHVWDUWGDWH
DQGHQGGDWHDUHFRQVLGHUHGDVVDPHHYHQW 
Name of Search 
Preferred Term 
Generalized Skin Reaction  
Acute febrile neutrophilic dermatosis 
Benign neoplasm of skin 
Blood blister 
Dry skin 
Eczema 
Eczema nummular 
Erythema infectiosum 
Furuncle 
Gangrene 
Henoch-Schonlein purpura 
Hypertrophic scar 
Neoplasm skin 
Dermatitis 
Dermatitis allergic 
Purpura fulminans 
Dermatitis exfoliative 
Dermatitis exfoliative generalised 
Skin disorder 
Drug eruption 
Skin dystrophy 
Xanthoma 
Acute generalised exanthematous pustulosis 
Dry gangrene 
Itching scar 
Cheilitis granulomatosa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Study 165-304 SAP 
Page 34 
 
Proprietary and Confidential 
 
Name of Search 
Preferred Term 
 
Granuloma 
Granuloma skin 
Keratolysis exfoliativa acquired 
Hypersensitivity vasculitis 
Septal panniculitis 
Erythema elevatum diutinum 
Acute cutaneous lupus erythematosus 
Rash rubelliform 
Eczema vesicular 
Hand dermatitis 
Pigmentation disorder 
Excessive granulation tissue 
Atypical fibroxanthoma 
Eruptive pseudoangiomatosis 
Capillaritis 
Cutaneovisceral angiomatosis with thrombocytopenia 
Coma blister 
Infected dermal cyst 
Skin wound 
Eosinophilic panniculitis 
Atypical lymphocytic lobular panniculitis 
Panniculitis 
Papule 
Purpura 
Chronic papillomatous dermatitis 
Xanthogranuloma 
Cheilosis 
Epidermolysis bullosa 
Granuloma annulare 
Haemorrhage subcutaneous 
Haemorrhage subepidermal 
Lipoatrophy 
Psoriatic arthropathy 
Rash papulosquamous 
Scar 
Seborrhoea 
Seborrhoeic dermatitis 
Skin irritation 
Stevens-Johnson syndrome 
Weber-Christian disease 
Rheumatoid nodule 
Thrombocytopenic purpura 
Thrombotic thrombocytopenic purpura 
 
 
 
 
 
 
 


 
Study 165-304 SAP 
Page 35 
 
Proprietary and Confidential 
 
Name of Search 
Preferred Term 
 
Excoriation 
Epidermolysis 
Vascular purpura 
Necrobiosis lipoidica diabeticorum 
Epidermal necrosis 
Lipohypertrophy 
Drug reaction with eosinophilia and systemic symptoms 
Cutaneous calcification 
Skin induration 
Palpable purpura 
Medical device site laceration 
Blister 
Blister infected 
Carbuncle 
Cellulitis 
Cellulitis enterococcal 
Cellulitis gangrenous 
Cellulitis staphylococcal 
Cellulitis streptococcal 
Cheilitis 
CREST syndrome 
Erythema nodosum 
Eyelid oedema 
Face oedema 
Idiopathic urticaria 
Infected skin ulcer 
Jaundice 
Laryngeal oedema 
Laryngotracheal oedema 
Lichenification 
Lip oedema 
Lip swelling 
Livedo reticularis 
Lupus vulgaris 
Morphoea 
Mucocutaneous ulceration 
Neurodermatitis 
Nodular vasculitis 
Oedema mouth 
Oropharyngeal swelling 
Osler's nodes 
Pemphigoid 
Pemphigus 
 
 
 
 
 
 
 
 
 
 


 
Study 165-304 SAP 
Page 36 
 
Proprietary and Confidential 
 
Name of Search 
Preferred Term 
Periorbital oedema 
Pharyngeal oedema 
Pruritus 
Psoriasis 
Skin mass 
Pustular psoriasis 
Pyoderma 
Red man syndrome 
Scleroderma 
Skin atrophy 
Skin hyperpigmentation 
Palisaded neutrophilic granulomatous dermatitis 
Skin hypopigmentation 
Skin hypoplasia 
Skin infection 
Subcutaneous abscess 
Subcutaneous haematoma 
Swelling face 
Swollen tongue 
Systemic lupus erythematosus 
Systemic lupus erythematosus rash 
Systemic sclerosis 
Tongue oedema 
Toxic epidermal necrolysis 
Urticaria 
Urticaria papular 
Skin maceration 
Lip blister 
Skin ulcer haemorrhage 
Lupus-like syndrome 
Skin tightness 
Sclerodactylia 
Granulomatous dermatitis 
Circumoral oedema 
Urticaria chronic 
Pruritus generalised 
Scleroedema 
Cutaneous lupus erythematosus 
Mucocutaneous rash 
Subacute cutaneous lupus erythematosus 
Chronic cutaneous lupus erythematosus 
Toxic skin eruption 
Dermatitis psoriasiform 


 
Study 165-304 SAP 
Page 37 
 
Proprietary and Confidential 
 
Name of Search 
Preferred Term 
Skin toxicity 
Erythema migrans 
Pruritus allergic 
Skin haemorrhage 
Overlap syndrome 
Haemorrhagic vasculitis 
Idiopathic angioedema 
Blister rupture 
Mouth swelling 
Autoimmune dermatitis 
Angioedema 
Cutaneous vasculitis 
Dermatitis atopic 
Dermatitis infected 
Ecchymosis 
Erythema 
Erythema induratum 
Erythema multiforme 
Macule 
Palmar erythema 
Panniculitis lobular 
Petechiae 
Rash 
Rash erythematous 
Rash follicular 
Rash generalised 
Rash macular 
Rash maculo-papular 
Rash morbilliform 
Rash papular 
Rash pruritic 
Rash pustular 
Rash vesicular 
Skin erosion 
Skin exfoliation 
Skin hypertrophy 
Skin lesion 
Skin necrosis 
Skin reaction 
Skin ulcer 
Vasculitic rash 
Rash maculovesicular 
Skin fibrosis 


 
Study 165-304 SAP 
Page 38 
 
Proprietary and Confidential 
 
Name of Search 
Preferred Term 
Skin swelling 
Skin oedema 
Haemorrhagic urticaria 
Recall phenomenon 
Vascular skin disorder 
Necrotising panniculitis 
Exfoliative rash 
Perivascular dermatitis 
Angiodermatitis 
Skin plaque 
Chronic pigmented purpura 
Dermatitis bullous 
Interstitial granulolmatous dermatitis 
Skin hyperplasia 
Vasculitic ulcer 
 
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