Conditions: Phenylketonuria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 157
Healthy volunteers: no

Brief summary:
The main purpose of this trial is to evaluate the efficacy of PTC923 in reducing blood phenylalanine (Phe) levels in participants with phenylketonuria as measured by mean change in blood Phe levels from baseline to Weeks 5 and 6 (that is, the average of each respective treatment dose 2-week period of double-blind treatment).

Detailed description:
The study includes 2 parts: Part 1 and 2. Part 1 of the study tests for responsiveness to PTC923, with 14 days of open-label treatment with PTC923. At the end of treatment in Part 1, the mean change in blood Phe levels over the 14-day treatment period for all participants will be assessed against their pretreatment (baseline) blood Phe level. Participants ≥2 years of age who experience a \<15% reduction in blood Phe levels will be classified as non-responsive and participation in the study will be terminated. Participants (≥2 years of age) who experience a ≥15% reduction in blood Phe levels will continue into Part 2. Participants \<2 years of age who experience ≥15% reduction in blood Phe levels will be offered the option to enroll directly into an open-label extension Study PTC923-MD-004-PKU. Participants \<2 years of age who experience a \<15% reduction in blood Phe levels will be classified as nonresponsive, and participation in the study will be terminated. Following the minimum 14-day PTC923 washout period, all eligible participants will be randomized in Part 2 to receive either PTC923 or placebo. After 6 weeks of treatment with either PTC923 or placebo, participants will be offered the option to enter an open-label extension Study PTC923-MD-004-PKU (NCT05166161).

Arms:
arm 1: Participants will receive PTC923 7.5 milligrams (mg)/kilogram (kg) (participants 0 to \<6 months of age), 15 mg/kg (participants 6 to \<12 months of age), 30 mg/kg (participants 12 months to \<2 years of age), or 60 mg/kg (participants ≥2 years of age) orally once daily for 14 days. arm 2: Participants will receive PTC923 20 mg/kg daily for Weeks 1 and 2, then PTC923 40 mg/kg daily for Weeks 3 and 4, then PTC923 60 mg/kg daily for Weeks 5 and 6. arm 3: Participants will receive equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the PTC923 treatment arm.

Interventions: intervention 1: PTC923 intervention 2: Placebo
Intervention descriptions: intervention 1: PTC923 powder for oral use will be suspended in water or apple juice prior to administration. intervention 2: Placebo matching to PTC923

Protocol document:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
A PHASE 3 STUDY OF PTC923 IN SUBJECTS WITH 
PHENYLKETONURIA 
PTC923-MD-003-PKU 
24 JUNE 2022 
VERSION 5.0 
PTC THERAPEUTICS 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 USA 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach of this 
obligation, PTC Therapeutics, Inc. should be notified promptly.
NCT #: NCT05099640


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PROTOCOL IDENTIFIERS 
Project Code 
PTC923 
Therapeutic Area 
Metabolic Disorders 
PTC Therapeutics Substance Identifier 
PTC923 
IND Number 
143698 
EudraCT Number 
2021-000474-29 
Protocol Number 
PTC923-MD-003-PKU 
Protocol Version 
5.0 
Protocol Version Date 
24 June 2022 
Protocol Phase 
Phase 3 
Protocol Title 
A Phase 3 Study of PTC923 in Subjects with 
Phenylketonuria 
 
 


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PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES 
Sponsor’s Approval 
The protocol has been approved by PTC Therapeutics. Reference to Sponsor as “PTC Therapeutics”, 
including PTC Therapeutics, Inc and PTC Therapeutics MP, Inc, collectively includes relevant entities, 
subsidiaries, and affiliates thereof. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
The eSignature page is located on the last page. 


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PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE 
 
I have read the protocol document and, on behalf of my institution, agree to comply with the protocol 
and all applicable regulations. 
 
 
 
 
Principal Investigator 
 
Date 
 
 
 
Institution: 
 
Address: 
 
City: 
 
State/Province: 
 
Country: 
 
Phone: 
 
Fax: 
 
E-mail: 
 
 


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SYNOPSIS 
Name of Sponsor/Company: PTC Therapeutics 
Name of Investigational Product: PTC923  
Protocol Number: PTC923-MD-003-PKU 
Phase: 3 
Country: Global 
Title of Study: A Phase 3 Study of PTC923 in Subjects with Phenylketonuria 
Study Period: 1.75 years 
Objectives:  
Primary: 
• To evaluate the efficacy of PTC923 in reducing blood phenylalanine (Phe) levels in 
subjects with phenylketonuria (PKU) as measured by mean change in blood Phe 
levels from baseline to Weeks 5 and 6 (ie, the average of each respective treatment 
dose 2-week period of double-blind treatment) 
Secondary: 
• To evaluate the proportion of subjects with baseline Phe levels ≥600 μmol/L who 
achieve Phe levels <600 μmol/L at the end of the double-blind treatment period 
• To evaluate the effect of PTC923 dose response on reducing blood Phe levels in 
subjects with PKU  
• To evaluate the pharmacokinetics (PK) of PTC923 in subjects with PKU  
• To assess the safety of PTC923 in subjects with PKU 
Exploratory Objectives: 
• To evaluate changes in blood tyrosine (Tyr) overtime, including the Phe:Tyr ratio  
Methodology:  
This is a Phase 3, double-blind, randomized, multi-center efficacy study of PTC923 
(a synthetic form of sepiapterin) versus placebo in subjects with PKU. Part 1 of the study tests 
for responsiveness to PTC923, with 14 days of open-label treatment with PTC923 7.5 mg/kg 
(subjects 0 to <6 months of age), 15 mg/kg (subjects 6 to <12 months of age), 30 mg/kg 
(subjects 12 months to <2 years of age), or 60 mg/kg (subjects ≥2 years of age) administered 
orally once a day followed by a minimum 14-day PTC923 washout. At the end of treatment in 
Part 1, the mean change in blood Phe levels over the 14-day treatment period for all subjects 
will be assessed against their pretreatment blood Phe level. Pretreatment blood Phe level will 
be the mean of Day -1 and Day 1 (predose) blood Phe levels. Subjects ≥2 years of age who 
experience a <15% reduction in blood Phe levels will be classified as nonresponsive, and 
participation in the study will be terminated. Subjects ≥2 years of age who experience a 
≥15% reduction in blood Phe levels will continue into Part 2, which is a randomized, 
placebo-controlled, double-blind treatment period. Subjects <2 years of age who experience a 
<15% reduction in blood Phe levels will be classified as nonresponsive, and participation in 
the study will be terminated. Subjects <2 years of age who experience a ≥15% reduction in 
blood Phe levels will be offered the option to enroll directly into an open-label extension 
Study PTC923-MD-004-PKU. Following the minimum 14-day PTC923 washout period, all 
eligible subjects ≥2 years of age will be randomized to receive either PTC923 or placebo. 
Subjects will be stratified based on their mean percent reduction in blood Phe levels 
(ie, subjects with mean % reduction in Phe levels of ≥15% to <30% and subjects with mean % 
reduction in Phe levels of ≥30%) and evenly distributed to either PTC923 or placebo treatment 
arms. Additionally, subjects will be stratified based on their baseline blood Phe concentration 


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(ie, subjects with baseline blood Phe <600 µmol/L and subjects with baseline blood Phe 
≥600 µmol/L) and evenly distributed to either PTC923 or placebo treatment. 
Subjects ≥2 years of age randomized to PTC923 will receive PTC923 20 mg/kg daily for 
Weeks 1 and 2, then PTC923 40 mg/kg daily for Weeks 3 and 4, then PTC923 60 mg/kg daily 
for Weeks 5 and 6.  
As dosing is weight-based and to maintain the blind, subjects randomized to placebo will 
receive equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of 
the PTC923 treatment arm. After 42 days of treatment with either PTC923 or placebo, subjects 
will be offered the option to enter an open-label extension Study PTC923-MD-004-PKU. 
Approximately 45 centers will participate in this study. The study design is summarized in the 
figure below. 
Abbreviations: Phe, phenylalanine 
Note: Phe responsiveness is defined as mean Phe reduction ≥15%.  
Screening Period (up to 45 Days): 
An informed consent and/or assent (as applicable) form must be signed before any 
study-related procedures are performed. After providing consent and/or assent (as applicable), 
subjects will undergo in-clinic screening procedures to determine study eligibility. Subject 
demographics and medical history information will be collected. Additionally, specific 
information related to previous use of sapropterin or pegvaliase-pqpz should be collected 
(ie, details on duration, dose, if discontinued, the reason(s) why, and if a subject is known to 
be tetrahydrobiopterin [BH4]-responsive). Vital signs, weight, and height measurements will 
be performed. Phenylalanine hydroxylase gene (PAH) genotyping should be performed unless 
already documented in the subject’s medical history. Blood Phe/Tyr levels will be measured. 
A full physical examination will be performed, and blood samples will be collected for clinical 
laboratory tests and pregnancy testing. Concomitant medication and adverse events (AEs) will 
be collected from provision of consent and/or assent (as applicable). Subjects will be 
instructed to continue their usual diet without modification (ie, no change in daily Phe 
consumption) throughout the entire study. Subjects will maintain a 3-day diet record during 
each week of Screening, and a dietician will monitor each subject’s diet to calculate total 
protein and corresponding Phe consumption, have regular contact with subjects, and reinforce 
the need for subjects to maintain their usual diet without modification. Subjects who enter the 
study and are receiving pegvaliase-pqpz (PALYNZIQ) supplementation at the Screening Visit 
must complete a 30-day washout period prior to dosing. Subjects who enter the study and are 
receiving BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) at the Screening 
Visit must complete a 7-day washout period prior to dosing. 


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Pegvaliase-pqpz Washout (30 Days):  
Following the initial Screening Visit, eligible subjects who are taking pegvaliase-pqpz must 
discontinue the medication as concomitant treatment/supplementation with pegvaliase-pqpz 
will not be permitted during the study. Subjects will continue their usual diet without 
modification (ie, no change in daily Phe consumption) and will maintain a 3-day diet record 
each week during the Pegvaliase-pqpz Washout. A dietician will monitor each subject’s diet to 
calculate total protein and corresponding Phe consumption, to have regular contact with 
subjects, and to reinforce the need for subjects to maintain their usual diet without 
modification. Blood Phe levels will be measured at each timepoint for the 30-day washout 
(Days 1, 20, and 30). 
BH4 Supplementation Washout (7 Days):  
Following the initial Screening Visit, eligible subjects who are taking BH4 supplementation 
must discontinue the medication as concomitant treatment/supplementation with BH4 will not 
be permitted during the study. Subjects will continue their usual diet without modification 
(ie, no change in daily Phe consumption) and will maintain a 3-day diet record during the BH4 
Supplementation Washout. A dietician will monitor each subject’s diet to calculate total 
protein and corresponding Phe consumption, to have regular contact with subjects, and to 
reinforce the need for subjects to maintain their usual diet without modification. Blood will be 
collected for determination of blood Phe levels using dried blood sampling levels at each 
timepoint for the 7-day washout (Days 1, 4, and 7). 
Part 1, Open-Label Responsiveness Test (28 to 35 Days): 
Following the initial screening and BH4 Supplementation/Pegvaliase-pqpz Washout 
(as necessary), all eligible subjects will be enrolled into Part 1 of the study to test for 
responsiveness to PTC923. Subjects will receive PTC923 7.5 mg/kg (subjects 0 to <6 months 
of age), 15 mg/kg (subjects 6 to <12 months of age), 30 mg/kg (subjects 12 months to <2 years 
of age), or 60 mg/kg (subjects ≥2 years of age) for 14 days. On Part 1 Day 1, subjects will take 
their dose of PTC923 while in the clinic; for all other dosing days, subjects will take their dose 
as an outpatient and prior to coming to the clinic when visits are scheduled. All visits will be 
outpatient visits or virtual visits. Study visits will occur on Part 1 Day 1, Part 1 Day 2 
(PK substudy only), and Part 1 Day 14 (virtual visit, unless in PK substudy). 
Blood Phe levels will be measured on Days -1, 1 (predose), 2 (PK substudy only), 5, 10, and 
14 of Part 1. Baseline blood Phe level will be calculated as the mean of the blood Phe levels 
from dried blood samples taken on Day -1 and Day 1 (predose). Blood Phe samples will be 
collected after fasting or no earlier than 3 hours postprandial at approximately the same time 
of day at each collection timepoint.  
Subjects will continue their usual diet without modification and will maintain 3-day diet 
records (ie, one corresponding to each week of the PTC923 open-label treatment period). 
A dietician will monitor each subject’s diet to calculate total protein and corresponding Phe 
consumption, to have regular contact with subjects, and to reinforce the need for subjects to 
maintain their usual diet without modification. 
Subjects participating in the PK substudy: Approximately 30 subjects ≥12 years of age will 
participate in the PK substudy. At least 12 out of the 30 subjects ≥12 years of age participating 
in the PK substudy will be female. In addition, up to 6 subjects from each of these age groups 
will be included: 1) <2 years; 2) 2 to 5 years; and 3) 6 to 11 years. Blood samples will be 
collected from subjects participating in PK substudy to characterize the PK of sepiapterin and 
BH4 following an intensive schedule on Part 1 Day 1 and Part 1 Day 2 for subjects ≥2 years. 


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For subjects <2 years of age participating in the substudy, blood samples (2 on each occasion; 
total of 4 samples) will be collected on Part 1 Day 1 and Part 1 Day 14.  
In addition to blood drawn for PK sampling at specified timepoints, a small amount of blood 
will be drawn to a minicollect tube (~0.25 mL) at the same time and applied to the VAMS 
device for blood Phe and Tyr measurement.  
Part 1, PTC923 Washout (14 Days Minimum) 
Following completion of 14 days of PTC923 open-label treatment, subjects will begin a 
minimum 14-day washout. No in-clinic study visits are required during the PTC923 washout. 
In Part 1, blood Phe levels will be measured on Days 19, 24, and 28. Blood Phe samples will 
be collected after fasting or no earlier than 3 hours postprandial at approximately the same 
time of day at each collection timepoint. Subjects will continue their usual diet without 
modification and will maintain a 3-day diet record (ie, one corresponding to each week of the 
PTC923 washout). A dietician will monitor each subject’s diet to calculate total protein and 
corresponding Phe consumption, to have regular contact with subjects, and to reinforce the 
need for subjects to maintain their usual diet without modification.  
During the PTC923 washout, the mean change in blood Phe levels over the 14 days of 
PTC923 treatment (mean of Part 1 Days 5, 10, and 14) will be measured and compared against 
their pretreatment blood Phe level (mean of Part 1 Day -1 and Part 1 Day 1 [predose]).  
Subjects who experience <15% reduction in blood Phe levels will be classified as 
nonresponsive and will be contacted to schedule an Early Termination Visit (ETV) (on or 
between Day 28 to Day 35).  
Subjects ≥2 years of age who experience a ≥15% reduction in blood Phe levels will be 
contacted to confirm their continued eligibility and to schedule the Part 2 Day 1 visit.  
Subjects <2 years of age who experience a ≥15% reduction in blood Phe levels will be offered 
the option to enroll directly into an open-label extension Study PTC923-MD-004-PKU.  
Part 1 for all subjects ends on Day 35. In no circumstances will a subject be permitted to 
continue in Part 1 beyond Day 35. If a subject’s blood Phe concentrations are not available for 
determination of responsiveness to PTC923 by Day 35 of Part 1, then that subject will be 
classified as nonresponsive and will be contacted to schedule an ETV and not be eligible to 
continue into Part 2 of the study or further participation in an open-label extension 
Study PTC923-MD-004-PKU. 
Part 2, Randomized, Double-Blind Treatment Period (42 Days): 
All eligible subjects ≥2 years of age will be randomized to receive either PTC923 or placebo 
for 42 days (ie, 6 weeks) in Part 2, the randomized, placebo-controlled, double-blind treatment 
period. Subjects will be stratified based on their mean percent blood Phe reduction in Part 1 
(mean % reduction in blood Phe levels of ≥15% to <30% and mean % reduction in blood Phe 
levels of ≥30%) and evenly distributed across both treatment arms (PTC923 or placebo). 
Additionally, subjects will be stratified based on their baseline blood Phe concentration 
(ie, subjects with baseline blood Phe <600 µmol/L and subjects with baseline blood Phe 
≥600 µmol/L) and evenly distributed to either PTC923 or placebo. This portion of the study is 
double-blinded. Subjects will continue their usual diet without modification and will maintain 
3-day diet records (one corresponding to each week of Part 2). A dietician will monitor each 
subject’s diet to calculate total protein and corresponding Phe consumption, to have regular 
contact with subjects, and to reinforce the need for subjects to maintain their usual diet without 
modification. Subjects randomized to PTC923 will receive PTC923 20 mg/kg daily for Days 1 
to 14 (ie, Weeks 1 and 2), then PTC923 40 mg/kg daily for Days 15 to 28 (ie, Weeks 3 and 4), 


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then PTC923 60 mg/kg daily for Days 29 to 42 (ie, Weeks 5 and 6). As dosing is weight-based 
and to maintain the blind, subjects randomized to placebo will received equivalent quantities 
of placebo to match the 20 to 40 to 60 mg/kg dose escalation with PTC923. 
On Part 2 Day 1, subjects will take their dose of study drug (PTC923 20 mg/kg or placebo) in 
clinic; for all other dosing days, subjects will take their dose at home and prior to coming to 
the clinic when visits are scheduled. All visits will be outpatient visits or virtual visits. 
Study visits will occur on Part 2 Day 1, Part 2 Day 14 (in-clinic visit for PK substudy only), 
Part 2 Day 28 (in-clinic visit for PK substudy population), and Part 2 Day 42 to conduct study 
evaluations, collect 3-day diet record, and capture any AEs and concomitant medications. 
Blood Phe levels will be measured in Part 2 on Days -1, 1 (predose), 5, 10, 14, 19, 24, 28, 33, 
38, and 42. Blood Phe samples will be collected after fasting or no earlier than 3 hours 
postprandial at approximately the same time of day at each collection timepoint. 
On Part 2 Day 1 (predose), the Phenylketonuria-quality of life (PKU-QOL) (Parent PKU-QOL 
[6 to 8 years]; Child PKU-QOL [9 to 11 years]; Adolescent PKU-QOL [12 to 17 years]; 
Adult PKU-QOL [≥18 years]) will be conducted using the tool in one of the following 
validated languages: English (British or American), Turkish, Dutch, German, Spanish, Italian, 
Portuguese, or French. Conduct of the PKU-QOL will not be required for subjects whose 
primary language is not one of the available validated languages. On Part 2 Day 1 (predose), 
the European Quality of Life - 5 Dimensions (EQ-5D) (European Quality of 
Life-5 Dimensions for Youth [EQ-5D-Y] Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 
15 years]; and 5-Level European Quality of Life - 5 Dimensions (EQ-5D-5L) [≥16 years]) will 
be conducted. 
PK substudy only: Blood samples (2 samples/occasion) will be collected from subjects in 
Part 2 on Days 1, 14, 28, and 42 visits to characterize the PK of sepiapterin and BH4 at predose 
(approximately 24 hours post the dose on prior day, except for Day 1, and prior to the dose of 
the day) and 4 hours postdose.  
End of Study: 
For subjects <2 years of age, End of Study is defined as their final visit in Part 1 and should 
occur on/between Part 1 Day 28 and Part 1 Day 35. All subjects <2 years of age who 
experience a ≥15% reduction in blood Phe levels during Part 1 will be offered the option to 
enroll directly into an open-label extension Study PTC923-MD-004-PKU. 
For subjects ≥2 years of age who complete Part 2, End of Study is defined as their final study 
visit on Part 2 Day 42. All subjects who complete Part 2 will be given the opportunity to 
continue treatment in the PTC923 Open-Label Extension Study, PTC923-MD-004-PKU. 
Early Termination Visit: 
An ETV will be performed on or between Day 28 to Day 35 for all subjects who are 
determined to be non-responders in Part 1, or within 2 days for any subject who discontinues 
the study prematurely during Part 1 or Part 2 for any other reason. During the ETV, 3-day diet 
records, AEs, concomitant medications, weight, vital signs, ECGs, and blood Phe/Tyr levels 
will be collected. A physical examination, clinical laboratory tests, and a pregnancy test will 
be performed. For non-responsive subjects and subjects who discontinue prematurely, 
following the End of Study visit, subjects may revert to their prestudy treatment for PKU 
(at the investigators and the subject’s treating physician discretion), and a phone follow-up 
visit will occur 30 (±3) days after the last dose of study drug to assess for serious adverse 
events (SAEs). 


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Sample Size Justification: 
All subjects ≥2 years of age with ≥15% response to PTC923 will be eligible to be randomized 
in Part 2 of the study. Subjects will be stratified in Part 2 based on their mean percent blood 
Phe reduction in Part 1 (ie, subjects with mean % reduction in blood Phe levels of ≥15% to 
<30% and subjects with mean % reduction in blood Phe levels of ≥30%). Within each stratum, 
subjects will be randomized and allocated 1:1 to receive either PTC923 or placebo. Enrollment 
will continue until approximately 80 subjects from the stratum of subjects with mean percent 
reduction in blood Phe levels of ≥30% during Part 1 have been randomized. Additionally, 
subjects will be stratified based on their baseline blood Phe concentration (ie, subjects with 
baseline blood Phe <600 µmol/L and subjects with baseline blood Phe ≥600 µmol/L) and 
evenly distributed to either PTC923 or placebo treatment arms.  
For the primary endpoint with a sample size of 80 subjects for the stratum of subjects with 
mean percent reduction in blood Phe levels of ≥30% during Part 1, the power to detect a 
difference in reduction in blood Phe between PTC923 and placebo is >95%, assuming a 
treatment difference of 250 µmol/L and a within-treatment-group standard deviation of 
250 µmol/L, with a 2-sided α of 0.05. 
For the primary endpoint for all subjects in Part 2, the power to detect a difference in reduction 
in blood Phe between PTC923 and placebo is >95%, assuming a treatment difference of 
200 µmol/L, a within-treatment-group standard deviation of 250 µmol/L, and a total sample 
size of 106, with a 2-sided α of 0.05. This sample size assumes approximately 60% of the 
subjects ≥2 years of age enrolled in Part 1 experience a ≥15% reduction in Phe levels. 
Number of Subjects (Planned):  
Approximately 80 subjects with PKU aged ≥2 years who achieve a ≥30% reduction from 
baseline in blood Phe levels during the responsiveness test (Part 1) will be enrolled in the 
placebo-controlled treatment period to receive either PTC923 or placebo (Part 2). 
Approximately 178 subjects are expected to be enrolled in Part 1 of the study to achieve this.  
Diagnosis and Main Criteria for Inclusion:  
Subjects with any PAH mutation are permitted to screen and enroll into the study. However, 
subjects with biochemically diagnosed classical PKU (ie, blood Phe birth levels ≥1200 µmol/L 
and or historical evidence of Phe concentrations ≥1200 µmol/L in their medical history) will 
be capped at 20% of the total study population. Genotyping will not be required for study 
eligibility; however, all subjects will undergo genotyping unless documented in their medical 
history and these data will be collected for analysis. 
Inclusion Criteria: 
1. Informed consent and assent (if necessary, at the investigator’s discretion [ie, for 
children and/or subjects who are mentally impaired secondary to disease]) with 
parental/legal guardian consent  
2. Male or female subjects of any age 
3. Uncontrolled blood Phe level ≥360 μmol/L on current therapy anytime during 
Screening and uncontrolled blood Phe level ≥360 μmol/L on current therapy when 
taking the average of the 3 most recent Phe levels from the subject’s medical history 
(inclusive of the Screening value) 
4. Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by past 
medical history of at least 2 blood Phe measurements ≥600 μmol/L 


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5. Women of childbearing potential, as defined in (CTFG 2020), must have a negative 
pregnancy test at Screening and agree to abstinence or the use of at least one highly 
effective form of contraception (with a failure rate of <1% per year when used 
consistently and correctly):  
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner with confirmed azoospermia 
Highly effective contraception or abstinence must be continued for the duration of the 
study and for up to 90 days after the last dose of the study drug. 
All females will be considered of childbearing potential unless they are 
postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age 
group without other known or suspected cause) or have been permanently sterilized 
surgically (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy). 
6. Males who are sexually active with women of childbearing potential who have not had 
a vasectomy must agree to use a barrier method of birth control during the study and 
for up to 90 days after the last dose of study drug. Males must also refrain from sperm 
donations during this time period. 
Males who are abstinent will not be required to use a contraceptive method unless they 
become sexually active. Males who have undergone a vasectomy are not required to 
use a contraceptive method if at least 16 weeks post procedure. 
7. Willing and able to comply with the protocol and study procedures 
8. Willing to continue current diet unchanged while participating in the study 
Exclusion Criteria:  
1. The individual, in the opinion of the investigator, is unwilling or unable to adhere to 
the requirements of the study 
2. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel 
disease, chronic gastritis, and peptic ulcer disease, etc.) that could affect the absorption 
of study drug 
3. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an 
antrectomy with vagotomy, or gastrectomy 
4. Inability to tolerate oral medication 
5. History of allergies or adverse reactions to synthetic BH4 or sepiapterin  
6. Current participation in any other investigational drug study or use of any 
investigational agent within 30 days prior to Screening 


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7. Any clinically significant laboratory abnormality as determined by the investigator. In 
general, each laboratory value from Screening and baseline chemistry and hematology 
panels should fall within the limits of the normal laboratory reference range, unless 
deemed not clinically significant by the investigator 
8. A female who is pregnant or breastfeeding, or considering pregnancy 
9. Serious neuropsychiatric illness (eg, major depression) not currently under medical 
control, that in the opinion of the investigator or sponsor, would interfere with the 
subject’s ability to participate in the study or increase the risk of participation for that 
subject 
10. Past medical history and/or evidence of renal impairment and/or condition including 
moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 mL/min) 
and/or under care of a nephrologist 
11. Any abnormal physical examination and/or laboratory findings indicative of signs or 
symptoms of renal disease, including calculated GFR <60 mL/min/1.73m2. 
In subjects ≥18 years of age, the Modification of Diet in Renal Disease Equation 
should be used to determine GFR. 
In subjects <18 years, the Bedside Schwartz Equation should be used to determine 
GFR. 
12. Requirement for concomitant treatment with any drug known to inhibit folate synthesis 
(eg, methotrexate) 
13. Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic 
mutations in 6-pyruvoyltetrahydropterin synthase, recessive GTP cyclohydrolase I, 
sepiapterin reductase, quinoid dihydropteridine reductase, or pterin-4-alpha-
carbinolamine dehydratase genes 
14. Major surgery within the prior 90 days of screening 
15. Concomitant treatment with BH4 supplementation (eg, sapropterin dihydrochloride, 
KUVAN) or pegvaliase-pqpz (PALYNZIQ) 
16. Unwillingness to washout from BH4 supplementation (eg, sapropterin dihydrochloride, 
KUVAN) or pegvaliase-pqpz (PALYNZIQ) 
Investigational Product, Dosage, and Mode of Administration:  
The test product is PTC923 Powder for Oral Use. All doses will be administered orally, once a 
day with food. 
Part 1: All subjects will receive PTC923 for 14 days: 
• Subjects 0 to <6 months of age: 7.5 mg/kg 
• Subjects 6 to <12 months of age: 15 mg/kg 
• Subjects 12 months to <2 years of age: 30 mg/kg 
• Subjects ≥2 years of age: 60 mg/kg 
Part 2: Subjects ≥2 years of age randomized to PTC923 treatment will receive PTC923 
(6 weeks in total): 
• 20 mg/kg for 14 days 
• 40 mg/kg for 14 days 
• 60 mg/kg for 14 days  


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Duration of Treatment:  
All enrolled subjects will receive PTC923 for 2 weeks in Part 1. Subjects ≥2 years of age with 
≥15% response to PTC923 will continue treatment in Part 2 with PTC923 or placebo for 
6 weeks. Subjects <2 years of age with ≥15% response to PTC923 in Part 1 will be offered the 
option to enroll directly into an open-label extension Study PTC923-MD-004-PKU. 
Reference Therapy, Dosage, and Mode of Administration:  
The reference therapy is Placebo for PTC923 Powder for Oral Use. In Part 2, subjects ≥2 years 
of age randomized to placebo will receive Placebo for PTC923 Powder for Oral Use for 
6 weeks. All doses will be administered orally, once a day with food. 
Criteria for Evaluation: 
Efficacy endpoints: 
The primary efficacy measure will be reduction in blood Phe levels in subjects with PKU as 
measured by mean change in Phe levels from baseline to Part 2 Weeks 5 and 6 (ie, the average 
of the 2-week period at the target dose of double-blind treatment). Baseline blood Phe level 
will be the mean of Day -1 and Day 1 (predose) blood Phe levels. 
The secondary efficacy endpoints are the proportion of subjects with baseline Phe levels 
≥600 μmol/L who achieve Phe levels <600 μmol/L at the end of the double-blind treatment 
period and the change from baseline in mean blood Phe levels at each PTC923 dose level 
(ie, each 2-week period in Part 2). 
The exploratory efficacy endpoint is the change from baseline in blood Tyr over time, 
including the Phe:Tyr ratio. 
Safety endpoints: 
Safety and tolerability of PTC923 as measured by severity and number of treatment-emergent 
adverse events (TEAEs), clinical laboratory tests, vital signs, physical examinations, and 
electrocardiograms (ECGs) will be compared to placebo. 
Pharmacokinetics endpoints: 
Depending on the number of samples obtained, the following PK parameters of sepiapterin 
and BH4 for a given subject may be calculated using noncompartmental methods: Cmax, Tmax, 
T1/2, area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h), 
area under the plasma concentration-time curve from time zero to infinity (AUC0-inf), apparent 
total clearance of the drug from plasma following oral administration (CL/F), and apparent 
volume of distribution during terminal phase after non-intravenous administration (Vz/F). 
Additionally, depending on the number of samples collected and subject demography, a 
population PK analysis will be performed using all PK samples collected in the study to 
further characterize the PK of sepiapterin and BH4 to examine potential source of PK 
variability, such as age, and to explore the relationship between exposure and response. 
Statistical Methods: 
Analysis Sets: 
Full Analysis Set (FAS): All subjects who are randomized and take at least 1 dose of 
double-blind study drug in Part 2 will be included in the FAS. Subjects will be analyzed 
according to their randomized treatment. All efficacy analyses will be based on the FAS. 
Per Protocol (PP) Analysis Set: The PP Analysis Set will include all subjects in the FAS who 
meet the study eligibility requirements and have no major protocol deviations that affect the 
validity of the efficacy measurements. The PP Analysis Set will be used for sensitivity 
analysis of the primary efficacy endpoint. The criteria for inclusion in the PP Analysis Set will 
be finalized prior to study unblinding and detailed in the statistical analysis plan (SAP). 


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Safety Analysis Set: All subjects who receive at least 1 dose of study drug, including during 
Part 1, will be included in the Safety Analysis Set. Subjects will be analyzed according to 
actual treatment received.  
Pharmacokinetic Analysis Set: All subjects who have at least one measurable plasma 
concentration of sepiapterin or BH4 will be included in the Pharmacokinetic Analysis Set. 
Efficacy: 
All efficacy analyses will be performed based on the FAS. The primary endpoint analysis will 
also be conducted using the PP Analysis Set. 
The null hypothesis of this study is that the mean change in Phe levels from baseline to end of 
the double-blind treatment period is the same in the PTC923 arm and in the placebo arm 
versus the alternative that they are different; a 2-sided test at the 5% alpha level will be 
applied.  
For the primary efficacy endpoint, a gatekeeping procedure will be used to control the 
familywise error rate: 
The stratum of subjects ≥2 years of age with mean percent reduction in Phe levels of ≥30% 
during Part 1 will be tested at the significance level of 0.05 (2-sided). If p<0.05 then the study 
will be declared positive in this stratum. 
Only if the stratum of subjects ≥2 years of age with mean percent reduction in Phe levels of 
≥30% during Part 1 is statistically significant at the 0.05 level, will the overall study with all 
subjects ≥2 years of age with a mean percent reduction in Phe levels of ≥15% during Part 1 be 
tested, also at the 0.05 significance level. 
For the primary endpoint of reduction in blood Phe for the stratum of subjects with mean 
percent reduction in blood Phe levels of ≥30% during Part 1, a mixed model repeated 
measures (MMRM) model will be fitted using the available blood Phe data. The response 
variable is the change from baseline in blood Phe measured at post-baseline assessments for 
each subject. The model will include fixed effects for treatment, baseline blood Phe, baseline 
Phe stratum (<600 μmol/L or ≥600 μmol/L), visit (categorical), and visit-by-treatment 
interaction. In addition, subject will be included as random effect. An unstructured 
within-subject covariance structure will be assumed. If the model does not converge under the 
unstructured covariance matrix, the following covariance structures will be employed in order 
until convergence is reached: heterogeneous Toeplitz, heterogeneous Compound Symmetry, 
heterogeneous first-order autoregressive, Toeplitz, Compound Symmetry, and first-order 
autoregressive. The least squares (LS) mean estimate for the average change at Part 2 Weeks 5 
and 6 will be used to perform treatment group comparisons. The LS means, treatment effect 
estimate, confidence interval, and 2-sided p value will be presented. Corresponding LS means 
from the same MMRM model will be used to estimate the treatment effects at each visit week. 
For the primary endpoint of reduction in blood Phe for all subjects, the same MMRM model 
used for the stratum of subjects with mean percent reduction in blood Phe levels of ≥30% 
during Part 1 will be used with the addition of a fixed effect for Phe reduction randomization 
strata (≥15% or ≥30%).  


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Missing data:  
For the primary analysis of the primary endpoint, MMRM model will be used on the available 
data assuming the missing assessments are missing at random (MAR). Missing data will be 
imputed using the multiple imputation procedure to further assess the influence of missingness 
and details of the method will be provided in the SAP. Briefly, these methodologies will 
include multiple imputation under an assumption of missing not at random and tipping-point 
analyses to explore how extreme the difference between randomized treatments would have to 
be among subjects with missing data to overwhelm the treatment effect obtained in the 
primary. In these analyses, the multiple imputation approach will be expanded to allow for 
varying impact of missing data by incorporating a shift parameter in the imputation model. 
The range of values for the shift parameter will explore the varying missing data assumptions, 
including the scenario where the imputation model is completely based on the control group 
(ie, control-based imputation). 
Safety: 
All safety analyses will be conducted based on the Safety Analysis Set. 
Safety data will include AEs, clinical laboratory tests, vital signs, physical examinations, and 
ECGs. Observed data will be listed by subject and summarized using descriptive statistics by 
treatment group. 
Pharmacokinetics: 
Pharmacokinetic parameters and plasma concentrations will be summarized separately 
following different PK sampling scheme and population using descriptive statistics. 
 


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TABLE OF CONTENTS 
PROTOCOL IDENTIFIERS ...........................................................................................................2 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES..............................................3 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE............................................4 
SYNOPSIS ......................................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERM ..................................................22 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Phenylketonuria ..........................................................................................................24 
1.2. 
Current Treatment of Phenylketonuria .......................................................................24 
1.3. 
PTC923 .......................................................................................................................25 
1.4. 
Rationale for Study .....................................................................................................26 
1.5. 
Rationale for Study Design and Control Group .........................................................27 
1.6. 
Study Duration ............................................................................................................28 
1.7. 
Risk/Benefit Assessment ............................................................................................28 
2. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................30 
2.1. 
Primary Objective .......................................................................................................30 
2.2. 
Secondary Objectives .................................................................................................30 
2.3. 
Exploratory Objective .................................................................................................30 
3. 
INVESTIGATIONAL PLAN .....................................................................................31 
3.1. 
Overall Study Design ..................................................................................................31 
3.1.1. 
Screening Period (Up to 45 Days) ..............................................................................32 
3.1.1.1. 
Pegvaliase-pqpz Washout (30 Days) ..........................................................................32 
3.1.1.2. 
BH4 Supplementation Washout (7 Days) ...................................................................32 
3.1.2. 
Part 1, Open-Label Responsiveness Test (28 to 35 Days)..........................................33 
3.1.2.1. 
Part 1, Open-Label Treatment (14 Days) ...................................................................33 
3.1.2.2. 
Part 1, PTC923 Washout (14 Days Minimum) ..........................................................34 
3.1.3. 
Part 2, Randomized Double-Blind Treatment Period (42 Days) ................................34 
3.1.4. 
End of Study ...............................................................................................................35 
3.1.5. 
Early Termination Visit ..............................................................................................36 
3.2. 
Number of Subjects ....................................................................................................43 


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3.3. 
Treatment Assignment ................................................................................................43 
3.3.1. 
Part 1, Open-Label Responsiveness Test....................................................................43 
3.3.2. 
Part 2, Randomized Double-Blind Treatment Period .................................................43 
3.4. 
Dose Adjustment Criteria ...........................................................................................43 
3.4.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................43 
3.5. 
Criteria for Study Termination ...................................................................................44 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................45 
4.1. 
Subject Inclusion Criteria ...........................................................................................45 
4.2. 
Subject Exclusion Criteria ..........................................................................................46 
4.3. 
Screen Failures ............................................................................................................47 
4.4. 
Subject Withdrawal Criteria .......................................................................................47 
4.4.1. 
Discontinuation from Study Drug Administration .....................................................47 
4.4.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................48 
4.5. 
Lost to Follow-Up.......................................................................................................48 
5. 
TREATMENT OF SUBJECTS ..................................................................................49 
5.1. 
Description of Study Drug ..........................................................................................49 
5.2. 
Selection and Timing of Dose for Each Subject .........................................................49 
5.3. 
Concomitant Medications ...........................................................................................49 
5.4. 
Total Blood Volume ...................................................................................................49 
5.5. 
Treatment Compliance ................................................................................................51 
5.6. 
Randomization and Blinding ......................................................................................51 
5.6.1. 
Measures to Minimize Bias: Randomization and Blinding ........................................52 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................53 
6.1. 
Study Drug ..................................................................................................................53 
6.2. 
Study Drug Dispensing ...............................................................................................53 
6.3. 
Study Drug Packaging and Labeling ..........................................................................53 
6.4. 
Study Drug Storage .....................................................................................................53 
6.5. 
Study Drug Preparation ..............................................................................................54 
6.6. 
Administration ............................................................................................................58 
6.7. 
Study Drug Accountability .........................................................................................58 
6.8. 
Study Drug Handling and Disposal ............................................................................58 
7. 
ASSESSMENT OF EFFICACY ................................................................................59 
7.1. 
Primary Efficacy: Phenylalanine Concentrations .......................................................59 


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7.2. 
Exploratory Efficacy: Tyrosine Concentrations .........................................................61 
8. 
ASSESSMENT OF SAFETY .....................................................................................62 
8.1. 
Safety Parameters .......................................................................................................62 
8.1.1. 
Demographic/Medical History ...................................................................................62 
8.1.2. 
Vital Signs, Weight, and Height .................................................................................62 
8.1.3. 
Physical Examination .................................................................................................62 
8.1.4. 
Electrocardiogram .......................................................................................................63 
8.1.5. 
Laboratory Assessments .............................................................................................63 
8.1.6. 
Laboratory Abnormalities ...........................................................................................64 
8.1.7. 
Diet Monitoring: 3-Day Diet Records ........................................................................64 
8.1.8. 
Pharmacokinetic Assessments ....................................................................................64 
8.1.8.1. 
Part 1 ...........................................................................................................................64 
8.1.8.2. 
Part 2 ...........................................................................................................................65 
8.1.9. 
PAH Genotype Testing ...............................................................................................65 
8.1.10. 
Quality of Life Baseline Assessments ........................................................................65 
8.1.10.1. 
Phenylketonuria Quality of Life Questionnaire ..........................................................65 
8.1.10.2. 
European Quality of Life - 5 Dimensions ...................................................................66 
8.2. 
Adverse Events and Serious Adverse Events .............................................................66 
8.2.1. 
Definition of Adverse Events .....................................................................................66 
8.2.2. 
Definition of Serious Adverse Events ........................................................................67 
8.2.3. 
Unexpected Adverse Events .......................................................................................68 
8.2.4. 
Eliciting Adverse Event Information ..........................................................................68 
8.2.5. 
Recording Non‑Serious Adverse Events and Serious Adverse Events ......................69 
8.2.6. 
Describing Adverse Event Relationship to Study Drug .............................................69 
8.2.7. 
Grading of Severity of Adverse Events ......................................................................70 
8.2.8. 
Adverse Event Reporting ............................................................................................70 
8.2.9. 
Serious Adverse Event Reporting ...............................................................................72 
8.2.10. 
Contraception ..............................................................................................................72 
8.2.11. 
Reporting Pregnancy ..................................................................................................73 
8.3. 
PTC Adverse Event Reporting Requirement to Regulatory Authorities, 
Investigators, and IRB/IEC .........................................................................................74 
9. 
STATISTICAL CONSIDERATIONS .......................................................................75 
9.1. 
Statistical Hypotheses .................................................................................................75 


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9.2. 
Sample Size Determination ........................................................................................75 
9.3. 
Population for Analyses ..............................................................................................75 
9.4. 
Statistical Analyses .....................................................................................................76 
9.4.1. 
General Approach .......................................................................................................76 
9.4.2. 
Analysis of Efficacy Endpoints ..................................................................................76 
9.4.3. 
Missing Data ...............................................................................................................77 
9.4.4. 
Pharmacokinetic Analyses ..........................................................................................77 
9.4.5. 
Safety Analyses ..........................................................................................................77 
9.4.5.1. 
Subject Disposition .....................................................................................................77 
9.4.5.2. 
Medical History and Prior Medication .......................................................................78 
9.4.5.3. 
Extent of Exposure and Treatment Compliance .........................................................78 
9.4.6. 
Baseline Descriptive Statistics ....................................................................................78 
9.4.6.1. 
Laboratory Parameters ................................................................................................78 
9.4.6.2. 
Adverse Events ...........................................................................................................78 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................79 
10.1. 
Study Monitoring ........................................................................................................79 
10.2. 
Audits and Inspections ................................................................................................79 
10.3. 
Institutional Review Board/Independent Ethics Committee ......................................79 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................80 
12. 
ETHICS ......................................................................................................................81 
12.1. 
Ethics Review .............................................................................................................81 
12.2. 
Ethical Conduct of the Study ......................................................................................81 
12.3. 
Informed Consent Process ..........................................................................................81 
13. 
DATA HANDLING AND RECORDKEEPING .......................................................82 
13.1. 
Inspection of Records .................................................................................................82 
13.2. 
Retention of Records ..................................................................................................82 
13.3. 
Protocol Deviations ....................................................................................................82 
14. 
PUBLICATION POLICY ..........................................................................................84 
15. 
PROTOCOL AMENDMENT HISTORY ..................................................................85 
15.1. 
Version 5.0: 24 June 2022 ..........................................................................................85 
15.2. 
Version 4.0: 13 January 2022 .....................................................................................85 
15.3. 
Version 3.0: 06 December 2021 .................................................................................86 
15.4. 
Version 2.0: 15 July 2021 ...........................................................................................87 


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16. 
REFERENCES ...........................................................................................................89 
17. 
APPENDICES ............................................................................................................92 
APPENDIX A. SAMPLING TIMEPOINTS AND PERMITTED WINDOWS ........................92 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments (Screening Period) .............................................................38 
Table 2: 
Schedule of Assessments (Part 1 and Part 2 Periods) .................................................40 
Table 3: 
Blood Volume – Screening (Screening Visit and Supplementation Washout 
Period) .........................................................................................................................50 
Table 4: 
Blood Volume – Part 1 (Open-Label Responsiveness Test Period) ...........................50 
Table 5: 
Blood Volume – Part 2 (Randomized Double-Blinded Treatment Period) ................51 
Table 6: 
20 mg/kg/day Dosing Table for Subjects ≥2 Years of Age Weighing ≤18 kg ...........54 
Table 7: 
40 mg/kg/day Dosing Table for Subjects ≥2 Years of Age Weighing ≤15 kg ...........55 
Table 8: 
60 mg/kg/day Dosing Table for Subjects ≥2 Years of Age Weighing ≤15 kg ...........55 
Table 9: 
7.5 mg/kg/day Per Day Dosing Table for Subjects <6 Months of Age 
Weighing ≤12 kg ........................................................................................................56 
Table 10: 15 mg/kg/day Dosing Table for Subjects ≥6 to <12 Months of Age Weighing 
≤15 kg .........................................................................................................................57 
Table 11: 30 mg/kg/day Dosing Table for Subjects ≥12 Months to <2 Years of Age 
Weighing ≤18 kg ........................................................................................................57 
Table 12: Phenylalanine/Tyr Sample Collection (Screening Period)a ........................................60 
Table 13: Phenylalanine/Tyr Sample Collections (Part 1 and Part 2)a .......................................60 
Table 14: Relationship of Study Drug to AE Relationship.........................................................69 
Table 15: Grading of Adverse Event Severity Grade .................................................................70 
Table 16: Investigator Site Requirements for Reporting Adverse Events ..................................70 
Table 17: Vital Signs Sampling Times (±Permitted Windows) for Subjects in PK 
Substudy on PK Sampling Days .................................................................................92 
Table 18: Electrocardiogram Sampling Times (±Permitted Windows) for Subjects in 
PK Substudy on PK Sampling Days ...........................................................................92 
Table 19: Pharmacokinetic Sampling Times (±Permitted Windows) for Plasma 
Samples for Part 1 .......................................................................................................92 
Table 20: Pharmacokinetic Sampling Times (±Permitted Windows) for Plasma 
Samples for Part 2 .......................................................................................................92 
 


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LIST OF FIGURES 
Figure 1: 
Endogenous Metabolism of BH4 From Sepiapterin ....................................................26 
Figure 2: 
Study Schema for Study PTC923-MD-003-PKU.......................................................37 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERM 
Abbreviation or 
Specialist Term 
Explanation 
ACMG 
American College of Medical Genetics 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate Aminotransferase 
AUC0-24h 
Area under the plasma concentration-time curve from time zero to 24 hours 
AUC0-inf 
Area under the plasma concentration-time curve from time zero to infinity 
BH4 
Tetrahydrobiopterin 
BUN 
Blood urea nitrogen 
CD 
Compact Disc 
CL/F 
Apparent total clearance of the drug from plasma following oral administration 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBS 
Dried blood sample 
eCRF 
Electronic case report form 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EQ-5D 
European Quality of Life - 5 Dimensions 
EQ-5D-Y 
European Quality of Life - 5 Dimensions for Youth 
ETV 
Early Termination Visit 
EU 
European Union 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
HEENT 
Head, eyes, ears, nose, and throat 
HPA 
Hyperphenylalaninemia 
HPLC/MS/MS 
High-performance liquid chromatography and mass spectrometry 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committees 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
Lactate dehydrogenase 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures 
NDA 
New Drug Application 
PAH 
Phenylalanine hydroxylase 
Phe 
Phenylalanine 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PKU 
Phenylketonuria 
PKU-QOL 
Phenylketonuria-quality of life 
PP 
Per Protocol 
QOL 
Quality of life 
RBC 
Red blood cell 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 


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Abbreviation or 
Specialist Term 
Explanation 
SAP 
Statistical analysis plan 
SoC 
Standard of care 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent adverse event 
Tyr 
Tyrosine 
USB 
Universal serial bus 
VAMS 
Volumetric absorptive microsampling 
Vz/F 
Apparent volume of distribution during terminal phase after non-intravenous 
administration 
WBC 
White blood cell 
 


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1. 
INTRODUCTION 
1.1. 
Phenylketonuria 
Phenylketonuria (PKU) is an autosomal-recessive inborn error of metabolism characterized by 
deficiency of the enzyme phenylalanine hydroxylase (PAH), which metabolizes phenylalanine 
(Phe) (Scriver 2001). Gene mutations of PAH result in decreased catalytic activity leading to 
hyperphenylalaninemia (HPA) (Al Hafid 2015). There are many different mutations in the PAH 
gene (>1100), resulting in phenotypic variation in the amount of enzyme produced and/or 
enzyme activity. Patients with severe forms of PKU, also known as “classical PKU”, typically 
have very high blood phenylalanine (Phe) levels (>1200 μmol/L). A partial deficiency of PAH 
activity results in a lower degree of blood Phe elevation. High levels of Phe are toxic to the brain 
and are associated with cognitive dysfunction, memory impairment, and can lead to psychiatric 
and behavioral problems (Kaufman 1989). If left untreated, severe and irreversible intellectual 
disability can occur (Scriver 2001, Waisbren 2007). Phenylketonuria is diagnosed at birth with 
the near universal adoption of newborn screening. Phenylketonuria has been described in all 
ethnic groups, and its incidence worldwide varies widely, but is estimated to occur in 
approximately 1 in every 23930 births (Hillert 2020).  
1.2. 
Current Treatment of Phenylketonuria 
Currently, there is no cure for PKU. Initial treatment consists of prompt institution of stringent 
Phe dietary restriction supplemented with specifically designed medical foods. Dietary control is 
considered the standard of care (SoC). The restriction in protein requires exclusion of natural 
foods such as meat, fish, milk, cheese, bread, nuts, and many other common food items. Even the 
intake of vegetables is limited. 
The success of dietary control, however, comes at high personal cost to affected individuals and 
their families. Compliance with a restrictive diet and Phe monitoring can be difficult for older 
children, adolescents, and adults (Fisch 2000, Walter 2002) and it is accepted that dietary burden 
does not improve with age (MacDonald 2012). Lifelong management of Phe levels is critical to 
avoid neurocognitive decline and other comorbidities as recognized by the European Guidance 
on PKU and the American College of Medical Genetics (ACMG) guidance on PKU (Vockley 
2014, van Wegberg 2017). Recently, it has been reported that >60% of adolescents and 70% of 
adult patients with PKU have uncontrolled blood Phe levels, with concentrations exceeding the 
upper limit of ACMG target range (360 μmol/L) (Jurecki 2017). The dietary restrictions lead to 
social difficulties and exclusions, with the potential to make people with PKU feel different and 
isolated. 
Synthetic tetrahydrobiopterin (BH4) (eg, sapropterin dihydrochloride), is commercially available 
as an approved drug for the treatment of HPA in PKU (FDA New Drug Application [NDA] 
22181, EMEA/H/C/000943). Sapropterin dihydrochloride is administered orally, once daily at a 
dose of 5 to 20 mg/kg (KUVAN USPI 2020). During the Phenylketonuria Scientific Review 
Conference: State of the Science and Future Research Needs, international experts concluded 
that most people with PKU have little or no benefit from sapropterin dihydrochloride, and 
evidence of long-term clinical improvements was lacking. They further concluded that “new 
drugs that are safe, efficacious, and impacting a larger proportion of individuals with PKU are 
needed” (Camp 2014). 


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PALYNZIQ (pegvaliase-pqpz) is a commercially available product that was recently approved 
for the treatment of adult patients with PKU (aged 16 years and older in the European Union 
[EU]) who have inadequate blood Phe control (blood Phe levels greater than 600 µmol/L) 
despite prior management with available treatment options including sapropterin (FDA Biologics 
License Application 761079, EMEA/H/C/004744). It is a pegylated form of the bacterial derived 
enzyme, phenylalanine ammonia lyase. While effective at helping lower blood Phe levels to 
<600 µmol/L, it requires a daily injection and patients in clinical studies experienced significant 
adverse reactions to PALYNZIQ treatment including anaphylactic reaction, hypersensitivity, 
anaphylactoid reaction, blood creatine phosphokinase increase, anxiety, arthralgia, 
serum-sickness, angioedema, hypophenylalaninemia, injection-site reactions, headache, rash, 
nausea, pruritus, and urticaria, to name a few. PALYNZIQ is not indicated for patients ≤18 years 
of age in the United States and ≤16 years of age in the EU, and accordingly does not address the 
unmet need for new medications that are safe and efficacious for children and adolescents 
(BioMarin 2020).  
1.3. 
PTC923 
PTC923 (formerly named CNSA-001) is (S)-2-amino-6-(2-hydroxypropanoyl)-7,8-
dihydropteridin-4(3H)-one with a molecular weight of 237.22 g/mol and a molecular formula of 
C9H11N5O3. 
The chemical structure of PTC923 is:  
 
PTC923 is a new molecular entity and synthetic form of sepiapterin. Sepiapterin serves as a 
substrate for de novo synthesis of BH4 via the pterin salvage pathway (Mayer 1995), making 
sepiapterin a naturally occurring precursor for BH4 (Figure 1). Tetrahydrobiopterin is an 
essential cofactor for enzymes including PAH (Kaufman 1989), tyrosine (Tyr) hydroxylase 
(Nagatsu 1964), tryptophan hydroxylase (Lovenberg 1967, Ichiyama 1970), fatty acid 
glycerylether oxygenase (Tietz 1964), and nitric oxide synthase (Kwon 1989, Mayer 1991). 
Following oral administration, PTC923 is rapidly converted to BH4 intracellularly (Smith 
2019a), the natural cofactor of PAH, and is intended to restore BH4 to physiological levels in 
patients who lack endogenous BH4, increase BH4 levels in patients who have lower than normal 
physiological levels of BH4, or enhance the chaperone effect on PAH in PAH-deficient patients 
by providing pharmacological levels of BH4 while also directly enhancing the thermal stability 
of PAH. 


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Figure 1: 
Endogenous Metabolism of BH4 From Sepiapterin 
 
Abbreviations: BH4, tetrahydrobiopterin 
1.4. 
Rationale for Study 
Currently, there is no cure for PKU. Control with dietary Phe restriction and/or BH4 
supplementation is suboptimal. Tetrahydrobiopterin supplementation with KUVAN has 
demonstrated clinically meaningful lowering of Phe plasma concentrations in approximately 
30% of patients with PKU and was well-tolerated at doses of 5 to 20 mg/kg/day over 22 weeks in 
BH4-responsive patients with PKU (Burnett 2007). Further studies showed that the effects on 
blood Phe are dose-related; however, doses of KUVAN higher than 20 mg/kg/day were not 
tested (KUVAN NDA 22-181 2007). PTC923 represents the first viable formulation of 
sepiapterin intended for the treatment of HPA in patients with PKU.  
Study PKU-001 was a Phase 1 exploratory study that assessed the safety, tolerability, and 
pharmacokinetics (PK) of escalating doses of PTC923 administered orally to healthy volunteers. 
This study showed that PTC923 was safe and well tolerated at single doses of up to 80 mg/kg or 
following once-daily dosing at doses up to 60 mg/kg for 7 days. Study PKU-001 also provided 
evidence of increased levels of BH4 when compared head to head with KUVAN across 
equivalent doses (Smith 2019b), that would be expected to result in improved efficacy. 
Following this, Study PKU-002, a Phase 2 study conducted in subjects with PKU, provided a 
direct head-to-head comparison of PTC923 and KUVAN, with a dose comparison of the effect 
of 20 mg/kg/day KUVAN versus 20 mg/kg/day PTC923 versus 60 mg/kg/day PTC923. In 
Study PKU-002, PTC923 60 mg/kg was significantly more effective than KUVAN 20 mg/kg in 
reducing blood Phe (p=0.0098). In addition, comparison of the change in mean blood Phe levels 
showed that the effect of PTC923 60 mg/kg on blood Phe was approximately 1.4 × larger than 
that of PTC923 20 mg/kg, driving dose decisions for future studies. There were no notable 
differences in the safety profile of the PTC923 and KUVAN. Study PKU-002 provided proof of 
the change in efficacy of PTC923 with statistically superior reductions in blood Phe levels versus 
KUVAN and helped to establish dose selection for this study.  
Study PTC923-MD-003-PKU is a Phase 3 study to assess the efficacy of PTC923 in reducing 
blood Phe levels in subjects with PKU. It is anticipated that a greater reduction in Phe will be 
observed in subjects with PKU who receive PTC923 versus those who receive placebo. This 
Phase 3 study is designed to support registration of PTC923 in subjects with PKU. 


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1.5. 
Rationale for Study Design and Control Group 
Study PTC923-MD-003-PKU is a double-blind, randomized study that compares PTC923 plus 
SoC to placebo plus SoC. Standard of care in PKU is a Phe-restricted diet. Aggressive and highly 
restrictive dietary control is the mainstay of treatment for the majority of patients. Initial and 
lifelong treatment consisting of prompt institution of Phe dietary restriction supplemented with 
specifically designed medical foods is the SoC for PKU (van Wegberg 2017). The prestudy 
Phe-restricted diet for each subject will be specifically determined and monitored in this study to 
ensure subjects maintain their current Phe-restricted diet throughout the study duration. 
The placebo control selected in this study is considered ethically acceptable, practical, and 
clinically relevant given that the underlining SoC of a Phe-restricted diet will be maintained for 
all subjects. Given the limited safe and effective pharmacological treatment options available for 
PKU, placebo control, together with 1:1 randomization, provides an optimal framework to 
directly assess the efficacy and safety of a new treatment. 
During Part 1 (the open-label Responsiveness Test), subjects with PKU will be enrolled and 
receive PTC923 for 14 days to identify subjects with ≥15% reduction from baseline in blood Phe 
levels.  
Subjects will receive the following doses of PTC923 for 14 days: 
• Subjects 0 to <6 months of age - 7.5 mg/kg 
• Subjects 6 to <12 months of age - 15 mg/kg 
• Subjects 12 months to <2 years of age - 30 mg/kg 
• Subjects ≥2 years - 60 mg/kg 
Subjects who experience <15% reduction in blood Phe levels will be classified as nonresponsive 
and will be contacted to schedule an Early Termination Visit (ETV) (on or between Day 28 to 
Day 35).  
Subjects <2 years of age who experience a ≥15% reduction in blood Phe levels will be offered 
the option to enroll directly into an open-label extension Study PTC923-MD-004-PKU.  
PTC923-responsive subjects ≥2 years of age will be entered into Part 2 (the double-blind, 
randomized Treatment Period). Subjects in the PTC923 treatment arm will receive PTC923 
20 mg/kg daily for Weeks 1 and 2, then PTC923 40 mg/kg daily for Weeks 3 and 4, then 
PTC923 60 mg/kg daily for Weeks 5 and 6. As dosing is weight-based and to maintain the blind, 
subjects in the placebo arm will receive equivalent quantities of placebo to match the 20 to 40 to 
60 mg/kg dose escalation of the PTC923 treatment arm. After 6 weeks of treatment with either 
PTC923 or placebo, subjects will be offered the option to enter an open-label extension 
Study PTC923-MD-004-PKU. 


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The study inclusion criteria were developed to include the broadest possible criteria to reflect the 
wider PKU population, while excluding subjects who may be at risk from participation or may 
confound data interpretation. Subjects must have a clinical diagnosis of PKU with HPA 
documented by past medical history of at least 2 blood Phe measurements ≥600 µmol/L. Another 
inclusion criterion specifies subjects must have blood Phe levels ≥360 µmol/L during screening, 
or when taking the average of the 3 most recent Phe levels from the subject’s medical history 
(inclusive of the Screening value). Setting the values at ≥360 µmol/L allows the inclusion of 
children, in whom Phe levels above 360 µmol/L would be considered uncontrolled. If the Phe 
levels were to be set at ≥600 µmol/L, the study would principally enroll adult subjects only. 
While larger changes in Phe levels may be observed if the starting levels are higher, excluding 
younger subjects with lower levels of Phe would be short-sighted. Nevertheless, a second 
stratification will ensure that subjects with baseline blood Phe of <600 µmol/L and subjects with 
baseline blood Phe ≥600 µmol/L are equally distributed to receive PTC923 or placebo. 
1.6. 
Study Duration 
The study duration for each subject will be up to 107 days from Screening to the final study visit. 
Following a screening period of up to 45 days, all enrolled subjects will receive PTC923 2 weeks 
followed by a minimum 14-day PTC923 washout period in Part 1. Subjects ≥2 years of age with 
≥15% response to PTC923 will continue treatment in Part 2 with either PTC923 or placebo for 
6 weeks. Subjects <2 years of age with ≥15% response to PTC923 will be offered the option to 
enroll directly into an open-label extension Study PTC923-MD-004-PKU. 
1.7. 
Risk/Benefit Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of PTC923 can be found in the current version of the IB and 
associated reference safety information.  
Clinical knowledge exists for PTC923 as it has been evaluated in more than 102 subjects in 
4 clinical studies including 24 subjects with PKU. Across all studies, PTC923 has been well 
tolerated and exhibited a favorable safety profile with manageable side effects. Further, 
Study PTC923-MD-003-PKU will have a data and safety monitoring board that will closely 
monitor the safety of subjects.  
When developing the inclusion/exclusion criteria and study design for this study, PTC 
Therapeutics (PTC) identified benefits and risks with mitigation strategies that ensured the safety 
of subjects and veracity of data collected. 
As per inclusion criteria 3, eligible subjects for this study have uncontrolled PKU with blood Phe 
level ≥360 μmol/L on current therapy anytime during Screening and uncontrolled blood Phe 
level ≥360 μmol/L on current therapy. PTC923 has been shown to provide statistically 
significant, dose-related reductions in blood Phe and was faster and more efficacious in reducing 
blood Phe compared to sapropterin in subjects with uncontrolled PKU (Bratkovic 2022). Further, 
in subjects with classical PKU, the reduction in mean blood Phe with PTC923 was also larger 
than that observed with sapropterin. 


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To minimize exposure to placebo, Part 2 (randomized, placebo-controlled, double-blind 
treatment period) duration is capped at 6 weeks. This duration permits adequate analysis of 
efficacy of PTC923 versus placebo but minimizes placebo exposure. During this period, blood 
Phe levels will be extensively monitored to ensure safety of subjects. No subject aged <2 years 
will be exposed to placebo. 
To reduce exposure of nonresponsive subjects to PTC923, in Part 1, all eligible subjects will be 
tested for responsiveness to PTC923. Subjects ≥2 years of age who experience <15% reduction 
in blood Phe levels and subjects <2 years of age who experience a <15% reduction in blood Phe 
levels will be classified as nonresponsive, and participation in the study will be terminated. To 
minimize exposure of subjects <2 years of age to placebo, subjects who experience a ≥15% 
reduction in blood Phe levels will be offered the option to enroll directly into an open-label 
extension Study PTC923-MD-004-PKU. 
During this study, blood Phe will be monitored frequently to assess the responsiveness and 
efficacy of treatment. PTC has demonstrated that dried blood sample collection using the 
volumetric absorptive microsampling (VAMS) high-performance liquid chromatography and 
mass spectrometry (HPLC/MS/MS) method is reliable, repeatable, and the results are 
comparable to a conventional venous blood sampling human plasma HPLC/MS/MS method. 
Samples collected in the Phase 2 study (Study PKU-002) demonstrated no bias over the 
measurable Phe concentration range using VAMS dried blood method. Compared to a standard 
blood draw (>2 mL) to measure blood Phe, dried blood VAMS uses sample volumes of 10 to 
20 µL and produces reliable blood Phe concentration quantification. The VAMS dried blood 
method allows blood Phe samples to be collected at home in accordance with GCP, a critical 
advantage given the current coronavirus disease 2019 (COVID-19) pandemic when 
unpredictable and unplanned closings of clinical sites occur and prevent regular clinical visits or 
potentially expose patients to unnecessary risks.  
Taking into account the measures taken to minimize risk to subjects participating in this study, 
the potential risks identified in association with PTC923 are justified by the anticipated benefits 
that may be afforded to subjects with PKU. 


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2. 
TRIAL OBJECTIVES AND PURPOSE 
2.1. 
Primary Objective 
• To evaluate the efficacy of PTC923 in reducing blood Phe levels in subjects with 
PKU as measured by mean change in blood Phe levels from baseline to Weeks 5 and 
6 (ie, the average of each respective treatment dose 2-week period of double-blind 
treatment) 
2.2. 
Secondary Objectives 
• To evaluate the proportion of subjects with baseline Phe levels ≥600 μmol/L who 
achieve Phe levels <600 μmol/L at the end of the double-blind treatment period 
• To evaluate the effect of PTC923 dose response on reducing blood Phe levels in 
subjects with PKU 
• To evaluate the PK of PTC923 in subjects with PKU 
• To assess the safety of PTC923 in subjects with PKU 
2.3. 
Exploratory Objective 
• To evaluate changes in blood Tyr overtime, including the Phe:Tyr ratio 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 3, double-blind, randomized, multi-center efficacy study of PTC923 versus 
placebo in subjects with PKU.  
Part 1 of the study tests for responsiveness to PTC923, with 14 days of open-label treatment with 
PTC923 7.5 mg/kg (subjects 0 to <6 months of age), 15 mg/kg (subjects 6 to <12 months of age), 
30 mg/kg (subjects 12 months to <2 years of age), or 60 mg/kg (subjects ≥2 years of age) 
administered orally once a day followed by a minimum of 14 days PTC923 washout. At the end 
of treatment in Part 1, the mean change in blood Phe levels over the 14-day treatment period for 
all subjects will be assessed against their pretreatment blood Phe level. Pretreatment blood Phe 
level will be the mean of Day -1 and Day 1 (predose) blood Phe levels. Subjects ≥2 years of age 
who experience a <15% reduction in blood Phe levels will be classified as non-responsive and 
participation in the study will be terminated. Subjects ≥2 years of age who experience a 
≥15% reduction in blood Phe levels will continue into Part 2, which is a randomized, 
placebo-controlled, double-blind treatment period. Subjects <2 years of age who experience 
≥15% reduction in blood Phe levels will be offered the option to enroll directly into an 
open-label extension Study PTC923-MD-004-PKU. Subjects <2 years of age who experience a 
<15% reduction in blood Phe levels will be classified as nonresponsive, and participation in the 
study will be terminated. Following the minimum 14-day PTC923 washout period, all eligible 
subjects will be randomized in Part 2 to receive either PTC923 or placebo. Subjects will be 
stratified based on their mean percent reduction in blood Phe levels (ie, subjects with mean % 
reduction in Phe levels of ≥15% to <30% and subjects with mean % reduction in Phe levels of 
≥30%) and evenly distributed to either PTC923 or placebo treatment arms. Additionally, subjects 
will be stratified based on their baseline blood Phe concentration (ie, subjects with baseline 
blood Phe <600 µmol/L and subjects with baseline blood Phe ≥600 µmol/L) and evenly 
distributed to either PTC923 or placebo. 
Subjects randomized to PTC923 will receive PTC923 20 mg/kg daily for Weeks 1 and 2, then 
PTC923 40 mg/kg daily for Weeks 3 and 4, then PTC923 60 mg/kg daily for Weeks 5 and 6. As 
dosing is weight-based and to maintain the blind, subjects randomized to placebo will receive 
equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the 
PTC923 treatment arm. After 6 weeks of treatment with either PTC923 or placebo, subjects will 
be offered the option to enter an open-label extension Study PTC923-MD-004-PKU. 
Approximately 45 centers will participate in this study. The study design is summarized in 
Figure 2 and the Schedule of Assessments is presented in Table 1 (Screening Period) and 
Table 2 (Parts 1 and 2). 
Throughout the study, subjects will maintain 3-day diet records corresponding to each week of 
the study. At each in-clinic visit, a dietician will monitor each subject’s diet to calculate total 
protein and corresponding Phe consumption, to have regular contact with subjects, and to 
reinforce the need for subjects to maintain their usual diet without modification (Section 8.1.7). 
Virtual visits are acceptable as indicated/or deemed necessary in the Schedule of Assessments 
(Table 2). However, if study staff feel it necessary and/or appropriate, these visits may be 
conducted at the study site instead. 


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3.1.1. 
Screening Period (Up to 45 Days) 
An informed consent and/or assent (as applicable) form must be signed before any study-related 
procedures are performed. After providing consent and/or assent (as applicable), subjects will 
undergo in-clinic screening procedures to determine study eligibility. Subject demographics and 
medical history information will be collected. Additionally, specific information related to 
previous use of sapropterin or pegvaliase-pqpz should be collected (ie, details on duration, dose, 
if discontinued, the reason[s] why, and if a subject is known to be BH4-responsive). Vital signs, 
weight, and height measurements will be performed. Phenylalanine hydroxylase gene (PAH) 
genotyping should be performed unless already documented in subject’s medical history. Blood 
Phe/Tyr levels will be measured. Vital signs, weight, and height measurements will be 
performed. A full physical examination will be performed, and blood samples will be collected 
for clinical laboratory tests and pregnancy testing. Concomitant medication and AEs will be 
collected from provision of consent and/or assent (as applicable). Subjects will be instructed to 
continue their usual diet without modification (ie, no change in daily Phe consumption) 
throughout the entire study. Subjects will maintain a 3-day diet record during each week of 
Screening, and a dietician will monitor each subject’s diet to calculate total protein and 
corresponding Phe consumption, have regular contact with subjects, and reinforce the need for 
subjects to maintain their usual diet without modification. Subjects who enter the study and are 
receiving pegvaliase-pqpz supplementation at the Screening Visit must complete a 30-day 
washout period prior to dosing. Subjects who enter the study and are receiving BH4 
supplementation (eg, sapropterin dihydrochloride, KUVAN) at the Screening Visit must 
complete a 7-day washout period prior to dosing. 
3.1.1.1. 
Pegvaliase-pqpz Washout (30 Days)  
Following the initial Screening Visit, eligible subjects who are taking pegvaliase-pqpz must 
discontinue the medication as concomitant treatment/supplementation with pegvaliase-pqpz will 
not be permitted during the study. Pegvaliase-pqpz will be discontinued 24 hours prior to starting 
the Washout. Subjects will continue their usual diet without modification (ie, no change in daily 
Phe consumption) and will maintain a 3-day diet record during the Pegvaliase-pqpz Washout. A 
dietician will monitor each subject’s diet to calculate total protein and corresponding Phe 
consumption, to have regular contact with subjects, and to reinforce the need for subjects to 
maintain their usual diet without modification. Blood Phe levels will be measured at each 
timepoint for the 30-day washout (Days 1, 20, and 30). 
3.1.1.2. 
BH4 Supplementation Washout (7 Days) 
Following the initial Screening Visit, eligible subjects who are receiving BH4 supplementation 
must discontinue the medication as concomitant treatment/supplementation with BH4 will not be 
permitted during the study. BH4 treatment (eg, sapropterin dihydrochloride, KUVAN) will be 
discontinued 24 hours prior to starting the Supplementation Washout. Subjects will continue 
their usual diet without modification (ie, no change in daily Phe consumption) and will maintain 
a 3-day diet record during the BH4 Supplementation Washout. A dietician will monitor each 
subject’s diet to calculate total protein and corresponding Phe consumption, to have regular 
contact with subjects, and to reinforce the need for subjects to maintain their usual diet without 
modification. Blood will be collected for determination of blood Phe levels at each timepoint for 
the 1-week washout (Days 1, 4, and 7) using dried blood sampling. 


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3.1.2. 
Part 1, Open-Label Responsiveness Test (28 to 35 Days) 
3.1.2.1. 
Part 1, Open-Label Treatment (14 Days) 
Following the initial Screening Visit and BH4 Supplementation/Pegvaliase-pqpz Washout 
(as necessary), all eligible subjects will be enrolled into Part 1 of the study to test for 
responsiveness to PTC923. Subjects will receive the following doses of PTC923 for 14 days: 
• Subjects 0 to <6 months of age: 7.5 mg/kg 
• Subjects 6 to <12 months of age: 15 mg/kg 
• Subjects 12 months to <2 years of age: 30 mg/kg 
• Subjects ≥2 years: 60 mg/kg 
On Part 1 Day 1, subjects will take their dose of PTC923 while in the clinic; for all other dosing 
days, subjects will take their dose at home and prior to coming to the clinic when visits are 
scheduled. All visits will be outpatient visits or virtual visits. Study visits will occur on Part 1 
Day 1, Part 1 Day 2 (PK substudy only), and Part 1 Day 14 (virtual visit, unless part of the PK 
substudy). 
In Part 1, blood Phe levels will be measured on Days -1, 1 (predose), 2 (PK substudy only), 5, 
10, and 14. Baseline blood Phe level will be calculated as the mean of the blood Phe levels from 
dried blood samples taken on Day -1 and Day 1 (predose). Samples will be collected after fasting 
or no earlier than 3 hours postprandial at approximately the same time of day at each collection 
timepoint.  
Subjects will continue their usual diet without modification and will maintain 3-day diet records 
(ie, one corresponding to each week of the PTC923 open-label treatment period). A dietician will 
monitor each subject’s diet to calculate total protein and corresponding Phe consumption and to 
have regular contact with subjects. 
PK substudy only:  
Approximately 30 subjects ≥12 years of age will participate in the PK substudy. At least 12 out 
of the 30 subjects ≥12 years of age participating in the PK substudy will be female. In addition, 
up to 6 subjects from each of these age groups will be included: 1) <2 years; 2) 2 to 5 years; and 
3) 6 to 11 years. Blood samples will be collected from subjects participating in the PK su-study 
to characterize the PK of sepiapterin and BH4 following an intensive schedule on Part 1 Day 1 
and Part 1 Day 2 from subjects ≥2 years. For subjects <2 years of age, blood samples (2 on each 
occasion; total of 4 samples) will be collected on Part 1 Day 1 and Part 1 Day 14. 
In addition to blood drawn for PK sampling at specified timepoints, a small amount of blood will 
be drawn to a minicollect tube (~0.25 mL) at the same time and applied to the VAMS device for 
blood Phe and Tyr measurement. Details will be described in the laboratory manual. 


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3.1.2.2. 
Part 1, PTC923 Washout (14 Days Minimum) 
Following completion of 14 days of PTC923 open-label treatment, subjects will begin a 
minimum 14-day washout. No in-clinic study visits are required during the PTC923 washout. In 
Part 1, blood Phe levels will be measured on Days 19, 24, and 28. Blood Phe samples will be 
collected after fasting or no earlier than 3 hours postprandial at approximately the same time of 
day at each collection timepoint. 
Subjects will continue their usual diet without modification and will maintain 3-day diet records 
(ie, one corresponding to each week of the PTC923 washout). A dietician will monitor each 
subject’s diet to calculate total protein and corresponding Phe consumption, to have regular 
contact with subjects, and to reinforce the need for subjects to maintain their usual diet without 
modification.  
During the PTC923 washout, the mean change in blood Phe levels over the 14 days of PTC923 
treatment (mean of Part 1 Days 5, 10, and 14) will be measured and compared against their 
pretreatment blood Phe level (mean of Part 1 Day -1 and Part 1 Day 1 [predose]). PTC will allow 
determination of a subject’s participation in Part 2 with ≤2 pretreatment blood Phe levels (but 
requiring a minimum of 1 pretreatment level) and ≤3 PTC923 treatment blood Phe levels (but 
requiring a minimum of 1 PTC923 treatment level), depending on the available data (on or 
between Part 1 Study Day 28 to Day 35). 
Subjects ≥2 years of age who experience <15% reduction in blood Phe levels will be classified as 
non-responsive and will be contacted to schedule an ETV (on or between Day 28 to Day 35) 
(Section 3.1.5). Subjects ≥2 years of age who experience a ≥15% reduction in blood Phe levels 
will be contacted to confirm their continued eligibility and to schedule the Part 2 Day 1 visit.  
Subjects <2 years of age who experience a <15% reduction in blood Phe levels will be classified 
as nonresponsive, and participation in the study will be terminated. Subjects <2 years of age who 
experience a ≥15% reduction in blood Phe levels will be offered the option to enroll directly into 
an open-label extension Study PTC923-MD-004-PKU. 
Part 1 for all subjects ends on Day 35. In no circumstances will a subject be permitted to 
continue in Part 1 beyond Day 35. If a subject’s blood Phe concentrations are not available for 
determination of responsiveness to PTC923 by Day 35 of Part 1, then that subject will be 
classified as nonresponsive and will be contacted to schedule an ETV and not be eligible to 
continue into Part 2 of the study or further participation in an open-label extension 
Study PTC923-MD-004-PKU. 
3.1.3. 
Part 2, Randomized Double-Blind Treatment Period (42 Days) 
All eligible subjects ≥2 years of age will be randomized to receive either PTC923 or placebo for 
42 days (ie, 6 weeks) in Part 2, the randomized, placebo-controlled, double-blind treatment 
period.  
Subjects will be stratified based on their mean percent blood Phe reduction in Part 1 (mean 
% reduction in blood Phe levels of ≥15% to <30% and mean % reduction in blood Phe levels of 
≥30%) and evenly distributed across both treatment arms (PTC923 or placebo). Additionally, 
subjects will be stratified based on their baseline blood Phe concentration (ie, subjects with 
baseline blood Phe <600 µmol/L and subjects with baseline blood Phe ≥600 µmol/L) and evenly 
distributed to either PTC923 or placebo. This portion of the study is double-blinded. Subjects 


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will continue their usual diet without modification and will maintain 3-day diet records 
(one corresponding to each week of Part 2). A dietician will monitor each subject’s diet to 
calculate total protein and corresponding Phe consumption, to have regular contact with subjects, 
and to reinforce the need for subjects to maintain their usual diet without modification.  
Subjects randomized to PTC923 will receive PTC923 20 mg/kg daily for Days 1 to 14 
(ie, Weeks 1 and 2), then PTC923 40 mg/kg daily for Days 15 to 28 (ie, Weeks 3 and 4), then 
PTC923 60 mg/kg daily for Days 29 to 42 (ie, Weeks 5 and 6). As dosing is weight-based and to 
maintain the blind, subjects randomized to placebo will receive equivalent quantities of placebo 
to match the 20 to 40 to 60 mg/kg dose escalation used with those randomized to PTC923. 
On Part 2 Day 1, subjects will take their dose of study drug (PTC923 20 mg/kg or placebo) 
in-clinic; for all other dosing days, subjects will take their dose at home and prior to coming to 
the clinic when visits are scheduled. All visits will be outpatient visits or virtual visits. Study 
visits will occur on Part 2 Day 1, Part 2 Day 14 (in-clinic visit for PK substudy only), Part 2 Day 
28 (in-clinic visit for PK substudy population), and Part 2 Day 42 to conduct study evaluations, 
collect 3-day diet records, and capture any AEs and concomitant medications. 
On Part 2 Day 1 (predose), the Phenylketonuria-quality of life (PKU-QOL) (Parent PKU-QOL 
[6 to 8 years]; Child PKU-QOL [9 to 11 years]; Adolescent PKU-QOL [12 to 17 years]; 
Adult PKU-QOL [≥18 years]) will be conducted using the tool in one of the following validated 
languages: English (British or American), Turkish, Dutch, German, Spanish, Italian, Portuguese, 
or French. Conduct of the PKU-QOL will not be required for subjects whose primary language is 
not one of the available validated languages. On Part 2 Day 1 (predose), the European Quality of 
Life - 5 Dimensions (EQ-5D) (European Quality of Life - 5 Dimensions for Youth [EQ-5D-Y] 
Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 15 years]; and 5-Level European Quality of 
Life - 5 Dimensions (EQ-5D-5L) [≥16 years]) will be conducted.  
Blood Phe levels will be measured in Part 2 on Days -1, 1 (predose), 5, 10, 14, 19, 24, 28, 33, 38, 
and 42. Samples will be collected after fasting or no earlier than 3 hours postprandial at 
approximately the same time of day at each collection timepoint.  
Subjects participating in the PK substudy: Blood samples (2 samples/occasion) will be 
collected from subjects in Part 2 on Days 1, 14, 28, and 42 visits to characterize the PK of 
sepiapterin and BH4 at predose (approximately 24 hours post the dose on prior day, except for 
Day 1 and prior to the dose of the day) and 4 hours postdose. 
3.1.4. 
End of Study 
For subjects <2 years of age, End of Study is defined as their final visit in Part 1 and should 
occur on/between Part 1 Day 28 and Part 1 Day 35. All subjects <2 years of age who experience 
a ≥15% reduction in blood Phe levels during Part 1 will be offered the option to enroll directly 
into an open-label extension Study PTC923-MD-004-PKU. 
For subjects ≥2 years of age who complete Part 2, End of Study is defined as their final study 
visit on Part 2 Day 42. All subjects who complete Part 2 will be given the opportunity to 
continue treatment in the PTC923 Open-Label Extension Study, PTC923-MD-004-PKU. 
Enrollment will continue until 80 subjects are randomized into the stratum of ≥30% blood Phe 
reduction PTC923-responsive subjects. The end of study is defined as the date of the last visit of 
the last subject in the study globally. 


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3.1.5. 
Early Termination Visit  
An ETV will be performed on or between Day 28 to Day 35 for all subjects who are determined 
to be non-responders in Part 1, or within 2 days for any subject who discontinues the study 
prematurely during Part 1 or Part 2 for any other reason. During the ETV, 3-day diet records, 
AEs, concomitant medications, weight, vital signs, ECGs, and blood Phe/Tyr levels will be 
collected. A physical examination, clinical laboratory tests, and a pregnancy test will be 
performed. For non-responsive subjects and subjects who discontinue prematurely, following the 
ETV, subjects may revert to their prestudy treatment for PKU (at the investigators and the 
subject’s treating physician discretion), and a phone follow-up visit will occur 30 (±3) days after 
the last dose of study drug to assess for serious adverse events (SAEs). 
 


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Figure 2: 
Study Schema for Study PTC923-MD-003-PKU 
 
Abbreviations: Phe, phenylalanine; QD, once daily 
Note: Phe responsiveness is defined as mean Phe reduction ≥15%.  


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Table 1: 
Schedule of Assessments (Screening Period) 
Evaluation 
Screening Period 
Screening Visit 
Supplementation Washout Period 
(Max 30 Days) a 
Study Day 
Up to 45 days 
Pegvaliase-pqpz 
30 days 
BH4 
7 days 
Informed consent/assent 
X 
 
 
PAH genotypingb 
X 
 
 
Confirm eligibility 
X 
 
 
Demographics 
X 
 
 
Medical historyc 
X 
 
 
In-clinic visit 
X 
 
 
Vital signs, weight, and heightd 
X 
 
 
Physical examinatione 
X 
 
 
Clinical laboratory testsf 
X g 
 
 
Serum/urine pregnancy test h 
X 
 
 
Concomitant medications i 
Collected throughout the study 
Adverse events j 
Collected throughout the study 
Blood Phe/Tyr levels k 
X 
Day 1, 20, 30 
Day 1, 4, 7 
Consistent diet/diet monitoring/3-day 
diet record distribution/collection l 
X 
X 
X 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate 
aminotransferase; BH4, tetrahydrobiopterin; BUN, blood urea nitrogen; ETV, Early Termination Visit; GGT, gamma 
glutamyl transferase; HEENT, head, eyes, ears, nose, and throat; LDH, lactate dehydrogenase; PAH, phenylalanine 
hydroxylase; Phe, phenylalanine; RBC, red blood cell; SAE, serious adverse event; Tyr, tyrosine; WBC, white blood 
cells  
a BH4 treatment (eg, sapropterin dihydrochloride, KUVAN) and pegvaliase-pqpz will be discontinued 24 hours prior to 
starting the Supplementation Washout. Subjects will remain off supplementation throughout the study. 
b To be performed unless documented in subject’s medical history. 
c Includes specific information related to any prior or existing medical conditions or surgical procedures involving the 
following systems: dermatologic, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, 
neurological, and skin. Newborn Phe concentrations and the 3 most recent Phe concentrations will be collected. 
d Includes blood pressure, pulse, respiratory rate, and temperature. Obtain vital signs prior to collection of any 
laboratory samples (including Phe). Vital signs should be collected prior to blood Phe/Tyr collection at the 
Screening Visit. If feasible, subjects will rest for 5 minutes in a supine position before vital signs are assessed. 
Height will be collected only at Screening. 
e Conduct a complete physical examination of general appearance, dermatologic, HEENT, lymphatic, cardiovascular, 
respiratory, gastrointestinal, musculoskeletal, neurological, and skin parameters. 
f Includes clinical chemistry panel (albumin, AP, ALT, AST, B12, BUN, calcium, CO2, chloride, serum creatinine, 
GGT, glucose, iron, LDH, phosphate, potassium, sodium, total bilirubin, direct bilirubin, total cholesterol, total 
protein, uric acid); hematology panel (hematocrit, hemoglobin, platelet count, RBC, WBC, WBC differential); and 
urinalysis (bilirubin, glucose, ketones, occult blood, pH, protein, specific gravity, urobilinogen and microscopic 
examination of WBC, RBC, and epithelial cells). Subjects should be fasted prior to collection of samples (minimum 
of 4 hours for subjects <6 years and minimum of 8 hours for subjects ≥6 years). 
g eGFR should be calculated for all subjects. 
h Pregnancy tests required for all women of childbearing potential (Section 8.1.5); serum testing to occur at the 
Screening Visit, and urine testing to occur during all other in-clinic visits. Any positive urine pregnancy test should 
be confirmed by a serum pregnancy test performed at the site’s local laboratory. 
i Record all treatments (including nutritional supplements) and over-the-counter medications (including herbal 
medications) starting from 30 days prior to Screening through the study. 
j AEs will be collected from the time of informed consent and/or assent (as applicable) until completion of Part 2 
Day 42 or ETV (for subjects who discontinue prematurely or are considered non-responders after Part 1, subjects 
will continue to be followed for 30 days after last dose for SAEs). Specific information related to previous use of 
sapropterin or pegvaliase-pqpz should be collected (ie, details on duration, dose, if discontinued, the reason(s) why, 
and if a subject is known to be BH4-responsive). If a subject elects not to continue into 
Study PTC923-MD-004-PKU, they should be followed up 30 days after their Day 42 visit for collection of AEs. 


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k Blood Phe/Tyr levels via dried blood sample will be measured at each timepoint indicated (Table 12). Samples will 
be collected after fasting or no earlier than 3 hours postprandial and at approximately the same time of day. Blood 
Phe/Tyr samples can be collected while the subject is either in the clinic or at home. Samples obtained at home will 
be shipped to the study site. Analysis of the screening blood Phe level can be performed at the site’s local 
laboratory for determination of eligibility; however, a separate sample for blood Phe/Tyr should still be sent to the 
central lab for the screening timepoint. Vital signs should be collected prior to blood Phe/Tyr collection at the 
Screening Visit. 
l Subjects are to maintain a consistent diet (with respect to Phe intake) during the study. A dietician will monitor each 
subject’s diet to calculate Phe consumption and to have regular contact with subjects. 3-day diet records will be 
given to subjects at the screening visit and are to be completed weekly throughout the study. The 3-day diet records 
will be collected weekly throughout the study. 


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Table 2: 
Schedule of Assessments (Part 1 and Part 2 Periods) 
Evaluation 
Part 1-Open-Label Responsiveness Test 
Part 2-Randomized, Placebo-Controlled, Double-
Blind Treatment Period 
ETV
v 
PTC923 Open-Label Treatment 
0 to <6 months: 7.5 mg/kg 
6 to <12 months: 15 mg/kg 
12 months to <2 years: 30 mg/kg 
≥2 years: 60 mg/kg 
14 Days 
PTC923 
Washouta 
Minimum of 
14 Days 
PTC923 
20>>40>>60 mg/kg vs Placebo) 
42 Days (6 Weeks) 
Study Day 
-1 
1 
2 
5 
10 
14 
19 
24 
28b -1 
1 
5 
10 
14 
19 
24 
28 
33 38 
42/ 
EOS 
 
Confirm eligibility 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
In-clinic visit 
 
X 
Xd 
 
 
Xd 
 
 
 
 
X 
 
 
Xd 
 
 
Xd 
 
 
X 
X 
Virtual visit 
 
 
 
 
 
X 
 
 
Xe 
 
 
 
 
X 
 
 
X 
 
 
 
 
At home assessment/ procedure 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsf, weight  
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
X 
X 
Heighth 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xv 
 
ECGsi 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical examinationj 
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
X 
X 
Clinical laboratory testsk 
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
Xl 
X 
Serum/urine pregnancy testm 
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
X 
X 
Concomitant medicationsn 
Collected throughout the study 
Adverse eventso 
Collected throughout the study 
Blood Phe/Tyr levels (DBS)p 
Sample to be taken at all timepoints 
Blood for Phe levels (plasma)q 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Blood for PK substudyr 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Consistent diet/diet monitoring /3-day 
diet records 
 
X 
 
X 
X 
QOL Assessmentst 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dose study drug 
 
Daily for 14 days 
 
 
 
 
Daily for 42 days (6 weeks) 
 
Dispense study drug 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Collect study drug, assess 
compliance 
 
 
 
 
 
Xu 
 
 
 
 
Xu 
 
 
Xu 
 
 
Xu 
 
 
Xu 
Xu 
Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; COVID-19, coronavirus 
disease 2019; DBS, dried blood sample; ECG, electrocardiogram; EOS, End of Study; ETV, Early Termination Visit; EQ-5D, European Quality of Life - 5 
Dimensions; EQ-5D-5L, 5-Level European Quality of Life - 5 Dimensions; EQ-5D-Y, European Quality of Life - 5 Dimensions for Youth; GGT, gamma glutamyl 
transferase; HEENT, head, eyes, ears, nose, and throat; LDH, lactate dehydrogenase; Phe, phenylalanine; PK, pharmacokinetics; PKU-QOL, Phenylketonuria-
quality of life; QOL, quality of life; RBC, red blood cell; SAE, serious adverse event; Tyr, tyrosine; VAMS, volumetric absorptive microsampling; WBC, white blood 
cell 


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a PTC923 washout period consists of a minimum 14-day washout (may be longer depending on timing for determination of response). During the PTC923 washout 
period, study drug will not be administered, and compliance will not be assessed.  
b Visit can occur at any point on or between Day 28 to Day 35. 
c Randomization can occur anytime during the PTC923 washout after confirmation of meeting PTC923-responsiveness of blood Phe reduction ≥15% and 
scheduling of Part 2 Day 1 in-clinic visit. 
d In-clinic visits will occur for all subjects on Part 1 Day 1, Part 2 Day 1, and Part 2 Day 42. Only for subjects participating in the PK substudy, additional in-clinic 
visits will also occur on Part 1 Day 2, Part 1 Day 14, Part 2 Day 14, and Part 2 Day 28 to obtain PK blood draws. There is a ±2-day window permitted for the 
Part 2 Day 42 visit. Subject should continue treatment until the Day 42 (±2 days) Phe sample has been collected. For subjects participating in the PK sub-study, 
if an in-clinic visit is scheduled for PK blood sampling, doses will be administered at the clinic with a meal. 
e Telephone call to confirm eligibility for continued participation and to schedule either Part 2 Day 1 visit or ETV. 
f Includes blood pressure, pulse, respiratory rate, and temperature. Obtain vital signs prior to collection of any laboratory samples (including Phe). If feasible, 
subjects will rest for 5 minutes in a supine position before vital signs are assessed. Vital signs will be collected both predose and 2-hours postdose on Part 1 
Day 1 and Part 2 Day 1; for all other timepoints, they will be taken at any time during the visit but prior to collection of any laboratory samples (including Phe). For 
subjects participating in the PK sub-study, windows for study days where PK samples are taken are presented in Table 17. For all other timepoints, Table 2 
should be followed. 
g To be completed prior to initial dosing and at additional timepoints where indicated (eg, 2-hours postdose vital signs). 
h Height should only be measured for subjects <18 years of age (at time of visit) at the indicated visits.  
i If feasible, subjects will rest for 5 minutes in a supine position before ECG is performed. Twelve-lead ECGs are to be performed at Part 1 Day 1 (predose) for all 
subjects, Part 2 Day 42/EOS, and at the ETV (if appropriate). Additional 12-lead ECGs will be performed for all subjects participating PK substudy at Part 1 
Day 1 at 2, 4, 6, and 8 hours postdose. Electrocardiograms will be performed in triplicate, with each read taken at least 1 minute apart. For subjects participating 
in the PK substudy, windows for study days where PK samples are taken are presented in Table 18. For all other timepoints, Table 2 should be followed. 
j Conduct a complete physical examination of general appearance, dermatologic, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, 
musculoskeletal, neurological, and skin parameters.  
k Includes clinical chemistry panel (albumin, AP, ALT, AST, B12, BUN, calcium, CO2, chloride, serum creatinine, iron, GGT, glucose, LDH, phosphate, potassium, 
sodium, total bilirubin, direct bilirubin, total cholesterol, total protein, uric acid); hematology panel (hematocrit, hemoglobin, platelet count, RBC, WBC, WBC 
differential); and urinalysis (bilirubin, glucose, ketones, occult blood, pH, protein, specific gravity, urobilinogen and microscopic examination of WBC, RBC, and 
epithelial cells). Subjects should be fasted prior to collection of samples (minimum of 4 hours for subjects <6 years and minimum of 8 hours for subjects 
≥6 years). 
l eGFR should be calculated (all subjects). 
m Pregnancy tests required for all women of childbearing potential (Section 8.1.5); serum testing to occur at the Screening visit, and urine testing to occur during all 
other in-clinic visits (excluding in-clinic visits specifically for the PK substudy). Any positive urine pregnancy test should be confirmed by a serum pregnancy test 
performed at the site’s local laboratory. 
n Record all treatments (including nutritional supplements) and over-the-counter medications (including herbal medications) starting from 30 days prior to 
Screening until completion of Part 2 Day 42 or ETV (if applicable).  
o AEs will be collected from the time of informed consent and/or assent (as applicable) until completion of Part 2 Day 42 or ETV (for subjects who discontinue 
prematurely or are considered nonresponders after Part 1, subjects will continue to be followed for 30 days after last dose for SAEs). If a subject elects not to 
continue into Study PTC923-MD-004-PKU, they should be followed up 30 days after their Day 42 visit for collection of AEs. 
p Blood Phe/Tyr levels via dried blood sample are measured at each timepoint indicated. Day -1 and Day 1 (predose) samples for both Part 1 and Part 2 should be 
taken predose. All other samples can be collected predose or postdose. Samples will be collected after fasting or no earlier than 3 hours postprandial and at 
approximately the same time of day. Samples obtained at home will be shipped to the study site or returned to the study site at the next clinic visit. Samples to be 
collected at home if no clinic visit is planned that day. If clinic visit is planned, sample should be collected in clinic where possible. A window ±1 day is permitted 
for samples collected after Day 1. For Day -1 and Day 1, samples must be collected on the specified day.    
q Blood (plasma) will be collected for determination of blood Phe levels collected by venipuncture on Part 2 Day 1 predose and Part 2 Day 42 at the time 
corresponding to the collection of blood Phe/Tyr levels via dried blood sample. Samples will be collected after fasting (eg, Part 2 Day 1 predose) or no earlier 
than 3 hours postprandial (eg, Part 2 Day 42) and within ±5 minutes of dried blood samples for Phe collection. 


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r  Blood samples will be collected for PK analysis from subjects participating PK substudy at the following timepoints.  
In Part 1, subjects ≥2 years, samples will be collected at Part 1 Day 1 (predose, and 0.5, 1, 2, 4, 6, 8, and 24 hours postdose). 
In Part 1, subjects <2 years, samples will be collected at Part 1 Day 1 (predose and 4 hours postdose), Part 1 Day 14 (2 and 6 hours postdose).  
In Part 2, samples will be collected on Days 1, 14, 28, and 42 at predose (approximately 24 hours post the dose on prior day, except for Day 1) and 4 hours 
postdose. 
In Part 1, for subjects participating in the PK substudy, additional small amount (~0.25 mL) of blood will be collected at the same time of PK sample collection 
and applied to VAMS for blood Phe and Tyr measurement.   
s Subjects are to maintain a consistent diet (with respect to Phe intake) during the study. At each in-clinic visit, a dietician will monitor each subject’s diet to 
calculate Phe consumption and to have regular contact with subjects. The 3-day diet records will be collected weekly throughout the study. 
t Phenylketonuria quality of life (Parent PKU-QOL [6 to 8 years]; Child PKU-QOL [9 to 11 years]; Adolescent PKU-QOL [12 to 17 years]; Adult PKU-QOL 
[≥18 years]) will be conducted using the tool in one of the following validated languages: English (British or American), Turkish, Dutch, German, Spanish, Italian, 
Portuguese, or French. Conduct of the PKU-QOL will not be required for subjects whose primary language is not one of the available validated languages. 
EQ-5D (EQ-5D-Y Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 15 years]; and EQ-5D-5L [≥16 years]) will also be conducted. 
u If feasible, study drug should be dispensed and returned at the study site. In the event that a subject cannot go into the study site (ie, due to COVID-19 
restrictions, inability to make visit), study drug may be shipped directly to the subject’s home/study site. In the event that a subject cannot go into the study site, 
unused study drug can be shipped directly back to the study site per local guidance.  
v An ETV will be performed on or between Day 28 to Day 35 for all subjects who are determined to be non-responders in Part 1, or within 2 days for any subject 
who discontinues the study prematurely during Part 1 or Part 2 for any other reason. If eGFR calculation is desired, subjects <18 years of age should have their 
height and serum creatinine measured and subjects ≥18years of age should have their serum creatinine measured. Additionally, a phone follow-up visit will occur 
30 (±3) days after the last dose of study drug to assess for SAEs. 
Note: If any unscheduled visits are performed when eGFR calculation is desired, alongside any assessments/procedures considered appropriate by the 
Investigator (or designee), subjects <18 years of age should have their height and serum creatinine measured and subjects ≥18years of age should have their 
serum creatinine measured. 


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3.2. 
Number of Subjects 
Approximately 80 subjects with PKU aged ≥2 years who achieve a ≥30% reduction from 
baseline in blood Phe levels during the responsiveness test (Part 1) will be enrolled in the 
placebo-controlled treatment period to receive either PTC923 or placebo (Part 2). Approximately 
178 subjects are expected to be enrolled in Part 1 of the study to achieve this. 
3.3. 
Treatment Assignment 
3.3.1. 
Part 1, Open-Label Responsiveness Test 
All subjects will receive PTC923 (7.5 mg/kg for subjects 0 to <6 months of age, 15 mg/kg for 
subjects 6 to <12 months of age, 30 mg/kg for subjects 12 months to <2 years of age, and 
60 mg/kg for subjects ≥2 years of age) for 14 days starting on Day 1. 
3.3.2. 
Part 2, Randomized Double-Blind Treatment Period 
Eligible subjects will be randomized to receive either PTC923 or placebo for 42 days (6 weeks). 
Subjects randomized to the PTC923 treatment arm will receive PTC923 20 mg/kg daily for 
Days 1 to 14 (ie, Weeks 1 and 2), then PTC923 40 mg/kg daily for Days 15 to 28 (ie, Weeks 3 
and 4), then PTC923 60 mg/kg daily for Days 29 to 42 (ie, Weeks 5 and 6). As dosing is 
weight-based and to maintain the blind, subjects randomized to placebo will receive equivalent 
quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of those randomized to 
PTC923. 
3.4. 
Dose Adjustment Criteria 
PTC923 is a powder for oral use and dosing is weight based.  
Given that PTC923 is packaged in sachets with 2 different dosage strengths, 250 mg and 
1000 mg, weight bands will be utilized to determine the sachet size and number required for each 
subject’s dose (Section 6.5). 
During Part 1, all subjects will be administered PTC923 orally once a day for 14 days to assess 
responsiveness; no change of the dose is allowed in this period. 
During Part 2, subjects randomized to PTC923 will undergo a forced dose escalation by 
receiving PTC923 20 mg/kg daily for Weeks 1 and 2, then PTC923 40 mg/kg daily for Weeks 3 
and 4, then PTC923 60 mg/kg daily for Weeks 5 and 6. Given the short duration of each dose 
level, deviation (ie, dose adjustments) from the prescribed dose levels and dose escalation will 
not be permitted in this study. 
3.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
As dose adjustments outside of the prescribed dose escalation scheme are not permitted, any 
adjustments to or stopping doses of study drug administration would result from concern by the 
investigator for the safety of the subject. Safety criteria for permanent discontinuation of study 
drug is discussed in Section 4.4. If a subject temporarily stops treatment at the occurrence of an 
AE, the subject may return to a previous dose if the investigator and medical monitor feel this is 
appropriate. 


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Given the requirement for pregnancy testing in women of childbearing potential at Screening and 
the requirements for highly effective methods of contraception during the study, it is unlikely 
that pregnancies will occur during study conduct. However, study drug will be discontinued 
should suspected or confirmed pregnancy or suspected or confirmed nursing during the study 
drug administration period occur. 
3.5. 
Criteria for Study Termination 
The study may be terminated if significant violations of GCP that compromise the ability to 
achieve the study objectives or compromise subject safety are observed at any time during the 
study. With regard to safety, the study may be temporarily suspended or terminated should the 
investigator, PTC, or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
determine that the safety of study participants is significantly jeopardized. The decision for a 
temporary or permanent study hold will depend on the nature, frequency, and severity of AEs 
that were observed in all enrolled subjects to date. In a temporary study hold, no additional 
subjects will be enrolled into the study or dosed with study drug until the study team members 
(including the investigator and the medical monitor) decide it is safe to proceed with the study. 
PTC reserves the right to discontinue the study prior to inclusion of the intended number of 
subjects. The investigator, after consultation with the medical monitor, reserves the right to 
discontinue the study at the investigator site for safety reasons at any time. 
After a decision to terminate the study, investigators must contact all subjects who are continuing 
their participation in the study and must do so within a time period set by PTC. As directed by 
PTC, all study materials must be collected, and all electronic data entry forms completed to the 
greatest extent possible. 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects with any PAH mutation are permitted to screen and enroll into the study. However, 
subjects with biochemically diagnosed classical PKU (ie, blood Phe birth levels ≥1200 µmol/L 
and or historical evidence of Phe concentrations ≥1200 µmol/L in their medical history) will be 
capped at 20% of the total study population. Genotyping will not be required for study eligibility; 
however, all subjects will undergo genotyping unless documented in their medical history and 
these data will be collected for analysis. 
4.1. 
Subject Inclusion Criteria 
Individuals eligible to participate in this study include subjects who meet all the following 
criteria: 
1. Informed consent and assent (if necessary, at the investigator’s discretion [ie, for children 
and/or subjects that are mentally impaired secondary to disease]) with parental/legal 
guardian consent  
2. Male or female subjects of any age 
3. Uncontrolled blood Phe level ≥360 μmol/L on current therapy anytime during Screening 
and uncontrolled blood Phe level ≥360 μmol/L on current therapy when taking the 
average of the 3 most recent Phe levels from the subject’s medical history (inclusive of 
the Screening value) 
4. Clinical diagnosis of PKU with HPA documented by past medical history of at least 
2 blood Phe measurements ≥600 μmol/L 
5. Women of childbearing potential, , as defined in (CTFG 2020), must have a negative 
pregnancy test at Screening and agree to abstinence or the use of at least one highly 
effective form of contraception (with a failure rate of <1% per year when used 
consistently and correctly): 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 


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• Vasectomized partner with confirmed azoospermia 
Highly effective contraception or abstinence must be continued for the duration of the 
study and for up to 90 days after the last dose of study drug. 
All females will be considered of childbearing potential unless they are postmenopausal 
(at least 12 months consecutive amenorrhea in the appropriate age group without other 
known or suspected cause) or have been permanently sterilized surgically (eg, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy). 
6. Males who are sexually active with women of childbearing potential who have not had a 
vasectomy must agree to use a barrier method of birth control during the study and for up 
to 90 days after the last dose of study drug. Males must also refrain from sperm donations 
during this time period. 
Males who are abstinent will not be required to use a contraceptive method unless they 
become sexually active. Males who have undergone a vasectomy are not required to use a 
contraceptive method if at least 16 weeks post procedure.  
7. Willing and able to comply with the protocol and study procedures 
8. Willing to continue current diet unchanged while participating in the study 
4.2. 
Subject Exclusion Criteria 
Individuals are not eligible to participate in this study if they have met or meet any of the 
following exclusion criteria: 
1. The individual, in the opinion of the investigator, is unwilling or unable to adhere to the 
requirements of the study 
2. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, 
chronic gastritis, and peptic ulcer disease, etc.) that could affect the absorption of study 
drug 
3. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy 
with vagotomy, or gastrectomy 
4. Inability to tolerate oral medication 
5. History of allergies or adverse reactions to synthetic BH4 or sepiapterin  
6. Current participation in any other investigational drug study or use of any investigational 
agent within 30 days prior to Screening 
7. Any clinically significant laboratory abnormality as determined by the investigator. In 
general, each laboratory value from Screening and baseline chemistry and hematology 
panels should fall within the limits of the normal laboratory reference range, unless 
deemed not clinically significant by the investigator 
8. A female who is pregnant or breastfeeding, or considering pregnancy 
9. Serious neuropsychiatric illness (eg, major depression) not currently under medical 
control, that in the opinion of the investigator or sponsor, would interfere with the 
subject’s ability to participate in the study or increase the risk of participation for that 
subject 


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10. Past medical history and/or evidence of renal impairment and/or condition including 
moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 mL/min) 
and/or under care of a nephrologist 
11. Any abnormal physical examination and/or laboratory findings indicative of signs or 
symptoms of renal disease, including calculated GFR <60 mL/min/1.73m2. 
In subjects ≥18 years of age, the Modification of Diet in Renal Disease Equation should 
be used to determine GFR. 
In subjects <18 years, the Bedside Schwartz Equation should be used to determine GFR. 
12. Requirement for concomitant treatment with any drug known to inhibit folate synthesis 
(eg, methotrexate) 
13. Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic 
mutations in 6-pyruvoyltetrahydropterin synthase, recessive GTP cyclohydrolase I, 
sepiapterin reductase, quinoid dihydropteridine reductase, or pterin-4-alpha-
carbinolamine dehydratase genes  
14. Major surgery within the prior 90 days of screening 
15. Concomitant treatment with BH4 supplementation (eg, sapropterin dihydrochloride, 
KUVAN) or pegvaliase-pqpz (PALYNZIQ) 
16. Unwillingness to washout from BH4 supplementation (eg, sapropterin dihydrochloride, 
KUVAN) or pegvaliase-pqpz (PALYNZIQ) 
4.3. 
Screen Failures 
Any subject who does not satisfy inclusion or exclusion criteria within the defined screening 
window prior to enrollment will be considered a screen failure. Screening and enrollment should 
occur within a 45-day period. Screen failures will be captured in the electronic data capture 
(EDC) system. Screen failures can be rescreened after consultation with the medical monitor. 
4.4. 
Subject Withdrawal Criteria 
4.4.1. 
Discontinuation from Study Drug Administration 
Premature discontinuation of study drug administration is defined as the discontinuation of study 
drug for an individual subject before the required full course of study drug is completed. Reasons 
for premature discontinuation from study drug administration should be recorded on the 
appropriate page(s) of the electronic case report form (eCRF) and may include, but are not 
limited to the following: 
• Occurrence of an AE, SAE, or clinically significant laboratory abnormality that, in 
the opinion of the investigator, warrants the subject’s permanent discontinuation from 
study drug administration 
• In the judgment of the investigator, the subject experiences a general or specific 
change(s) that renders the subject unsuitable for continued study drug administration  
• There is a need for concomitant medication that makes the subject ineligible for 
further study drug administration 


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Adult subjects (ie, ≥18 years) who discontinue from treatment but who do not discontinue from 
the study will be instructed to maintain adherence to the study schedule of assessments, 
including all planned safety and efficacy assessments, in the aim of minimizing the risk of 
missing data (Table 2). After completion of these assessments, the subject should revert to their 
prestudy SoC to treat PKU (at the discretion of the investigator or the subject’s physician). 
Pediatric subjects (ie, <18 years of age) who discontinue from treatment will not be instructed to 
maintain adherence to the study schedule of assessments but should revert to their prestudy SoC 
to treat PKU (at the discretion of the investigator or the subject’s physician). In addition, a phone 
follow-up visit will occur 30 (±3) days after the last dose of study drug to assess for SAEs. 
4.4.2. 
Participant Discontinuation/Withdrawal from the Study 
Subjects may withdraw from the study for any reason or be withdrawn at the request of the 
investigator or sponsor. The reason for a subject’s withdrawal must be recorded on the 
appropriate page(s) of the eCRF. Reasons for withdrawal from the study may include, but are not 
limited to: 
• Withdrawal of consent and/or assent (as applicable) 
• AEs or SAEs 
• Significant subject noncompliance, defined as refusal or inability to adhere to the 
protocol requirements 
• The investigator determines that it is in the best interest of the subject to withdraw 
from study participation 
Each subject who withdraws from the study after receipt of any amount of study drug will be 
asked to undergo the ETV assessments. However, subjects may withdraw consent to participate 
in this study at any time without penalty. Withdrawn subjects will not be replaced. 
4.5. 
Lost to Follow-Up 
A subject is considered lost to follow-up if he or she does not complete the study and attempts to 
contact the subject are unsuccessful. Efforts must be made on the part of the site to avoid any 
subject being lost to follow-up during the study. Before any subject is considered lost to 
follow-up, a minimum of 2 documented telephone contact attempts and 1 certified letter within a 
week of the most recent planned study assessment must be sent in efforts to contact the subject. 
After being considered lost to follow-up, a subject’s status may be changed if the subject makes 
contact at a later time, provided that the study is ongoing. 


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5. 
TREATMENT OF SUBJECTS 
5.1. 
Description of Study Drug 
PTC923 is a new chemical entity and synthetic form of sepiapterin. Sepiapterin is (S)-2-amino-6-
(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one with a molecular weight of 237.22 g/mol 
and a molecular formula of C9H11 N5O3. 
PTC923 Powder for Oral Use is a powder for oral use with a yellow to orange colour. PTC923 
Powder for Oral Use will be suspended in water or apple juice prior to administration. Additional 
details on the study drug are included in Section 6. 
5.2. 
Selection and Timing of Dose for Each Subject 
PTC923 will be dispensed at Part 1 Day 1 and Part 2 Day 1 in-clinic visits. The first dose in each 
treatment period will be taken in the clinic with a meal; for all other dosing days, subjects will 
take their morning dose as an outpatient with a meal.  
For subjects participating in the PK substudy, if an in-clinic visit is scheduled for PK blood 
sampling, doses will be administered in-clinic with a meal. 
5.3. 
Concomitant Medications 
Concomitant use of any drugs known to inhibit folate synthesis (eg, methotrexate, pemetrexed, 
and trimetrexate), pegvaliase-pqpz, BH4 (eg, sapropterin dihydrochloride, KUVAN), or any 
investigational therapy will not be permitted. 
Any treatments (including nutritional supplements) and over-the-counter medications (including 
herbal medications) taken by a subject 30 days prior to the Screening Visit and during the course 
of the study and the reason for use of the medication will be recorded on the eCRF. Additionally, 
specific information related to previous use of sapropterin or pegvaliase-pqpz should be collected 
(ie, details on duration, dose, if discontinued, the reason[s] why, and if a subject is known to be 
BH4-responsive). During Screening, each subject will be instructed to report the use of any 
medication to the investigator. Subjects will also be instructed about the importance of not taking 
any medication throughout the study (including over-the-counter medications) without 
consulting the investigator. 
COVID-19 vaccination is permitted during the study and subjects are encouraged to be 
vaccinated according to local guidelines. Given the mode of action of PTC923, it is considered 
unlikely there would be an interaction/immune response between PTC923 and the COVID-19 
vaccination. Vaccination should be reported to the investigator in-line with standard concomitant 
medication reporting. 
5.4. 
Total Blood Volume 
The total volume of blood that will be collected from each subject for Screening, Part 1, and 
Part 2 of the study is presented in Table 3, Table 4, and Table 5, respectively. Blood volumes 
taken are in accordance with current guidance that recommends a blood draw limit of 1% of total 
blood volume corresponding to a single time point and 3% of total blood volume during a period 
of four weeks (European Parliament 2008). Total blood volume is estimated to be 80 to 
90 mL/kg body weight (100 mL/kg body weight for neonates). Subjects of all ages are permitted 
for inclusion into this study. Based on growth charts for newborns, 5% to 95% of boys weigh 2.6 


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to 4.2 kg and girls weigh 2.5 to 4.0 kg (CDC 2010a, CDC 2010b). Accordingly, the maximum 
total blood volume permitted for newborns would be 2.5 mL at a single time and 7.5 mL over 
4 weeks. Based on growth charts for subjects 2 years old, 5% to 95% of boys weigh 10.6 to 
15.2 kg and girls weigh 10.2 to 14.6 kg (CDC 2010a, CDC 2010b). Accordingly, the maximum 
total blood volume permitted for subjects 2 years old would be 8.2 mL at a single time and 
24.5 mL over 4 weeks. To adhere to the guidance, three groups are represented with 
corresponding blood volumes in Table 3 and Table 4. Table 5 only includes 2 groups as only 
subjects ≥2 years of age will participate in Part 2 of the study. 
Screening, consisting of the Screening visit and Supplementation Washout Period, may last up to 
45 days (6 weeks). If a subject weighs less than 4.5kg and PAH genotyping is required, then 
PAH genotyping should be performed on a separate day from the collection of blood chemistry, 
hematology, vitamin B12/iron, and blood Phe/Tyr levels. 
Table 3: 
Blood Volume – Screening (Screening Visit and Supplementation Washout Period) 
 
Subjects ≥12 Years 
Subjects ≥2 years 
<12 Years 
Subjects <2 Years 
 
Vol × 
Frequency 
Total Vol 
Vol × 
Frequency 
Total Vol 
Vol × 
Frequency 
Total 
Vol 
Blood chemistry  
5.0 mL×1  
5.0 mL  
1.2 mL×1 
1.2 mL 
1.2 mL×1 
1.2 mL 
Hematology 
3.0 mL×1  
3.0 mL  
1.2 mL×1 
1.2 mL 
1.2 mL×1 
1.2 mL 
Vitamin B12/iron (incl. serum 
pregnancy test in female 
subjects [if applicable]) 
3.5 mL×1  
3.5 mL  
Blood Phe and Tyr levels 
0.12 mL×1  
0.12 mL  
0.12 mL×1  
0.12 mL  
0.12 mL×1  
0.12 mL  
PAH genotyping a 
2.0 mL×1  
2.0 mL  
2.0 mL×1  
2.0 mL  
2.0 mL×1  
2.0 mL  
Blood Phe and Tyr levels 
during supplementation 
washout 
0.12 mL×3  
0.36 mL  
0.12 mL×3  
0.36 mL  
0.12 mL×3  
0.36 mL  
Total Blood Volume 
13.98 mL  
4.88 mL  
4.88 mL  
Abbreviations: Phe, phenylalanine; Tyr, tyrosine 
a Only required if genotyping is not part of PKU medical history (Section 8.1.9) 
Part 1, consisting of the open-label PTC923-responsiveness test and PTC923 washout period, 
may last up to 35 days (5 weeks).  
Table 4: 
Blood Volume – Part 1 (Open-Label Responsiveness Test Period) 
 
Subjects ≥12 Years 
Subjects ≥2 years 
<12 Years 
Subjects <2 Years 
 
Vol × 
Frequency 
Total Vol 
Vol × 
Frequency 
Total Vol 
Vol × 
Frequency 
Total Vol 
Blood chemistry 
5.0 mL×1 
5.0 mL 
1.2 mL×1 
1.2 mL 
1.2 mL×1 
1.2 mL 
Hematology 
3.0 mL×1 
3.0 mL 
1.2 mL×1 
1.2 mL 
1.2 mL×1 
1.2 mL 
Vitamin B12/iron (incl. serum 
pregnancy test in female 
subjects [if applicable]) 
3.5 mL×1 
3.5 mL 
Blood Phe and Tyr levels  
0.12 mL×8 
0.96 mL 
0.12 mL×8 
0.96 mL 
0.12 mL×8 
0.96 mL 
Total Blood Volume  
12.46 mL 
3.36 mL 
3.36 mL 
Additional blood volume for subjects participating in PK substudy 
PTC923 PK samples (PK 
subpopulation) 
2.0 mL×8 
16.0 mL 
0.5 ml ×8 
4.0 mL 
0.5 mL×4 
2.0 mL 
Phe/Tyr from PK samples 
(PK subpopulation) 
0.25 mL×8 
2.0 mL 
0.25 mL×8 
2.0 mL 
0.25 mL×4 
1 mL 
Total Blood Volume  
30.46 mL 
9.36 mL 
6.36 mL 
Abbreviations: Phe, phenylalanine; PK, pharmacokinetics; Tyr, tyrosine 


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Part 2, consisting of the randomized double-blind treatment period may last up to 42 days 
(6 weeks).  
Table 5: 
Blood Volume – Part 2 (Randomized Double-Blinded Treatment Period)  
 
Subjects ≥12 Years 
Subjects ≥2 years <12 Years 
 
Vol × Frequency 
Total Vol 
Vol × Frequency 
Total Vol 
Blood chemistry  
5.0 mL×2 
10.0 mL 
1.2 mL×2 
1.2 mL 
Hematology 
3.0 mL×2 
6.0 mL 
1.2 mL×2 
1.2 mL 
Vitamin B12/iron (incl. serum pregnancy 
test in female subjects [if applicable]) 
3.5 mL×2 
7.0 mL 
Blood Phe and Tyr levels 
0.12 mL×11 
1.32 mL 
0.12 mL×11 
1.32 mL 
Blood plasma Phe levels 
2.0 mLx2 
4.0 mL 
2.0 mLx2 
4.0 mL 
Total Blood Volume  
28.32 mL 
10.12 mL 
Additional blood volume for subjects participating in PK substudy 
PTC923 PK levels (PK subpopulation) 
2.0 mL×8 
16.0 mL 
0.5 mL×8 
4.0 mL 
Total Blood Volume  
44.32 mL 
14.12 mL 
Abbreviations: ETV, Early Termination Visit; Phe, phenylalanine; PK, pharmacokinetics; Tyr, tyrosine 
Note: If an ETV is conducted, depending on timing, an additional blood chemistry sample will be taken. 
5.5. 
Treatment Compliance 
Study drug will be dispensed on Day 1 of each treatment period. Subjects will be instructed to 
return all used (empty) and unused study drug sachets at each scheduled study visit after Part 1 
Day 1. Compliance with the dosing regimen will be assessed by reconciliation of used and 
unused study drug. The quantities dispensed, returned, used, and lost will be recorded on the 
dispensing log provided for the study. 
5.6. 
Randomization and Blinding 
In Part 1 of the study, all subjects will receive open-label treatment with PTC923 administered 
orally once a day.  
Following the minimum 14-day PTC923 washout period, all eligible subjects will proceed to 
Part 2 and be randomized to receive either PTC923 or placebo. 
Part 2 of this study will be performed in a double-blinded fashion. The investigator and study 
staff (including processing laboratory personnel), the subjects, and the sponsor’s staff will 
remain blinded to the treatment until study closure. The investigational drug and its matching 
placebo are indistinguishable and will be packaged in the same way. Subjects will be randomized 
1:1 to either PTC923 or placebo using a central randomization process. The randomization will 
be stratified based on their mean percent reduction in blood Phe levels (ie, subjects with mean % 
reduction in Phe levels of ≥15% to <30% and subjects with mean % reduction in Phe levels of 
≥30%) and evenly distributed to either PTC923 or placebo treatment arms. Additionally, subjects 
will be stratified based on their baseline blood Phe concentration (ie, subjects with baseline 
blood Phe <600 µmol/L and subjects with baseline blood Phe ≥600 µmol/L) and evenly 
distributed to either PTC923 or placebo treatment arms. 
Subjects who are unblinded could potentially remain in the study, per principal investigator (PI) 
discretion and based on discussions with medical monitor as needed.  


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5.6.1. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization is an accepted means to reduce bias and allows for the highest standard of 
evidence in documenting a treatment effect. The block randomization technique will be used. 
The process will be established and performed centrally by an experienced Contract Research 
Organization (CRO) through an Interactive Response Technology (IRT) system to maximize the 
integrity and security of the randomization and ensure appropriate access and 
convenience-of -use by the investigational sites. 
Blinding is important for validity of this clinical study: however, the blind may be broken in the 
event of a medical emergency, in which knowledge of the study drug identity is critical to the 
management of the subject’s course of treatment. Before breaking the blind, the investigator 
should determine that the information is necessary (ie, that it will alter the subject’s immediate 
course of treatment). In many cases, particularly when the emergency is clearly not study -drug 
related, the problem may be effectively managed by assuming that the subject is receiving an 
active study drug without the need for unblinding. If deemed necessary to break the blind for a 
study subject, the investigator has the final decision and unilateral right to break the blind and 
should notify the PTC medical monitor as soon as possible after breaking the blind for a subject. 
To identify a subject’s study drug, the investigator or designee must electronically contact the 
IRT system to identify a subject’s study drug assignment. Record the date of unblinding, the 
reason for unblinding, and the initials of the investigational center staff member who performed 
the unblinding on the subject’s study file.  
Subjects who are unblinded could potentially remain in the study, per PI discretion and based on 
discussions with medical monitor as needed. 
Instructions for use of the IRT system will be provided to each investigator prior to the initiation 
of subject enrollment at her/his center. 


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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug 
The test product is PTC923 Powder for Oral Use. The excipients include microcrystalline 
cellulose, isomalt, mannitol, croscarmellose sodium, xantham gum, colloidal silicon dioxide, 
sucralose, and magnesium stearate. PTC923 will be suspended in water or apple juice prior to 
administration. PTC923 is packaged in aluminum foil sachets. Each sachet contains either 
250 mg or 1000 mg of PTC923.  
Placebo for PTC923 Powder for Oral Use is also provided as a powder for oral use and is 
packaged in aluminum foil sachets to match PTC923 in appearance. The excipients include 
microcrystalline cellulose, isomalt, mannitol, croscarmellose sodium, xantham gum, colloidal 
silicon dioxide, sucralose, and colorants, tartrazine (soluble) and tartrazine (insoluble). Placebo 
for PTC923 Powder for Oral Use will be suspended in water or apple juice prior to 
administration. As Placebo for PTC923 Powder for Oral Use is to be used only in Part 2, subjects 
assigned to the placebo treatment arm during Part 2 will be given equivalent quantities of 
placebo to maintain the blind. 
6.2. 
Study Drug Dispensing 
Study drug will be dispensed as shown in Table 2. A sufficient supply of study drug will be 
dispensed for dosing each time (with additional days provided to account for lost or damaged 
product). Details on the preparation of study drug, dosing guidelines, and storage will be 
provided in a pharmacy manual for the site and an instruction guide for subjects. 
6.3. 
Study Drug Packaging and Labeling 
PTC923 Powder for Oral Use is packaged in heat-sealed aluminum foil sachets that are available 
in 2 strengths. Each sachet contains either 250 mg or 1000 mg of PTC923. 
PTC923 Powder for Oral use and Placebo for PTC923 for Oral Use are packaged in heat-sealed 
aluminum foil sachets. A kit will contain 30 sachets.  
All kits and sachets will be labelled in accordance with local regulatory requirements. 
6.4. 
Study Drug Storage 
PTC923 Powder for Oral Use should be stored at refrigerated conditions (2 to 8oC). Constituted 
PTC923 suspension should be administered immediately. During the time from constitution to 
administration, the resulting suspension may be stored at room temperature. 
Placebo for PTC923 Powder for Oral Use should be stored in refrigerated conditions (2 to 8oC). 
Constituted Placebo for PTC923 Powder for Oral Use should be administered immediately. 
During the time from constitution to administration, the resulting suspension may be stored at 
room temperature. 


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6.5. 
Study Drug Preparation 
As dosing is weight-based, subjects will receive kits containing the required number of sachets 
for each 2-week period. Study drug will be provided to each subject based on their current/most 
recent weight, age, and randomization sequence (as applicable) such that subjects will be 
informed about how many sachets to use for each dose (eg, 3 large sachets and 1 small sachet, or 
2 large sachets and 3 small sachets).  
PTC923 Powder for Oral Use is provided as 250 mg and 1000 mg sachets. The calculated daily 
dose on body weight should be rounded to the nearest multiple of 250 mg or 1000 mg, as 
appropriate. For instance, a calculated dose of 1251 to 1374 mg should be rounded down to 
1250 mg corresponding to 1×250 mg sachet and 1×1000 mg sachet. A calculated dose of 1375 to 
1499 mg should be rounded up to 1500 mg corresponding to 2×250 mg sachets and 1×1000 mg 
sachet. 
The full contents of a single 250 mg or 1000 mg sachet may be suspended in 10 mL or 20 mL of 
water or apple juice, respectively. Once added, the combination should be shaken or stirred for at 
least 30 seconds to form the suspension. After mixture, all of the resulting suspension or an 
appropriate quantity of the resulting suspension depending on the weight of the individual should 
be measured and administered PO to the subject immediately. Dosing is weight based on 1 mg of 
PTC923 per kg of subject basis. 
Subjects will be instructed to open their study drug kit and remove the required number of 
sachets when preparing their daily dose.  
For subjects ≥2 years of age weighing ≤18 kg administering 20 mg/kg dose 
For subjects ≥2 years of age weighing ≤18 kg, PTC923 Powder for Oral Use should be 
suspended in 9 mL of water or apple juice per 250 mg sachet and an aliquot of this suspension 
corresponding to a 20 mg/kg dose may be administered orally via an oral dosing syringe. Table 6 
provides dosing information for subjects at 20 mg/kg doses. A graduated dosing syringe will be 
provided for subjects weighing ≤18 kg for this dose. 
Table 6: 
20 mg/kg/day Dosing Table for Subjects ≥2 Years of Age Weighing ≤18 kg 
Subject 
Weight 
(kg)a 
Target Dose: 20 mg/kg/dayb 
Dose 
(mg)  
PTC923 or Placebo for PTC923 Powder 
for Oral Use, 250 mg Sachets Suspendedc 
Dilution 
Volume (mL)d 
Administered Dose 
Volume (mL)e 
8 
160 
1 
9 
6.4 
9 
180 
1 
9 
7.2 
10 
200 
1 
9 
8 
12 
240 
1 
9 
9.6 
12.5 
250 
1 
9 
10 
15 
300 
2 
18 
12 
18 
360 
2 
18 
14.4 
a Round the subject’s weight to the nearest listed weight in the table in kg. For instance, a subject who weighs 
between 2.01 and 2.24 kg should be rounded down to 2 kg and a subject who weighs between 4.75 and 4.99 kg 
should be rounded up to 5 kg. 
b Target dose of 20 mg/kg/day for subjects. 
c PTC923 Powder for Oral Use, 250 mg, or Placebo for PTC923 Powder for Oral Use, 250 mg provided in single use 
sachets. 
d Volume of liquid (water or apple juice) to suspend PTC923 Powder for Oral Use, 250 mg, or Placebo for PTC923 
Powder for Oral Use, 250 mg. 
e Discard remainder of mixture after volume to be administered is drawn. 


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For subjects ≥2 years of age weighing ≤15 kg administering 40 and 60 mg/kg doses 
For subjects ≥2 years of age weighing ≤15 kg, PTC923 Powder for Oral Use should be 
suspended in 9 mL of water or apple juice per 250 mg sachet and an aliquot of this suspension 
corresponding to a 40 and 60 mg/kg dose may be administered orally via an oral dosing syringe. 
Table 7 and Table 8 provide dosing information for subjects at 40 and 60 mg/kg doses, 
respectively. A graduated dosing syringe will be provided for subjects weighing ≤15 kg for these 
2 doses. 
Table 7: 
40 mg/kg/day Dosing Table for Subjects ≥2 Years of Age Weighing ≤15 kg 
Subject Weight 
(kg)a 
Target Dose: 40 mg/kg/dayb 
Dose 
(mg) 
PTC923 or Placebo for PTC923 
Powder for Oral Use, 250 mg 
Sachets Suspendedc 
Dilution 
Volume (mL)d 
Administered 
Dose Volume 
(mL)e 
8 
320 
2 
18 
12.8 
9 
360 
2 
18 
14.4 
10 
400 
2 
18 
16 
12 
480 
2 
18 
19.2 
12.5 
500 
2 
18 
20 
15 
600 
3 
27 
24 
a Round the subject’s weight to the nearest listed weight in the table in kg. For instance, a subject who weighs 
between 2.01 and 2.24 kg should be rounded down to 2 kg and a subject who weighs between 4.75 and 4.99 kg 
should be rounded up to 5 kg. 
b Target dose of 40 mg/kg/day for subjects. 
c PTC923 Powder for Oral Use, 250 mg, or Placebo for PTC923 Powder for Oral Use, 250 mg provided in single use 
sachets. 
d Volume of liquid (water or apple juice) to suspend PTC923 Powder for Oral Use, 250 mg, or Placebo for PTC923 
Powder for Oral Use, 250 mg. 
e Discard remainder of mixture after volume to be administered is drawn. 
Table 8: 
60 mg/kg/day Dosing Table for Subjects ≥2 Years of Age Weighing ≤15 kg 
Subject Weight 
(kg)a 
Target Dose: 60 mg/kg/dayb 
Dose 
(mg) 
PTC923 or Placebo for PTC923 
Powder for Oral Use, 250 mg 
Sachets Suspendedc,f 
Dilution 
Volume (mL)d 
Administered 
Dose Volume 
(mL)e 
8 
480 
2 
18 
19.2 
9 
540 
3 
27 
21.6 
10 
600 
3 
27 
24 
12 
720 
3 
27 
28.8 
12.5 
750 
3 
27 
30 
15 
900 
1 × 1000 mg sachet 
36 
36 
a Round the subject’s weight to the nearest listed weight in the table in kg. For instance, a subject who weighs 
between 2.01 and 2.24 kg should be rounded down to 2 kg and a subject who weighs between 4.75 and 4.99 kg 
should be rounded up to 5 kg. 
b Target dose of 60 mg/kg/day for subjects. 
c PTC923 Powder for Oral Use, 250 mg, or Placebo for PTC923 Powder for Oral Use, 250 mg provided in single use 
sachets. 
d Volume of liquid (water or apple juice) to suspend PTC923 Powder for Oral Use, 250 mg, or Placebo for PTC923 
Powder for Oral Use, 250 mg. 
e Discard remainder of mixture after volume to be administered is drawn. 
f Use 1000 mg sachets when indicated. 


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For subjects <6 months of age weighing ≤12 kg administering 7.5 mg/kg dose 
For subjects <6 months of age weighing ≤12 kg, PTC923 Powder for Oral Use should be 
suspended in 9 mL of water or apple juice per 250 mg sachet and an aliquot of this suspension 
corresponding to a 7.5 mg/kg dose may be administered orally via an oral dosing syringe. 
Table 9 provides dosing information for subjects <6 months at 7.5 mg/kg dose. A graduated 
dosing syringe will be provided for subjects weighing ≤12 kg for this dose. 
Table 9: 
7.5 mg/kg/day Per Day Dosing Table for Subjects <6 Months of Age Weighing 
≤12 kg 
Subject 
Weight (kg)a 
Target Dose: 7.5 mg/kg/dayb 
Dose 
(mg)  
PTC923 Powder for Oral Use, 
250 mg Sachets Suspendedc 
Dilution Volume 
(mL)d 
Administered Dose 
Volume (mL)e 
1 
7.5 
1 
9 
0.3 
1.2 
9 
1 
9 
0.36 
1.4 
10.5 
1 
9 
0.42 
1.7 
12.8 
1 
9 
0.51 
2 
15 
1 
9 
0.6 
2.5 
18.8 
1 
9 
0.75 
3 
22.5 
1 
9 
0.9 
3.5 
26.3 
1 
9 
1.05 
4 
30 
1 
9 
1.2 
4.5 
33.8 
1 
9 
1.35 
5 
37.5 
1 
9 
1.5 
6 
45 
1 
9 
1.8 
7 
52.5 
1 
9 
2.1 
8 
60 
1 
9 
2.4 
9 
67.5 
1 
9 
2.7 
10 
75 
1 
9 
3 
12 
90 
1 
9 
3.6 
a Round the subject’s weight to the nearest listed weight in the table in kg. For instance, a subject who weighs 
between 2.01 and 2.24 kg should be rounded down to 2 kg and a subject who weighs between 4.75 and 4.99 kg 
should be rounded up to 5 kg. 
b Target dose of 7.5 mg/kg/day for subjects 
c PTC923 Powder for Oral Use, 250 mg provided in single use sachets. 
d Volume of liquid (water or apple juice) to suspend PTC923 Powder for Oral Use, 250 mg. 
e Discard remainder of mixture after volume to be administered is drawn. 
For subjects ≥6 to <12 months of age weighing ≤15 kg administering 15 mg/kg dose 
For subjects ≥6 to <12 months of age weighing ≤15 kg, PTC923 Powder for Oral Use should be 
suspended in 9 mL of water or apple juice per 250 mg sachet and an aliquot of this suspension 
corresponding to a 15 mg/kg dose may be administered orally via an oral dosing syringe. 
Table 10 provides dosing information for subjects ≥6 to <12 months of age at 15 mg/kg dose. A 
graduated dosing syringe will be provided for subjects weighing ≤15 kg for this dose. 


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Table 10: 
15 mg/kg/day Dosing Table for Subjects ≥6 to <12 Months of Age Weighing ≤15 kg 
Subject Weight 
(kg) a 
Target Dose: 15 mg/kg/dayb 
Dose 
(mg) 
PTC923 Powder for Oral Use, 
250 mg Sachets Suspendedc 
Dilution 
Volume (mL)d 
Administered Dose 
Volume (mL)e 
4 
60 
1 
9 
2.4 
4.5 
67.5 
1 
9 
2.7 
5 
75 
1 
9 
3 
6 
90 
1 
9 
3.6 
7 
105 
1 
9 
4.2 
8 
120 
1 
9 
4.8 
9 
135 
1 
9 
5.4 
10 
150 
1 
9 
6 
12 
180 
1 
9 
7.2 
15 
225 
1 
9 
9 
a Round the subject’s weight to the nearest listed weight in the table in kg. For instance, a subject who weighs 
between 2.01 and 2.24 kg should be rounded down to 2 kg and a subject who weighs between 4.75 and 4.99 kg 
should be rounded up to 5 kg. 
b Target dose of 15 mg/kg/day for subjects ≥6 months but <12 months. 
c PTC923 Powder for Oral Use, 250 mg provided in single use sachets. 
d Volume of liquid (water or apple juice) to suspend PTC923 Powder for Oral Use, 250 mg. 
e Discard remainder of mixture after volume to be administered is drawn. 
For subjects ≥12 months to <2 years of age weighing ≤18 kg administering 30 mg/kg dose 
For subjects ≥12 months to <2 years of age weighing ≤18 kg, PTC923 Powder for Oral Use 
should be suspended in 9 mL of water or apple juice per 250 mg sachet and an aliquot of this 
suspension corresponding to a 30 mg/kg dose may be administered orally via an oral dosing 
syringe. Table 11 provides dosing information for subjects ≥12 months to <2 years of age at 
30 mg/kg dose. A graduated dosing syringe will be provided for subjects weighing ≤18 kg for 
this dose. 
Table 11: 
30 mg/kg/day Dosing Table for Subjects ≥12 Months to <2 Years of Age Weighing 
≤18 kg 
Subject Weight 
(kg)a 
Target Dose: 30 mg/kg/dayb 
Dose 
(mg) 
PTC923 or Placebo for PTC923 
Powder for Oral Use, 250 mg 
Sachets Suspendedc 
Dilution 
Volume (mL)d 
Administered 
Dose Volume 
(mL)e 
5 
150 
1 
9 
6 
6 
180 
1 
9 
7.2 
7 
210 
1 
9 
8.4 
8 
240 
1 
9 
9.6 
9 
270 
2 
18 
10.8 
10 
300 
2 
18 
12 
12 
360 
2 
18 
14.4 
15 
450 
2 
18 
18 
18 
540 
3 
27 
21.6 
a Round the subject’s weight to the nearest listed weight in the table in kg. For instance, a subject who weighs 
between 2.01 and 2.24 kg should be rounded down to 2 kg and a subject who weighs between 4.75 and 4.99 kg 
should be rounded up to 5 kg. 
b Target dose of 30 mg/kg/day for subjects. 
c PTC923 Powder for Oral Use, 250 mg provided in single use sachets. 
d Volume of liquid (water or apple juice) to suspend PTC923 Powder for Oral Use, 250 mg. 
e Discard remainder of mixture after volume to be administered is drawn. 


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6.6. 
Administration 
During Part 1, all subjects will receive PTC923 administered orally once a day for 14 days.  
During Part 2, subjects in the PTC923 treatment arm will receive PTC923 20 mg/kg for Weeks 1 
and 2, then PTC923 40 mg/kg for Weeks 3 and 4, then PTC923 60 mg/kg for Weeks 5 and 6. As 
dosing is weight-based and to maintain the blind, subjects in the placebo arm will receive 
equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the 
PTC923 treatment arm. 
All doses will be administered orally, once a day with food and are weight based. Subjects will 
be instructed to administer each dose immediately upon reconstitution of the powder into a 
suspension by drinking the entire contents of the suspension. Subjects will be instructed to rinse 
the glass with additional water or apple juice and drink the rinse to ensure that the full dose has 
been administered. In the case of subjects who weigh ≤18 kg or 15 kg (dose level-dependent), 
the volume administered will be prescribed and administration will be completed via a dosing 
syringe (Section 6.5).  
If a subject vomits after taking a dose of study drug, this should be recorded as an AE and the 
subject should wait until the next scheduled timepoint to administer a dose. A missed dose 
should be taken as soon as possible, but 2 doses should not be taken on the same day. 
6.7. 
Study Drug Accountability 
All drug product required for completion of this study will be provided by PTC. It is the 
responsibility of the pharmacy staff or study staff to ensure that a current record of drug 
inventory and drug accountability is maintained. Inventory and PTC923 accountability records 
must be readily available for inspection by the study monitor and are open to inspection at any 
time by applicable regulatory authorities. 
6.8. 
Study Drug Handling and Disposal 
Used and unused clinical supplies must be returned to PTC or its designee after the study is 
completed. If the Standard Operating Procedure (SOP) at any site states that the drug cannot be 
returned and must be disposed of onsite, PTC must review the SOP of that site prior to any final 
disposition done by site. Records documenting the date of study drug destruction or shipping, 
and amount destroyed or shipped should be kept. 


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7. 
ASSESSMENT OF EFFICACY 
7.1. 
Primary Efficacy: Phenylalanine Concentrations 
The ACMG guidelines recommend lifelong treatment of PKU, with the primary goal of therapy 
to lower blood Phe to the range of 120 to 360 μmol/L (Vockley 2014). As such, blood Phe levels 
are universally used in the diagnosis and clinical management of patients with HPA due to PKU. 
The reliability of blood Phe levels as a predictive biomarker of clinical outcomes in the 
development of treatments for PKU was assessed in a systematic literature review and 
meta-analysis of published trials of PKU, which included Phe level and neurological and dietary 
compliance outcome measures. Within-study correlations between Phe level and IQ were 
extracted from 40 studies. Significant, proportional correlations were found during critical 
periods (from 0 to 12 years of age) for early-treated patients with PKU (r=-0.35; 95% CI: -0.44 
to -0.27), where each 100 µmol/L increase in Phe predicted a 1.3- to 3.1-point reduction in IQ. 
Similar significant correlations were observed between IQ and mean lifetime Phe level for 
early-treated patients (r=0.34; 95% CI: -0.42 to -0.25), where each 100 µmol/L increase in Phe 
predicted a 1.9- to 4.1-point reduction in IQ. Moderate correlations were found between 
concurrent Phe level and IQ for early-treated patients. In conclusion, these results confirm a 
significant correlation between blood Phe level and IQ in patients with PKU and support the use 
of Phe as a predictive biomarker for IQ in clinical trials (Waisbren 2007). 
Furthermore, there is clinical and regulatory precedent for the use of this surrogate clinical 
efficacy endpoint, which was accepted for both KUVAN and PALYNZIQ in global marketing 
authorizations (Levy 2007, Harding 2018, Thomas 2018). 
The primary efficacy endpoint evaluates the absolute reduction in Phe levels at the optimal dose 
of PTC923. Using the average over a 2-week period reduces the impact of variations between 
weeks. It is well established that blood Phe decreases during the day, with the highest blood Phe 
levels presenting early in the morning following an overnight fast (van Wegberg 2017).  
Blood collection, processing, and shipping information will be provided in a laboratory manual. 
Blood Phe levels will be measured at the timepoints indicated in Table 12 and Table 13. Samples 
should be collected after fasting or no earlier than 3 hours postprandial and at approximately the 
same time of day at each collection timepoint. Samples collected on Day -1 and Day 1 (predose) 
for Part 1 and Part 2 of each treatment period should be collected predose. At other timepoints, 
samples can be collected pre-or post-dose. 
Samples for blood Phe levels measurement will be collected while the subject is either in the 
clinic or at home, depending on whether the subject has a scheduled clinic visit. Dried blood 
samples obtained at home will be shipped to the study site. Samples will be collected using the 
VAMS technology by utilizing the Mitra microsampling devices provided by Neoteryx (CA, 
USA) and blood Phe level will be measured using an HPLC/MS/MS method. The method has 
been validated. Dried blood VAMS provides convenience to the subjects, allowing blood 
samples (20 µL per sample) to be collected at home, without clinical visits, and samples are 
shipped at room temperature. When subjects provide samples in clinic, site staff can provide 
additional training on the sampling technique if considered necessary or requested. Analysis of 
the blood Phe value from Screening can be performed at the site’s local laboratory. 


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Table 12: 
Phenylalanine/Tyr Sample Collection (Screening Period)a 
Evaluation 
Screening Period (up to 45 days) 
Screening Visit 
Supplement Washout Period (Max 30 Days) 
Study Day 
Up to 45 Days 
Pegvaliase-pqpz 
30 Days 
BH4 
7 Days 
DBS 
X 
Day 1, 20, 30 
Day 1, 4, 7 
Abbreviations: BH4, tetrahydrobiopterin; DBS, dried blood sample; Tyr, tyrosine 
a Analysis of the screening blood Phe level can be performed at the site’s local laboratory for determination of eligibility; however, a separate sample for blood 
Phe/Tyr should still be sent to the central lab for the screening timepoint.  
Table 13: 
Phenylalanine/Tyr Sample Collections (Part 1 and Part 2)a 
Evaluation 
Part 1 – Open-Label Responsiveness Test 
Part 2 – Randomized, Placebo-Controlled, Double-Blind 
Treatment Period 
PTC923 Open-Label Treatment 
14 Days 
PTC923 Washout 
Minimum 14 Days 
PTC923 20>>40>>60 mg/kg vs Placebo) 
42 Days (6 Weeks) 
Study Day 
-1 
1 
2b 
5 
10 
14 
19 
24 
28 
-1 
1 
5 
10 
14 
19 
24 
28 
33 
38 
42 
DBS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasmac 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Abbreviations: DBS, dried blood sample; ETV, Early Termination Visit; Phe, phenylalanine; Tyr, tyrosine  
Note: If a subject discontinues the study early, an additional DBS should be taken at the ETV. 
Samples will be collected after fasting or no earlier than 3 hours postprandial at approximately the same time of day at each collection timepoint. 
Day -1 and Day 1 samples for both Part 1 and Part 2 should be taken predose. All other samples can be collected predose or postdose.  
a A window ±1 day is permitted for samples collected after Day 1. For Day -1 and Day 1, samples must be collected on the specified day. 
b For subjects participating in the PK substudy only. 
c Phe only. Samples will be collected after fasting (eg, Part 2 Day 1 predose) or no earlier than 3 hours postprandial (eg, Part 2 Day 42) and within ±5 minutes of 
dried blood samples for Phe collection.


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7.2. 
Exploratory Efficacy: Tyrosine Concentrations 
Blood collection, processing, and shipping information will be provided in a laboratory manual. 
Blood Tyr levels via dried blood samples will be measured at the timepoints indicated in 
Table 12 (Part 1) and Table 13 (Part 2). Samples should be collected after fasting or no earlier 
than 3 hours postprandial and at approximately the same time of day at each collection timepoint. 
Samples for blood Tyr levels measurements will be collected while the subject is either in the 
clinic or at home, dependent on whether the subject has a scheduled clinic visit. Dried blood 
samples obtained at home will be shipped to the study site. Samples will be collected using the 
VAMS technology by utilizing the Mitra microsampling devices provided by Neoteryx (CA, 
USA) and blood Phe levels will be measured using an HPLC/MS/MS method. The method has 
been validated. Dried blood VAMS provides convenience to the subjects, allowing blood 
samples (20 µL per sample) to be collected at home, without clinic visits, and samples are 
shipped at room temperature. When subjects provide samples in clinic, site staff can provide 
additional training on the sampling technique if considered necessary or requested. 


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8. 
ASSESSMENT OF SAFETY 
8.1. 
Safety Parameters 
8.1.1. 
Demographic/Medical History 
A detailed medical/surgical history will be obtained at Screening. The history will include 
specific information related to any prior or existing medical conditions or surgical procedures 
involving the following systems: dermatologic; head, eyes, ears, nose, and throat (HEENT); 
lymphatic; cardiovascular; respiratory; gastrointestinal; musculoskeletal; neurological; and skin. 
Additionally, specific information related to previous use of sapropterin or pegvaliase-pqpz 
should be collected (ie, details on duration, dose, if discontinued, the reason(s) why, and if a 
subject is known to be BH4-responsive). 
Newborn Phe concentrations and the 3 most recent Phe concentrations will be collected.  
Demographic data will include age, gender, and self-reported race/ethnicity. 
8.1.2. 
Vital Signs, Weight, and Height 
Vital signs assessments will include blood pressure, pulse, respiratory rate, and temperature. 
Vital signs should be obtained prior to collection of any laboratory samples (including Phe). If 
feasible, subjects will rest for 5 minutes in a supine position before vital signs are assessed.  
Vital signs will be collected at the Screening Visit, Part 1 Day 1, Part 2 Days 1 and 42, and ETV 
(if applicable). Vital signs will be collected both predose and 2 hours postdose on Part 1 Day 1 
and Part 2 Day 1; for all other timepoints, they will be taken at any time during the visit prior to 
laboratory sampling. 
Weight will be collected at the Screening Visit, Part 1 Day 1, Part 2 Days 1 and 42, and ETV (if 
applicable). Measurements to be completed prior to initial dosing for Part 1 Day 1 and Part 2 
Day 1. Weight can be measured at any time during the other visits.  
Height will be collected at the Screening Visit. Additionally, for subjects <18 years of age, 
height should be measured at Part 2 Day 42 (EOS) Visit and at any Unscheduled Visits when 
eGFR calculation is desired. 
Permitted time windows are presented in Table 2 and Table 17 (PK sampling days). 
8.1.3. 
Physical Examination 
A full physical examination will be performed predose at the Screening Visit, Part 1 Day 1, 
Part 2 Days 1 and 42, and ETV (if applicable). General appearance, dermatologic, HEENT, 
lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, and skin 
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8.1.4. 
Electrocardiogram  
Twelve-lead electrocardiograms (ECGs) will be obtained before any other study-related 
procedures are performed. If feasible, ECGs will be performed after a 5-minute rest in the supine 
position. Twelve-lead ECGs are to be performed at Part 1 Day 1 (predose) for all subjects and at 
the ETV (if applicable). Additional 12-led ECGs will be performed for all subjects participating 
in the PK substudy at Part 1 Day 1 at 2, 4, 6, and 8 hours postdose. Electrocardiograms will be 
performed in triplicate, with each read taken at least 1 minute apart.  
Permitted time windows are presented in Table 2 and Table 18 (PK sampling days). 
The following parameters will be collected and recorded in the eCRF: RR interval, PR interval, 
QRS interval, QT interval, and QTc interval. In addition, the tracing should be reported as 
normal, abnormal clinically significant, or abnormal not clinically significant. If abnormalities 
are noted on the ECG, these should be recorded in the eCRF. 
8.1.5. 
Laboratory Assessments 
Blood and urine samples for clinical chemistry, hematology, and urinalysis will be collected at 
the timepoints in Table 1 and Table 2. Subjects should be fasted prior to collection of samples 
(minimum of 4 hours for subjects <6 years and minimum of 8 hours for subjects ≥6 years prior to 
sample collection). Serum and urine pregnancy tests are required for all women of childbearing 
potential; serum testing to occur during the initial Screening Visit and urine testing to occur 
during all other in-clinic visits. Any positive urine pregnancy test should be confirmed by a 
serum pregnancy test performed at the site’s local laboratory. 
Laboratory parameters that will be assessed will include, but not be limited to: 
• Hematology: hematocrit, hemoglobin, platelet count, red blood cell count (RBC), 
white blood cell count (WBC), and WBC differential 
• Clinical chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, B12, blood urea nitrogen, calcium, CO2, chloride, direct bilirubin 
gamma-glutamyl transpeptidase, glucose, iron, lactate dehydrogenase, phosphate, 
potassium, serum creatinine, sodium, total bilirubin, direct bilirubin, total cholesterol, 
total protein, and uric acid 
• Urinalysis: bilirubin, glucose, ketones, occult blood, pH, protein, specific gravity, 
urobilinogen, microscopic examination of WBC, RBC, and epithelial cells 
• Pregnancy testing: serum human chorionic gonadotrophin (hCG) (at Screening), urine 
hCG (at Screening and Part 2 Day 1) 
Additionally: 
• at the EOS Visit, eGFR should be calculated (all subjects). 
• at any Unscheduled Visits in which eGFR calculation is desired serum creatinine 
should be measured. 


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8.1.6. 
Laboratory Abnormalities 
Laboratory values will be collected throughout the study to assess for safety. The investigator 
must review and assess all laboratory results in a timely manner and determine whether the 
abnormal laboratory values, if any, are clinically significant or not clinically significant and 
whether there are associated signs and symptoms. The investigator must make the determination 
whether the clinically significant abnormal laboratory values are AEs. An abnormal laboratory 
finding in absence of any other signs or symptoms is not necessarily an AE. If the abnormal 
laboratory finding is accompanied by signs or symptoms, report the signs and symptoms as the 
AE in lieu of the abnormal laboratory value. If a diagnosis is available, report the diagnosis. 
Clinically significant laboratory abnormalities after taking study medication that reflect a 
meaningful change from the screening value(s) and that require active management are to be 
considered by the investigator as AEs (eg, abnormalities that require study treatment dose 
modification, discontinuation, more frequent follow-up assessments, etc). 
8.1.7. 
Diet Monitoring: 3-Day Diet Records 
Subjects will be instructed to continue their usual diet without modification (ie, no change in 
daily Phe consumption). Subjects will maintain 3-day diet records during the study as indicated 
in Table 1 and Table 2. The 3-day diet records will be completed over 3 consecutive days within 
each period and collected weekly. At each in-clinic visit, a dietician will monitor each subject’s 
diet to calculate Phe consumption and to have regular contact with the subjects. The total Phe 
consumption during the 3-day period will be calculated by the dietician and entered in the eCRF.  
8.1.8. 
Pharmacokinetic Assessments 
Pharmacokinetic sample collection, processing, storage, and shipment will be performed 
according to instructions outlined in the PK laboratory manual separate from this protocol. 
Additionally, for subjects participating in the PK substudy, blood Phe and Tyr samples will be 
collected at all timepoints from the PK samples, prior to plasma harvesting in Part 1. After the 
blood samples are withdrawn, the blood will be applied to the VAMS device for Phe and Tyr 
collection and analysis (ie, no additional finger prick will be required for collection of these 
samples). Sepiapterin and BH4 plasma concentrations will be determined by Syneos Health, 
using a validated liquid chromatography with tandem mass spectrometry method. 
Pharmacokinetic parameters include Cmax, Tmax, T1/2, area under the plasma concentration-time 
curve from time zero to 24 hours (AUC0-24h), area under the plasma concentration-time curve 
from time zero to infinity (AUC0-inf), CL/F, and Vz/F. 
Table 19 and Table 20 in Appendix A present sampling times and permitted windows. 
8.1.8.1. 
Part 1 
Blood samples (at least 1 mL; duplicate samples should be taken at each timepoint) will be 
collected from a subset of subjects to characterize the PK of sepiapterin and BH4.  
Approximately 30 subjects aged ≥12 years will participate in the PK substudy. At least 12 out of 
the 30 subjects of age ≥12 years participating in the PK substudy will be female. In addition, up 
to 6 subjects from these age groups will be included: 1) <2 years; 2) 2 to 5 years; and 3) 6 to 
11 years.  


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For subjects aged <2 years: 
• Part 1 Day 1: Predose and 4 hours postdose  
• Part 1 Day 14: 2 and 6 hours postdose 
For subjects aged ≥2 years:  
• Part 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, and 24 hours postdose  
8.1.8.2. 
Part 2 
Sparse blood samples (at least 1 mL; duplicate samples should be taken at each timepoint) will 
be collected from a subset of subjects to characterize the PK of sepiapterin and BH4. To achieve 
sparse sampling from 30 subjects in Part 2, this subset of subjects will consist of those who 
participated in the Part 1 PK substudy and continued into Part 2 and also additional subjects who 
did not participate in the Part 1 PK substudy. Samples will be collected at the following 
timepoints: 
• Part 2 Days 1, 14, 28, and 42: Predose and 4 hours postdose 
8.1.9. 
PAH Genotype Testing 
PAH genotype testing will not be required for inclusion/exclusion; however, all subjects will 
undergo genotyping during screening, unless documented in their medical history, and these data 
will be collected for analysis. 
8.1.10. 
Quality of Life Baseline Assessments 
Testing will be performed at Part 2 Day 1 (predose). The following tests will be performed: 
• PKU-QOL: Parent PKU-QOL (6 to 8 years), Child PKU-QOL (9 to 11 years), 
Adolescent PKU-QOL (12 to 17 years), and Adult PKU-QOL (≥18 years) to be 
conducted using the tool in one of the following validated languages: English 
(British or American), Turkish, Dutch, German, Spanish, Italian, Portuguese, or 
French. Conduct of the PKU-QOL will not be required for subjects whose primary 
language is not one of the available validated languages. 
• EQ-5D: EQ-5D-Y Proxy Version 1 (3 to 7 years); EQ-5D-Y (8 to 15 years); and 
EQ-5D-5L (≥16 years) 
8.1.10.1. Phenylketonuria Quality of Life Questionnaire 
In this study, a PKU-specific version of the quality of life (QOL) questionnaire will be used. 
Four versions of the PKU-QOL will be used: parent (ages 6 to 8 years old, 54 items), child (9 to 
11 years old, 40 items), adolescent (12 to 17 years old, 58 items), and adult (≥18 years, 
65 items). Each version is available in one of the following validated languages: English 
(British or American), Turkish, Dutch, German, Spanish, Italian, Portuguese, or French. Conduct 
of the PKU-QOL will not be required for subjects whose primary language is not one of the 
available validated languages. 


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Phenylketonuria quality of life questionnaires comprise of 4 modules: 1) PKU symptoms, 
2) PKU in general, 3) administration of Phe-free protein supplements, and 4) dietary protein 
restriction. The recall period focused on the past 1 week for all sections except for ‘patient’s 
general feeling’ where the recall period was ‘in general’. The following interpretation rules were 
applied for all domain scores in a range from 0 to 100: for symptom scores, a higher score is 
associated with more frequent symptoms; for adherence scores, a higher score is associated with 
a poorer adherence; for other scores, a higher score is associated with a greater impact (Alptekin 
2018). 
8.1.10.2. European Quality of Life - 5 Dimensions  
In this study, 3 versions of the EQ-5D will be used: EQ-5D-Y Proxy Version 1 (3 to 7 years), 
EQ-5D-Y (8 to 15 years), and EQ-5D-5L (≥16 years). 
For subjects aged ≥16 years, the EQ-5D-5L will be used. For the EQ-5D-5L, subjects will rate 
their own health on each dimension, with each dimension having 5 levels of severity. 
Dimensions include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  
For children/adolescents aged 8 to 15 years, the EQ-5D-Y will be used. This is a child-friendly 
version of the EQ-5D-5L. Dimensions include mobility, looking after myself, doing usual 
activities, having pain or discomfort, and feeling worried, sad, or happy. The younger subject 
will be asked to indicate his/her health state by ticking the box next to the most appropriate 
statement in each of the 5 dimensions. The instructions and wording are more suitable for 
children and adolescents. 
For children aged 3 to 7 years, a proxy version of the EQ-5D-Y will be used. This is for use 
when children or adolescents are mentally or physically incapable of reporting on their own 
health-related QOL. For a proxy version, a caregiver who knows the child or adolescent well will 
rate the health related QOL in their opinion. 
8.2. 
Adverse Events and Serious Adverse Events 
8.2.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered related to the drug. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease in a study 
subject who is administered with study drug in this study. 
For this protocol, untoward medical occurrences that should be reported as AEs include the 
following: 
• All AEs during the course of treatment with study drug administration 
• All AEs resulting from medication misuse, abuse, withdrawal, or overdose, of study 
drug 
• All AEs resulting from medication errors, such as dispensing or administration error 
outside of what is described in the protocol 
• Apparent unrelated illnesses, including worsening of a pre-existing illness 


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• Injury or accidents. Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) 
and the accident (fall) should be reported as 2 separate AEs. The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test) 
• Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an 
already reported clinical event. Laboratory abnormalities associated with a clinical 
event should be captured in the source documents. Laboratory abnormalities not 
requiring clinical intervention or further investigation will be captured as part of 
overall laboratory monitoring and should not be reported as AEs. 
• Pre-existing condition (eg, allergic rhinitis) must be noted on the appropriate eCRF 
for screening but should not be reported as an AE unless the condition worsens or the 
episodes increase in frequency during the AE reporting period. Diagnostic and 
therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE. For example, an 
acute appendicitis that occurs during the treatment with study drug should be reported 
as the AE, and the resulting appendectomy should be recorded in the source 
documents and eCRF. If a surgical procedure was planned prior to entry into the 
study, and the surgery is not performed because of a worsening of a baseline 
condition, this should not be reported as an AE. Note that, as described in 
Section 8.2.2, any hospitalization occurring as the consequence of an AE during the 
study period should be reported as an SAE. 
Each AE is to be classified as serious or non-serious by the investigator using medical and 
scientific judgment. 
8.2.2. 
Definition of Serious Adverse Events 
An SAE is an untoward medical occurrence or effect associated with the use of a study drug at 
any dose, regardless of whether it is considered to be related to the study drug, which results in 
one of the following: 
• Result in death. This includes all deaths on treatment or within 30 days after last 
study drug administration, including deaths due to disease progression. Any death 
occurring later than 30 days following the last dose need not be reported as an SAE 
unless it is a result of an event that started within the period covered by the on-study 
definition. The reported AE should be the event that caused the death. In addition, 
any AE resulting in death that occurs subsequently to the AE reporting period and 
that the investigator assesses as possibly related to the study drug should also be 
reported as serious. 


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• Is life-threatening. This refers to an event in which the subject was at risk of death at 
the time of the event. It does not include an event that, had it occurred in a more 
severe form, hypothetically might have caused death. 
• Requires hospitalization or prolongation of existing hospitalization (excluding 
hospitalizations for administration of the study drug, procedures required by the study 
protocol, or treatment-related diagnostic procedures; other planned hospitalizations; 
or hospitalizations related only to progression of disease). Emergency room visits that 
do not require admission to the hospital do not fall into this category, but the event 
may be serious due to another seriousness criterion.  
• Results in persistent or significant disability or incapacity or substantial disruption of 
the ability to conduct normal life functions. 
• Any other medically important event that the investigator or the sponsor judges to be 
serious or which is defined as serious by the regulatory agency in the local country. 
These are AEs that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. Medical judgment should be 
exercised in deciding whether an AE is serious based on above definition. Examples 
of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
• A pregnancy resulting in spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly (including that in an aborted fetus). 
All SAEs that occur after any subject has been enrolled, before treatment, during treatment, or 
within 30 calendar days following the cessation of treatment, whether or not they are related to 
the study, must be recorded on forms provided by PTC. 
8.2.3. 
Unexpected Adverse Events  
The Investigator’s Brochure contains the Reference Safety Information (RSI), which will be used 
for assessing expectedness. If an event is not listed in the RSI, it should be considered 
unexpected; if the AE occurs at a greater severity, specificity, or frequency, it should also be 
considered unexpected. 
8.2.4. 
Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject/parent(s)/legal guardian/legally acceptable representative. In addition, each study 
subject/parent(s)/legal guardian/legally acceptable representative will be questioned about AEs at 
each scheduled clinic visit after study drug administration or during any telephone contact with 
the subject/parent(s)/legal guardian/legally acceptable representative. The type of question asked 
should be open-ended, for example, “How have you been feeling?” or a similar type of query. 


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8.2.5. 
Recording Non‑Serious Adverse Events and Serious Adverse Events 
All AEs (both serious and non-serious) that occur in subjects during the AE reporting period 
must be recorded, whether or not the event is considered drug related. In addition, any known 
untoward event that occurs subsequently to the AE reporting period that the investigator assesses 
as possibly related to the investigational drug/product should also be recorded as an AE. 
All AEs are to be recorded in the source documents and on the eCRF using concise medical 
terminology; whenever possible, terms contained in the Medical Dictionary for Regulatory 
Activities (MedDRA) should be employed. In addition, the following information should be 
recorded: 
• Indication of whether the event is serious or non-serious (Section 8.2.2) 
• Relationship to study drug (Section 8.2.6) 
• Severity of the event (Section 8.2.7) 
• Onset date 
• Resolution date, or date of death 
• Action taken 
• Outcome of the event 
Classification of the event as serious or non-serious determines the reporting procedures to be 
followed. 
8.2.6. 
Describing Adverse Event Relationship to Study Drug 
The investigator should provide an assessment of the relationship of the AE to the study drug, 
ie, whether there is a reasonable possibility that the study drug caused the AE, using the 
considerations outlined in Table 14. 
Table 14: 
Relationship of Study Drug to AE Relationship 
Relationship 
Description  
Probable  
A clinical event in which a relationship to the study drug seems probable because of 
factors such as consistency with known effects of the drug, a clear temporal 
association with the use of the drug, improvement upon withdrawal of the drug, 
recurrence upon re-challenge with the drug, and lack of alternative explanations for the 
event.  
Possible  
A clinical event occurring coincident with administration of the study drug and which 
may or may not be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal or re-challenge may be lacking.  
Unlikely  
A clinical event with a temporal relationship to the study drug exposure that does not 
preclude causality but for which there is a clear alternate cause that is more likely to 
have caused the adverse event than study drug. Such alternatives include a 
concomitantly administered drug, the subject’s disease state, other medical conditions, 
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Relationship 
Description  
Unrelated  
A clinical event in which a relationship to the study drug seems improbable because of 
factors such as inconsistency with known effects of the study drug, lack of a temporal 
association with study drug administration, lack of association of the event with study 
drug withdrawal or re-challenge, and/or presence of alternative explanations for the 
event. Alternative explanations might include a known relationship of the AE to a 
concomitant drug, medical history of a similar event, the subject’s disease state, other 
medical conditions, or environmental factors.  
8.2.7. 
Grading of Severity of Adverse Events 
The severity of AE will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 (refer to the study manual). For each episode, the highest severity grade 
attained should be reported. 
If a CTCAE criterion does not exist, the investigator should use the following grade or adjectives 
to describe the maximum intensity of the AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life-threatening), or Grade 5 (fatal). For purposes of consistency with the 
CTCAE, these intensity grades are defined in Table 15. 
Table 15: 
Grading of Adverse Event Severity Grade 
Grade 
Adjective  
Description  
Grade 1  
Mild  
Sign or symptom is present, but it is easily tolerated, is not expected 
to have a clinically significant effect on the subject’s overall health and 
well-being, does not interfere with the subject’s usual function, and is 
not likely to require medical attention  
Grade 2  
Moderate  
Sign or symptom causes interference with usual activity or affects 
clinical status and may require medical intervention  
Grade 3  
Severe  
Sign or symptom is incapacitating or significantly affects clinical status 
and likely requires medical intervention and/or close follow-up  
Grade 4  
Life-threatening  
Sign or symptom results in a potential threat to life  
Grade 5  
Fatal  
Sign or symptom results in death  
8.2.8. 
Adverse Event Reporting  
Investigator site reporting requirements for AEs are summarized in Table 16. 
Table 16: 
Investigator Site Requirements for Reporting Adverse Events 
Event 
Recorded on the 
eCRF 
Reported on the SAE Report Form to PTC 
Pharmacovigilance Within 24 Hours of 
Awareness 
SAE 
All  
All  
Non-serious AE 
All  
None  
Exposure to the study 
drug during pregnancy 
or breastfeeding, and 
occupational exposure 
All (regardless of 
whether associated 
with an AE), except 
occupational exposure 
Exposure during pregnancy, exposure via 
breastfeeding, occupational exposure (regardless 
of whether associated with an AE) 
Abbreviations: AE, adverse event; eCRF, electronic case report form; SAE, serious adverse event 


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Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and pulse 
need not be reported as AEs. However, abnormal values that constitute an SAE or lead to 
discontinuation of administration of study drug must be reported and recorded as an AE. 
Information about AEs and SAEs will be collected from the date of signing of the Informed 
Consent Form (ICF) until 30 calendar days following the last dose of study drug. 
The AE term should be reported in standard medical terminology when possible. For each AE, 
the investigator will evaluate and report the onset (date and time), resolution (date and time), 
outcome, intensity, causality, action taken with study drug, serious criteria (if applicable), and 
whether or not it caused the subject to discontinue the study. 
Intensity will be assessed according to the scaling demonstrated in Table 15 (Section 8.2.7). 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
(Section 8.2.7), whereas seriousness is defined by the criteria under Section 8.2.2. An AE of 
severe intensity may not be considered serious. 
Should a pregnancy occur in a subject, or a female partner of a subject, it must be recorded on 
PTC’s Pregnancy Form and reported to PTC within 24 hours of first awareness (see contact 
details below). Pregnancy in itself is not regarded as an AE unless there is a suspicion that an 
investigational product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
All AEs should be followed up by the investigator until they are resolved, or until the 
investigator assesses them as chronic or stable. The investigator should consider protocol 
guidelines and use his/her discretion in ordering additional tests as necessary to monitor the 
resolution of such events. In the event of additional investigations, the PTC Pharmacovigilance 
Department or designee should be informed via e-mail or fax. A subject withdrawn from the 
study because of an AE must be followed by the investigator until clinical recovery is complete 
and laboratory results have returned to normal, or until progression has been stabilized. 
Follow-up may need to continue after the subject has discontinued from the study, and additional 
investigations may be requested by the medical monitoring team. 
The first day of AE reporting will coincide with the date of signing of informed consent and/or 
assent (as appropriate). 


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8.2.9. 
Serious Adverse Event Reporting 
All SAEs should be reported via the “SAE Report Form” to PTC immediately, without undue 
delay, but under no circumstances later than 24 hours of becoming aware of the event(s). In 
addition, the AE portion of the eCRF must also be completed in EDC. 
The SAE Report Form should be signed by the investigator; however, if the investigator is 
unable to sign at the time of the event or within 24 hours, the form should be signed by the 
clinical staff member reporting the SAE (eg, the study coordinator). The SAE Report Form must 
be faxed or e-mailed to the PTC Pharmacovigilance Department or designee and to the site 
IRB/EC (if required by local regulations) within 24 hours. 
Follow-up information to the SAE should be clearly documented with “Follow-up” box checked 
and the follow-up number in the SAE Report Form completed and faxed or e-mailed to the same 
party. All follow-up SAE Report Forms for the event must be signed by the investigator. Any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, and 
discharge summaries) provided to the sponsor should be redacted so that the subject’s name, 
address, and other personal identity information are obscured. Only the subject’s study number 
and initials are to be provided (in regions where the provision of such information is permitted). 
The information in the AE portion of the eCRF and the SAE Report Form(s) must match or be 
reconciled. Where the same data are collected, the information on the SAE Report Form must be 
completed in a consistent manner. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if a subject initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and to document his/her first awareness of the AE. 
The PTC Pharmacovigilance Department contact information for reporting SAEs is provided 
below. This information is also provided in the Study Manual and in the SAE Report Form.  
PTC Safety Department 
Attention: Pharmacovigilance 
E-mail: 
, Facsimile: 
 
PTC is responsible for notifying the relevant regulatory authorities of certain events. It is the PI’s 
responsibility to notify the IRB or IEC of all SAEs that occur at his or her site. Investigators will 
also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) that 
occur during the clinical trial. Each site is responsible for notifying its IRB or IEC of these 
additional SAEs. 
8.2.10. 
Contraception 
Women of childbearing potential includes any female who has experienced menarche and who 
has not undergone successful permanent surgical sterilization (eg, hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy) or is not postmenopausal. Postmenopausal is 
defined as ≥12 months with no menses without an alternative medical cause. Females who are 
using an active method of birth control, are practicing abstinence, or where the partner is sterile 
(eg, vasectomy), are considered to be women of childbearing potential.  


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Women of childbearing potential must use at least 1 form of highly effective contraception for 
the duration of study participation and for 90 days after last administration of study drug in a 
manner such that risk of failure is minimized. Periodic and/or temporary abstinence such as 
declaration of abstinence during study participation or fertility awareness-based methods to 
prevent pregnancy (including but not limited to symptothermal and ovulation estimation by 
either calendar day or salivary/cervical secretions) are not considered effective methods of birth 
control; however, true (absolute) sexual abstinence (ie, in line with the preferred and usual 
lifestyle of the subject) may be permitted. Highly effective methods of birth control approved for 
use in this study are as follows: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner with confirmed azoospermia 
Prior to trial enrollment, women of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation. During the study, all women of childbearing 
potential will be instructed to contact the investigator immediately if they suspect they might be 
pregnant (eg, missed or late menstrual period). 
8.2.11. 
Reporting Pregnancy  
PTC should be notified in the event that a female subject in the study, or a female partner of a 
male subject in the study, becomes pregnant on-study or within 90 days of the last administration 
of study drug; this must be reported on a Pregnancy Notification Form (see Study Manual for 
details). This must be done whether or not an AE has occurred and within 24 hours of awareness 
of the pregnancy. The information submitted should include the anticipated date of birth or 
pregnancy termination. 
Written consent is required prior to collecting and reporting any information on a female partner 
of a male subject in the study. 
In any of the four situations listed below, the subject will be provided with a 
“Pregnancy/Pregnant Partner Data Release Form” to request their consent to follow the progress 
of the pregnancy and the birth and the health of their child. 
• Subject becomes pregnant while participating in the study 


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• Female partner of a male subject participating in the study becomes pregnant  
• Subject becomes pregnant up to 90 days after the last administration of the study drug 
(60 days after the 30-day safety follow-up telephone call) 
• Female partner of a male subject participating in the study becomes pregnant up to 
90 days after the partner completed the study 
Because the risk to an unborn child is unknown, the subject should be asked to sign this consent 
form. However, signing this form is voluntary; it is up to the subjects to decide whether to agree 
to the collection of this information or not. Upon signing, the subject’s and the child’s medical 
records relating to the pregnancy and delivery, and the health of the child, will be reviewed for 
up to 1 year of age. 
If possible, the investigator should follow the subject, or the pregnant female partner of a male 
subject, until completion of the pregnancy and notify the PTC medical monitor of the outcome 
within 5 days or as specified below. The investigator will provide this information as a follow-up 
to the initial Pregnancy Notification Form via the Pregnancy Outcome Form (see the study 
manual for details). 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus]), the investigator should follow the procedures for reporting SAEs (ie, report the 
event to PTC Therapeutic Pharmacovigilance Department and follow-up by submission of 
appropriate AE eCRFs). 
All information collected with regard to the pregnancy, the delivery of the child, and the health 
of the child is confidential to the limit allowed by law. These data will be coded to hide the 
subject’s identity and the identity of the child. In particular, the subject’s name and the child’s 
name will not be reproduced on any other paper or electronic document. These data will not be 
disclosed voluntarily by PTC. However, regulatory agencies may have to examine these data to 
ensure that the study is done properly. 
Of note, if the pregnant female partner of a male subject participating in the study does not wish 
to provide such information, this will not prevent the partner from continuing with the study. 
8.3. 
PTC Adverse Event Reporting Requirement to Regulatory Authorities, 
Investigators, and IRB/IEC 
As the sponsor of the study, PTC is responsible for reporting any suspected unexpected serious 
adverse reactions, and any other applicable SAEs, to regulatory authorities, IRB/IEC, 
investigators, and study sites in an expedited manner, in accordance with national regulations in 
the country. The initial expedited safety report will be provided as required according to local 
regulations (eg, within 15 days) after the earliest date PTC or an agent of PTC (eg, a site 
monitor) becomes aware of a SAE. This awareness date is the date the regulatory reporting clock 
begins, and the date is considered Day 0.  
The investigator should also forward a copy of all expedited reports to IRB/IEC, as per local 
requirements. SAEs will not be reported to the IRB/IEC immediately, but instead will be sent 
periodically via inclusion in the annual safety report (eg, Development Safety Update Report) to 
the reviewing committee per local requirements. 


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9. 
STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP) will be prepared and approved prior to study unblinding to 
provide a more detailed description of the nature of the analyses and the manner in which results 
will be compiled. The SAP will include details of the statistical models to be used and the test 
statistics to be employed. 
9.1. 
Statistical Hypotheses 
The null hypothesis of this study is that the mean change in Phe levels from baseline to end of 
the double-blind treatment period is the same in the PTC923 arm and in the placebo arm versus 
the alternative that they are different; a 2-sided test at the 5% alpha level will be applied.  
9.2. 
Sample Size Determination 
All subjects ≥2 years of age with ≥15% response to PTC923 will be eligible to be randomized in 
Part 2 of the study. Subjects will be stratified in Part 2 based on their mean percent blood Phe 
reduction in Part 1 (ie, subjects with mean % reduction in blood Phe levels of ≥15% to <30% and 
subjects with mean % reduction in blood Phe levels of ≥30%). Within each stratum, subjects will 
be randomized and allocated 1:1 to receive either PTC923 or placebo. Enrollment will continue 
until approximately 80 subjects from the stratum of subjects with mean percent reduction in 
blood Phe levels of ≥30% during Part 1 have been randomized. Additionally, subjects will be 
stratified based on their baseline blood Phe concentration (ie, subjects with baseline blood Phe 
<600 µmol/L and subjects with baseline blood Phe ≥600 µmol/L) and evenly distributed to either 
PTC923 or placebo treatment arms.  
For the primary endpoint with a sample size of 80 subjects ≥2 years of age for the stratum of 
subjects with mean percent reduction in blood Phe levels of ≥30% during Part 1, the power to 
detect a difference in reduction in blood Phe between PTC923 and placebo is >95%, assuming a 
treatment difference of 250 µmol/L and a within-treatment-group standard deviation of 
250 µmol/L, with a 2-sided α of 0.05. 
For the primary endpoint for all subjects in Part 2, the power to detect a difference in reduction 
in blood Phe between PTC923 and placebo is >95%, assuming a treatment difference of 
200 µmol/L, a within-treatment-group standard deviation of 250 µmol/L, and a total sample size 
of 106, with a 2-sided α of 0.05. This sample size assumes approximately 60% of subjects 
≥2 years of age enrolled in Part 1 experience a ≥15% reduction in Phe levels. 
9.3. 
Population for Analyses 
Four study populations will be analyzed: 
• Full Analysis Set (FAS): All subjects who are randomized and take at least 1 dose of 
double-blind study drug in Part 2 will be included in the FAS. Subjects will be 
analyzed according to their randomized treatment. All efficacy analyses will be based 
on the FAS. 


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• Per Protocol (PP) Analysis Set: The PP Analysis Set will include all subjects in the 
FAS who meet the study eligibility requirements and have no major protocol 
deviations that affect the validity of the efficacy measurements. The PP Analysis Set 
will be used for sensitivity analysis of the primary efficacy endpoint. The criteria for 
inclusion in the PP Analysis Set will be finalized prior to study unblinding and 
detailed in the SAP. 
• Safety Analysis Set: All subjects who receive at least 1 dose of study drug, including 
during Part 1, will be included in the Safety Analysis Set. Subjects will be analyzed 
according to actual treatment received.  
• Pharmacokinetic Analysis Set: All subjects who have at least one measurable plasma 
concentration of sepiapterin or BH4 will be included in the Pharmacokinetic Analysis 
Set. 
9.4. 
Statistical Analyses 
9.4.1. 
General Approach 
For continuous variables, median, mean, standard deviation, minimum, maximum, and the 
number of subjects with non-missing data will be provided for each treatment group. For 
categorical variables, the number (percent) of subjects in each category will be provided. 
9.4.2. 
Analysis of Efficacy Endpoints 
All efficacy analyses will be performed based on the FAS. The primary endpoint analysis will 
also be conducted using the PP Analysis Set. 
For the primary efficacy endpoint, a gatekeeping procedure will be used to control the 
family-wise error rate: 
The stratum of subjects ≥2 years of age with mean percent reduction in Phe levels of ≥30% 
during Part 1 will be tested at the significance level of 0.05 (2-sided). If p<0.05, then the study 
will be declared positive in this stratum. 
Only if the stratum of subjects ≥2 years of age with mean percent reduction in Phe levels of 
≥30% during Part 1 is statistically significant at the 0.05 level, will the overall study with all 
subjects ≥2 years of age with a mean percent reduction in Phe levels of ≥15% during Part 1 be 
tested, also at the 0.05 significance level. 
For the primary endpoint of reduction in blood Phe for the stratum of subjects with mean percent 
reduction in blood Phe levels of ≥30% during Part 1, a mixed model repeated measures 
(MMRM) model will be fitted using the available blood Phe data. The response variable is the 
change from baseline in blood Phe measured at postbaseline assessments for each subject. The 
model will include fixed effects for treatment, baseline blood Phe, baseline Phe stratum 
(<600 μmol/L or ≥600 μmol/L), visit (categorical), and visit-by-treatment interaction. In 
addition, subject will be included as random effect. An unstructured within-subject covariance 
structure will be assumed. If the model does not converge under the unstructured covariance 
matrix, the following covariance structures will be employed in order until convergence is 
reached: heterogeneous Toeplitz, heterogeneous Compound Symmetry, heterogeneous first-order 
autoregressive, Toeplitz, Compound Symmetry, and first-order autoregressive. The least squares 


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(LS) mean estimate for the average change at Part 2 Weeks 5 and 6 will be used to perform 
treatment group comparisons. The LS means, treatment effect estimate, confidence interval, and 
2-sided p value will be presented. Corresponding LS means from the same MMRM model will 
be used to estimate the treatment effects at each visit week. 
For the primary endpoint of reduction in blood Phe levels for all subjects, the same MMRM 
model used for the stratum of subjects with mean percent reduction in blood Phe levels of ≥30% 
during Part 1 will be used with the addition of a fixed effect for Phe reduction randomization 
strata (≥15% or ≥30%).  
The secondary efficacy endpoint of change from baseline in mean blood Phe levels at each 
PTC923 dose level (ie, each 2-week period in Part 2) will be assessed using an MMRM model. 
The proportion of subjects with baseline Phe levels ≥600 μmol/L who achieve Phe levels 
<600 μmol/L at the end of the double-blind treatment period will be estimated and compared 
between treatment arms. 
9.4.3. 
Missing Data 
For the primary analysis of the primary endpoint, MMRM model will be used on the available 
data assuming the missing assessments are missing at random (MAR). Missing data will be 
imputed using the multiple imputation procedure (Rubin 1987, Ouyang 2017) to further assess 
the influence of missing primary endpoint data and details of the method will be provided in the 
SAP. Briefly, these methodologies will include multiple imputation under an assumption of 
missing not at random and tipping-point analyses to explore how extreme the difference between 
randomized treatments would have to be among subjects with missing data to overwhelm the 
treatment effect obtained in the primary. In these analyses, the multiple imputation approach will 
be expanded to allow for varying impact of missing data by incorporating a shift parameter in the 
imputation model. The range of values for the shift parameter will explore the varying missing 
data assumptions, including the scenario where the imputation model is completely based on the 
control group (ie, control-based imputation). 
9.4.4. 
Pharmacokinetic Analyses 
Pharmacokinetic parameters and plasma concentrations will be summarized separately following 
different PK sampling scheme and population using descriptive statistics. 
Additionally, depending on the number of samples collected and subject demography, a 
population PK analysis will be performed using all PK samples collected in the study to further 
characterize the PK of sepiapterin and BH4 to examine potential source of PK variability, such as 
age, and to explore the relationship between exposure and response. 
9.4.5. 
Safety Analyses 
9.4.5.1. 
Subject Disposition 
The disposition of subjects, including the number of subjects screened, the number of 
randomized subjects, the number of randomized subjects who received at least 1 dose of study 
drug, and the number of subjects who prematurely discontinue study drug, as well as the reason 
for the premature termination, will be tabulated.  


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9.4.5.2. 
Medical History and Prior Medication 
Medical history and prior medication information will be descriptively summarized. 
9.4.5.3. 
Extent of Exposure and Treatment Compliance 
The extent of exposure to study drug is defined as the last dose date minus the first dose date 
+1 day. Compliance will be assessed in terms of the percentage of drug actually taken relative to 
the amount that should have been taken during the study. Exposure and compliance will be 
summarized descriptively. 
9.4.6. 
Baseline Descriptive Statistics 
Demographic and baseline characteristics of subjects will be summarized descriptively by means 
and standard deviations for continuous variables, and frequency distribution for categorical 
variables. Summaries will be performed based on all randomized subjects. 
9.4.6.1. 
Laboratory Parameters 
Changes in clinical laboratory tests from baseline (last measurement prior to randomization) and 
laboratory marked abnormalities using pre-defined abnormality criteria will be descriptively 
summarized. 
9.4.6.2. 
Adverse Events 
Summary information (the number and percent of subjects by treatment) will be tabulated for: 
• Treatment-emergent adverse events (TEAEs) 
• Treatment-related AEs 
• TEAEs by severity 
• SAEs 
• AEs leading to discontinuation 
Summaries will be presented by treatment group and categorized by MedDRA System Organ 
Class and Preferred Term. The frequencies of AEs displayed will be the crude rates that 
represent the number of subjects experiencing AEs divided by the total number of subjects. 


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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
10.1. 
Study Monitoring 
In accordance with 21 Code of Federal Regulations Part 312.56 and/or relevant ICH guidelines, 
PTC or a designee will periodically inspect all eCRFs, study documents, research facilities, and 
clinical laboratory facilities associated with this study at mutually convenient times, before, 
during, and after completion of the study. As required by applicable regulations (Responsibilities 
of Sponsors and Investigators), the monitoring visits provide PTC with the opportunity to 
evaluate the progress of the study; verify the accuracy and completeness of data in the eCRFs; 
ensure that all protocol requirements, relevant regulations, and investigator’s obligations are 
being fulfilled; and resolve any inconsistencies in the study records. This includes inspection of 
all documents and records required to be maintained by the investigator, including but not 
limited to medical records (office, clinic, or hospital) for the subjects in this study. The names 
and identities of all research subjects will be kept in strict confidence and will not appear on 
eCRFs or other records provided to or retained by PTC. The investigator/institution guarantees 
direct access to source documents by PTC and appropriate regulatory authorities. 
It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
10.2. 
Audits and Inspections 
Authorized representatives of PTC, a regulatory authority, or an IEC/IRB may visit the site to 
perform audits or inspections, including source data verification. The purpose of a PTC audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP guidelines of the ICH, and any 
applicable regulatory requirements. The investigator should contact PTC immediately if 
contacted by a regulatory agency about an inspection. 
10.3. 
Institutional Review Board/Independent Ethics Committee 
The investigator (or designee) will submit this protocol, any protocol modifications, and the 
subject consent/assent form to be utilized in this study, to the appropriate IRB/IEC for review 
and approval. Documentation of approval of the protocol and the informed consent/assent 
document must be provided to PTC (or designee) prior to initiation of this study. 
The investigator is responsible for assuring continuing review and approval of the clinical study. 
The investigator must also promptly report all changes in the research activity and all 
unanticipated problems involving risk to the subjects or others to his/her IRB/IEC. The 
investigator will not make any changes in the protocol without IRB/IEC approval except as 
necessary to eliminate apparent immediate hazards to the subjects. The investigator will provide 
progress reports to the IRB/IEC as required by the IRB/IEC. If the study remains in progress for 
>1 year, the investigator must obtain annual renewal and re-approval from the IRB/IEC. 
Documentation of renewal must be submitted to PTC (or designee). The investigator will provide 
notice to the IRB/IEC of completion of participation in the study. 


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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, PTC may conduct a 
quality assurance audit. Please see Section 10.2 for more details regarding the audit process. 


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12. 
ETHICS 
12.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved, or given a 
favorable opinion in writing by an IRB/IEC as appropriate. The investigator must submit written 
approval to PTC before he or she can enroll any subject into the study. 
The investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB/IEC must approve all advertising used 
to recruit subjects for the study. The protocol must be re-approved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. 
The investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug. PTC will 
provide this information to the investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
12.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and PTC’s policy on Bioethics. 
12.3. 
Informed Consent Process 
By signing the protocol, the investigator assures that informed consent or assent (as required) 
will be obtained from each subject or legally authorized representative prior to study entry and 
that the informed consent will be obtained in accordance with current regulations. 
The investigator or qualified representative will give each subject or legally authorized 
representative full and adequate verbal and written information regarding the objectives and 
procedures of the study and the possible risks involved. An informed consent document will be 
provided to each subject or legally authorized representative in a language in which the subject is 
fluent, or translated, according to local regulations. This information must be provided to the 
subject or legally authorized representative prior to undertaking any study-related procedure. 
Adequate time should be provided for the subject or legally authorized representative to read the 
informed consent, to understand the risks and benefits of participating in the study, and to ask 
any questions that the subject may have about the study. The subject or legally authorized 
representative should be able to ask additional questions as and when needed during the conduct 
of the study. The subject or legally authorized representative’s signature on the ICF should be 
obtained at the investigator site in the presence of the investigator or a qualified representative 
(eg, sub-investigator).  
Each subject will be given a copy of the signed consent/assent form. The original signed ICFs 
will be retained by the investigator with the study records. 


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13. 
DATA HANDLING AND RECORDKEEPING 
To enable evaluations and/or audits from regulatory authorities or PTC (or designee), the 
investigator agrees to keep accurate and complete records, including the identity of all 
participating subjects (sufficient information to link eCRFs and clinic records/source 
documents), all original signed ICFs, electronic copies (ie, CD-ROM, USB, etc.) or paper copies 
of the data that have been captured in the EDC for each subject (eCRFs), and detailed records of 
study drug disposition. All records and documents pertaining to the study will be maintained by 
the investigator until notification is received from PTC that the records no longer need to be 
retained. 
The investigator must obtain written permission from PTC before disposing of any records. The 
investigator will promptly notify PTC in the event of accidental loss or destruction of any study 
records. If the investigator relocates, retires, or for any reason withdraws from the study, the 
study records may be transferred to an acceptable designee, such as another investigator, another 
institution, or to PTC as applicable. 
13.1. 
Inspection of Records 
PTC will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
13.2. 
Retention of Records 
The investigator must maintain all documentation relating to the study for at least 15 years (or 
longer depending on local requirements) after completion or discontinuation of the trial or at 
least 2 years after the granting of the last marketing authorization in the EU (when there are no 
pending or contemplated marketing applications in the EU) or for at least 2 years after formal 
discontinuation of clinical development of the investigational product, whatever is the longest. 
If it becomes necessary for PTC or the regulatory authority to review any documentation relating 
to the study, the investigator must permit access to such records. 
13.3. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications that are specifically prohibited in the protocol 
• Missed or out-of-window visits (excluding COVID-19 related site closures) 
• Drug dosing not administered within the time frame specified in the protocol 


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• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. - either tests not done, incorrect 
tests done, or not done within the time frame specified in the protocol 
• Procedural deviations such as incorrect storage of study drug, failure to update the 
informed consent/assent form when new risks become known, or failure to obtain 
IRB/IEC approvals for the protocol and informed consent/assent form revisions 
Major deviations are any deviations that impact subject eligibility (ie, protocol 
inclusion/exclusion violations), subject safety, or a subject’s ability to continue in the clinical 
trial. 
At the outset of the study, a process for defining and handling protocol deviations will be 
established with the CRO. This will include determining which deviations will be designated 
major; thus, requiring immediate notification to the medical monitor and the sponsor. 
Prospective deviations (eg, protocol waivers) are prohibited per PTC policy. 
The investigator is responsible for seeing that any known protocol deviations are recorded as 
agreed. 


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14. 
PUBLICATION POLICY 
The information developed during the conduct of this clinical study is considered confidential by 
PTC. This information may be disclosed as deemed necessary by PTC. Clinical trial results will 
be entered in EudraCT and subsequently will be published on clinicaltrialsregister.eu. 
PTC intends that the data from this study will be presented and published. The PTC staff under 
the direction of the PTC Chief Medical Officer or designee in collaboration with the investigator 
will be responsible for writing presentations and manuscripts for publication. Investigators will 
not be allowed to publish or present the data from this study without prior agreement with PTC. 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any 
public disclosure (including publicly accessible websites) related to the protocol or study results, 
other than study recruitment materials and/or advertisements, is the sole responsibility of the 
sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
Data from all sites participating in the study will be pooled and analyzed by the sponsor or the 
sponsor’s designee. The first publication of the study results shall be made in conjunction with 
the results from other study sites as a multicenter publication. If a multicenter publication is not 
forthcoming within 24 months of completion of the study at all sites, the investigator may 
publish or present the results generated at his or her site. 
The investigator will provide the sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication. The sponsor shall inform the investigator in writing of any changes or deletions 
in such presentation or publication required to protect the sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results. At the expiration of such 60-day period, the 
investigator may proceed with the presentation or submission for publication unless the sponsor 
has notified the institution or the investigator in writing that such proposed publication or 
presentation discloses the sponsor’s confidential and proprietary technical information. 
Furthermore, upon the request of the sponsor, the investigator will delay the publication or 
presentation for an additional 90 days to permit the sponsor to take necessary actions to protect 
its intellectual property interests. 


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15. 
PROTOCOL AMENDMENT HISTORY 
Version 1.0: 23 March 2021 
Version 2.0: 15 July 2021  
Version 3.0: 06 December 2021 
Version 4.0: 13January 2022 
Version 5.0: 24 June 2022 
15.1. 
Version 5.0: 24 June 2022 
The overall reasons for Version 5.0 of the protocol were to incorporate Health Authority 
feedback and to include additional blood (plasma) sampling. 
Protocol 
Section 
Version 5.0/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. 
Editorial and administrative revisions (eg, typographical errors, 
punctuation, tenses, abbreviations) were incorporated to provide clarity. 
The synopsis, study schema, and Schedule of Assessments were 
updated to be consistent with changes in the protocol.  
Update 
Section 3.1.2.2  Language was added to clarify determination of subject’s participation in 
Part 2 of the study. 
Update 
Table 1, 
Section 8.1.5  
Table footnote and section were updated to specify confirmatory serum 
pregnancy test should be performed at the site’s local laboratory. 
Update 
Table 2  
Row and applicable footnote (q) were added to detail blood (plasma) 
samples should be taken at Part 2 Day 1 (predose) and Part 2 Day 42. 
Update 
Section 4.1a 
Inclusion criterion 5 was updated for consistency with CTFG 2020 
guidance. 
Update 
Section 5.4 a 
Section was updated to correct an error. 
Update 
Table 5  
Table was updated to add additional blood samples taken in Part 2. 
Update 
Table 13  
Table was updated to add additional blood samples taken in Part 2. 
Update 
Section 8.2.10a 
Contraceptive requirements were clarified for full alignment with 
Section 4.1. 
Update 
Section 8.2.11  
A clarification was added around the reporting period for pregnancy 
after completion of the study. 
Update 
Section 14 a 
A sentence was added to specify trial results will be entered into 
EudraCT. 
Update 
a These changes were previously included in country-specific protocols (Version 4.1 [UK] and Version 4.1 
[Denmark]). 
15.2. 
Version 4.0: 13 January 2022 
The overall reason for Version 4.0 of the protocol was to incorporate Health Authority feedback 
and to update blood sample volumes. 
Protocol 
Section 
Version 4.0/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. 
Editorial and administrative revisions (eg, typographical errors, 
punctuation, tenses, abbreviations) were incorporated to provide clarity. 
The synopsis, study schema, and Schedule of Assessments were 
updated to be consistent with changes in the protocol.  
Update 


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Protocol 
Section 
Version 4.0/Update 
Reason/ 
Rationale 
Section 3.1.4  Additional detail was added to clarify enrollment period and provide an 
end of study definition. 
Update 
Table 1 
Footnote g was added to specify eGFR should be calculated. 
Update 
Table 2 
An additional row and footnote (h) was added to explicitly specify when 
height should be measured. 
Footnote was added to specify when eGFR should be calculated. 
Table note was added to provide details around unscheduled visits and 
eGFR calculation. 
Update 
Section 4.2  
Exclusion criterion 13 was expanded to include specific pathogenic 
mutations. 
Update 
Section 4.4.1  Additional detail was added around discontinuation of pediatric subjects. 
Update 
Section 5.4 
Clarifications of total blood volumes were provided by age group. 
Update 
Section 8.1.2  Additional detail was added when height should be measured for 
subjects <18 years of age. 
Update 
Section 8.1.5  Additional detail around timepoints for eGFR calculations was added. 
Update 
15.3. 
Version 3.0: 06 December 2021 
The overall reason for Version 3.0 of the protocol was to incorporate feedback from various 
Health Authorities. 
Protocol 
Section 
Version 3.0/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. 
Editorial and administrative revisions (eg, typographical errors, 
punctuation, tenses, abbreviations) were incorporated to provide clarity. 
The synopsis, study schema, and Schedule of Assessments were 
updated to be consistent with changes in the protocol.  
Update 
Protocol 
It was updated that Phe responsiveness is defined as mean Phe 
reduction is ≥15% for subjects <2 years.   
Update 
Section 1.7  
A Risk/benefit assessment section was added. 
Update 
Section 3.1.4, 
Section 3.1.5, 
Table 2  
The definition of End of Study was updated for subjects <2 years of age. 
Update 
Table 1, 
Section 7.1  
The row for Enrollment was removed. 
Footnote j was updated to specify that analysis of the screening blood 
Phe can be performed at the site’s local laboratory. 
Update 
Table 2  
A row for Enrollment was added. 
Footnote o was updated with sampling timepoints for Part 2. 
Update 
Section 4.1, 
Section 8.2.11 
Criterium 3 was updated to specify “uncontrolled” blood Phe levels while 
on current therapy. 
Criterium 5 was updated that effective contraception/abstinence must 
be utilized for up to 90 days after the last dose of study drug. 
Update 
Section 4.4.1  
Additional detail was added to specify requirements around subjects 
who discontinue from treatment but not from study. 
Update 
Section 5.2  
Additional detail was added around the timing of dosing on PK sampling 
days. 
Update 
Section 5.4  
Total blood volume was updated  
Update 
Section 6.1  
Details of the excipients were added. 
Update 
Section 8.1.2  
Specified that vital sign measurement should occur prior to laboratory 
sampling. 
Update 
Section 8.1.4  
Specified that ECGs reads must be taken at least 1 minute apart. 
Update 
Section 8.1.6  
A section was added to detail assessment of laboratory abnormalities. 
Update 


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Protocol 
Section 
Version 3.0/Update 
Reason/ 
Rationale 
Section 8.1.8.2  PK sampling timepoints were updated. 
Update 
Section 8.2.9  
SAE reporting timeframe was updated. 
Update 
Section 8.2.11  
Reporting timeframe was updated. 
Update 
15.4. 
Version 2.0: 15 July 2021  
The overall reasons for Version 2.0 of the protocol were to include subjects from birth and to 
provide the appropriate age- and weight-based dosing for these subjects. 
Protocol 
Section 
Version 2.0/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. 
Editorial and administrative revisions (eg, typographical error, 
punctuation, tenses, abbreviations) were incorporated to provide 
clarity. The synopsis, study schema, and schedule of assessments 
were updated to be consistent with changes in the protocol.  
Update 
Protocol 
The dosing schedule was updated throughout to detail age-dependent 
dosing.  
Screening visit was updated to up to 45 days. 
Window for the ETV was extended to 21 days of last dose 
Specified throughout that subjects from birth can be included in this 
study. 
Statement was removed throughout that all subjects will receive 
PTC923 60 mg/kg in Part 1 of the study. 
Statement was added throughout to include specific details on 
subjects <2 years of age with ≥30% response to PTC923 and 
enrollment into Study PTC923-MD-004-PKU. 
Statement was added throughout to state subjects who experience 
<15% reduction (≥2 years of age) or <30% reduction (<2 years of age) 
will be classified as nonresponsive and will be contacted to schedule 
an ETV (on or between Day 28 to Day 35). 
Specified throughout that the Days -1 and 1 samples for Parts 1 and 2 
should be taken predose. 
Update 
Section 3.1.1, 
Section 5.3, 
Section 8.1.1 
Specified that specific information pertaining to previous use of 
sapropterin and pegvaliase-pqpz should be collected. 
Clarification 
Section 3.1.1.1, 
Table 12  
Specified that blood Phe levels should be measured on Days 1, 20, 
and 30 during the Pegvaliase-pqpz washout. 
Update 
Section 3.1.2.1, 
Table 2, 
Section 8.1.8 
Additional details added regarding collection of blood Phe and Tyr 
samples and timepoints for subjects participating in the PK substudy. 
Update 
Section 3.1.2.2 
Specified that blood Phe levels should be measured on Days 19, 24, 
and 28. 
Update 
Table 1, 
Section 3.1.2.2 
Randomization at screening row was removed. 
Table was updated to include blood Phe/Tyr sample collection at 
Screening 
Footnote j was updated to specify that blood Phe/Tyr samples 
collected at home will be shipped to the study site. 
Updates 


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Protocol 
Section 
Version 2.0/Update 
Reason/ 
Rationale 
Table 2  
Updated to detail age dependent dosing during Part 1 open-label 
treatment. 
Day 15 was removed.  
Randomization was moved to occur on Part 2 Day -1 
Pregnancy testing was removed from Part 1 Days 2 and 15 and Part 2 
Days 14 and 28. 
Footnote c was updated to specify a ±2-day window for Part 2 Day 42 
visit. 
Footnote m was updated to specify sampling windows for blood 
Phe/Tyr sampling at home. 
Footnote q was updated to detail study drug return procedure. 
Updates 
Section 4  
“Biochemically diagnosed” was added classical PKU 
Clarification 
Section 4.1  
Criteria 5 and 6 were updated to align with current (2020) CTFG 
guidance. 
Criterion 14 clarified surgery was not permitted within 90 days of 
screening  
Update 
Section 4.2 
Criteria 10 and 11 were added to exclude subjects with renal 
impairment/disease. 
Update 
Table 4 
Total blood volume for Part 1 was updated. 
Update 
Table 5 
Total blood volume for Part 2 was updated. 
Update 
Section 5.5  
Instructions for returning used/unused drug were updated 
Update 
Section 5.6, 
Section 5.6.1  
Statement added regarding unblinding and continuing study 
participation. 
Update 
Section 6.5 
Age-based dosing specifications were updated and added. 
Update 
Table 12  
DBS study day and pegvaliase-pqpz sample days updated. 
Update 
Table 13 
Part 1 and 2 PK sampling time windows updated 
Update 
Table 13  
Specified that the PTC923 washout should be a minimum of 14 days. 
Day 15 was removed. 
Specified that the additional sample taken at the ETV should be a 
DBS. 
Update 
Section 7.1  
Updated to include sample collection on Day -1 and Day 1 for both 
Part 1 and Part 2.   
 
Section 8.2.1 
Language was updated as per PTC standard procedures. 
Update 
Section 8.2.8 
Language was updated as per PTC standard procedures. 
Update 
Section 8.2.9 
Language was updated as per PTC standard procedures. 
Update 
Section 8.2.11  
Language was updated as per PTC standard procedures. 
Update 
Section 8.3 
Section was added as per PTC standard procedures. 
Update 


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17. 
APPENDICES 
APPENDIX A. 
SAMPLING TIMEPOINTS AND PERMITTED WINDOWS 
Table 17: 
Vital Signs Sampling Times (±Permitted Windows) for Subjects in PK Substudy on 
PK Sampling Days 
Scheduled Sample Time 
Permitted Time Window 
Predose 
Within 1 hour prior to dose 
Postdose 
±15 min 
Note: This table relates to study days where PK samples are taken. For all other timepoints, vital signs 
measurements should be taken as outlined in Table 2.  
Table 18: 
Electrocardiogram Sampling Times (±Permitted Windows) for Subjects in PK 
Substudy on PK Sampling Days 
Scheduled Sample Time 
 
Permitted Time 
Window 
Predose 
 
Within 1 hour prior to 
dose 
≤4 hours after study drug administration 
 
±15 min 
>4 hours and ≤24 hours after study drug 
administration 
 
±30 min 
Note: This table relates to study days where PK samples are taken. For all other timepoints, ECGs should be 
performed as outlined in Table 2. 
Table 19: 
Pharmacokinetic Sampling Times (±Permitted Windows) for Plasma Samples for 
Part 1  
 
 
Day 1 (Hours)* 
Day 14 (Hours) 
Predose 
Postdose 
Predose 
Postdose 
0.5 
1 
2 
4 
6 
8 
24 
2 
4 
6 
Age 
(Years) 
Window 
≤60 Min 
of Dose 
±5 Min 
±10 Min 
±30 Min 
≤60 Min 
±5 Min 
±10 Min 
<2 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
≥2 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Note: Additionally, a small amount (~ 0.25 mL) blood will be collected at the same time of PK sample collection and 
applied to VAMS for blood Phe/Tyr measurement. 
Table 20: 
Pharmacokinetic Sampling Times (±Permitted Windows) for Plasma Samples for 
Part 2  
 
Day 1, 14, 28, 42 
 
Predose 
Postdose (4 hours) 
Window 
Within 60 min prior to dose of the day and 
approximately 24 hours post dose of the prior day 
(except for Day 1) 
±15 min 
 


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SAP_001.pdf: 
V1.0 
PTC Therapeutics - Confidential 
Page 1 of 45 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NUMBER: 
PTC923-MD-003-PKU 
STUDY TITLE: 
A PHASE 3 STUDY OF PTC923 IN SUBJECTS WITH 
PHENYLKETONURIA 
13 APRIL 2023 
VERSION 1.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 US 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required 
by applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach 
of this obligation, PTC Therapeutics, Inc. should be notified promptly.
NCT #: NCT05099640


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PTC THERAPEUTICS STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES 
 
Author: 
 
 
 
 
 
 
 
 
  
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
Approver (Biostatistics): 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
Approver (Clinical): 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The eSignature Page is located on the last page. 


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TABLE OF CONTENTS 
PTC THERAPEUTICS STATISTICAL ANALYSIS PLAN APPROVAL 
SIGNATURES .................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1. 
INTRODUCTION AND OVERVIEW ........................................................................7 
1.1. 
Study Design .................................................................................................................7 
1.2. 
Study Objectives ...........................................................................................................8 
1.2.1. 
Primary Objective .........................................................................................................8 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Exploratory Objective ...................................................................................................9 
1.3. 
Study Endpoints ............................................................................................................9 
1.3.1. 
Primary Endpoint ..........................................................................................................9 
1.3.2. 
Secondary Endpoints ....................................................................................................9 
1.3.3. 
Exploratory Endpoints ................................................................................................10 
1.4. 
Sample Size ................................................................................................................10 
1.5. 
Randomization ............................................................................................................11 
2. 
ANALYSIS SETS ......................................................................................................12 
2.1. 
Full Analysis Set .........................................................................................................12 
2.2. 
Safety Analysis Set .....................................................................................................12 
2.3. 
Per-Protocol Analysis Set ...........................................................................................12 
2.4. 
Pharmacokinetic Analysis Set ....................................................................................12 
3. 
GENERAL CONSIDERATIONS ..............................................................................13 
3.1. 
Estimands ....................................................................................................................13 
3.2. 
Interim Analysis ..........................................................................................................17 
3.3. 
Multicenter Study .......................................................................................................17 
3.4. 
Data Definitions and Analysis Issues .........................................................................17 
3.4.1. 
Baseline Definitions ....................................................................................................17 
3.4.2. 
Blood Phe Data ...........................................................................................................18 
3.4.3. 
Baseline Characteristics and Treatment Group Comparability ..................................18 
3.4.4. 
Study Analysis Visit ...................................................................................................19 


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3.4.5. 
Multiplicity Control ....................................................................................................20 
3.5. 
Changes to Protocol Specified Analysis .....................................................................20 
4. 
PATIENT DATA ........................................................................................................21 
4.1. 
Patient Disposition ......................................................................................................21 
4.2. 
Data Sets Analyzed .....................................................................................................21 
4.3. 
Demographics and Baseline Characteristics ...............................................................21 
4.4. 
Disease Characteristics ...............................................................................................22 
4.5. 
Medical History ..........................................................................................................22 
4.6. 
Prior and Concomitant Medications and Non-Drug Treatments ................................22 
4.7. 
Extent of Exposure .....................................................................................................22 
4.8. 
Treatment Compliance ................................................................................................22 
4.9. 
Quality of Life Baseline Assessments ........................................................................23 
5. 
EFFICACY ANALYSIS ............................................................................................25 
5.1. 
Primary Endpoint Analysis .........................................................................................25 
5.2. 
Sensitivity Analysis ....................................................................................................25 
5.2.1. 
Analysis on PP Analysis Set .......................................................................................25 
5.2.2. 
Different Methods to Handle Missing Data ................................................................25 
5.2.3. 
Handling Subjects with Potential Change of Diet ......................................................26 
5.2.4. 
T-test with Completers ...............................................................................................26 
5.2.5. 
Analysis of Phe levels at Steady State ........................................................................26 
5.3. 
Subgroup Analysis ......................................................................................................26 
5.4. 
Secondary Endpoints Analysis ...................................................................................27 
5.5. 
Exploratory Endpoints ................................................................................................28 
6. 
SAFETY ANALYSES ...............................................................................................29 
6.1. 
Adverse Events ...........................................................................................................29 
6.2. 
Vital Signs and Weight ...............................................................................................30 
6.3. 
Physical Examination .................................................................................................30 
6.4. 
Electrocardiogram .......................................................................................................30 
6.5. 
Central Laboratory Values ..........................................................................................31 
6.6. 
Contraception and Pregnancy Reporting ....................................................................31 
6.7. 
Diet Monitoring: 3-Day Diet Records ........................................................................32 
7. 
MOCK TABLES, LISTINGS, AND GRAPHS .........................................................33 
8. 
REVISION HISTORY ...............................................................................................34 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................35 
APPENDIX 2. DETAILS ON SENSITIVITY ANALYSIS ON MISSING 
DATA – MULTIPLE IMPUTATION ........................................................................42 
APPENDIX 3. EQ5D INDEX SCORE DERIVATION .............................................................44 
9. 
REFERENCES ...........................................................................................................45 
 
LIST OF TABLES 
Table 1: 
Study Endpoints and Estimands .................................................................................13 
Table 2: 
Study Analysis Visit ...................................................................................................19 
Table 3: 
Schedule of Assessments (Screening Period) .............................................................35 
Table 4: 
Schedule of Assessments (Part 1 and Part 2 Periods) .................................................37 
Table 5: 
Phenylalanine/Tyr Sample Collection (Screening Period) a .......................................40 
Table 6: 
Phenylalanine/Tyr Sample Collections (Part 1 and Part 2) a ......................................40 
Table 7: 
Vital Signs Sampling Times (±Permitted Windows) for Subjects in PK 
Substudy on PK Sampling Days .................................................................................41 
Table 8: 
Electrocardiogram Sampling Times (±Permitted Windows) .....................................41 
Table 9: 
Pharmacokinetic Sampling Times (±Permitted Windows) for Plasma 
Samples for Part 1 .......................................................................................................41 
Table 10: Pharmacokinetic Sampling Times (±Permitted Windows) for Plasma 
Samples for Part 2 .......................................................................................................41 
 
LIST OF FIGURES 
Figure 1: 
Study Schema for Study PTC923-MD-003-PKU.........................................................8 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialized Term 
Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AP 
Alkaline phosphatase  
AST 
Aspartate aminotransferase 
BH4 
Tetrahydrobiopterin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBS 
Dried blood sample 
ECG 
Electrocardiogram 
EOS 
End of Study 
EQ-5D 
European Quality of Life - 5 Dimensions 
EQ-5D-5L 
5-Level European Quality of Life - 5 Dimensions 
EQ-5D-Y 
European Quality of Life - 5 Dimensions for Youth 
ETV 
Early Termination Visit 
FAS 
Full Analysis Set 
GGT 
Gamma glutamyl transferase  
hCG 
Human chorionic gonadotrophin 
HEENT 
Head, eyes, ears, nose, and throat 
LDH 
Lactate dehydrogenase 
LS 
Least square 
MAR 
Missing at random 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI 
Multiple imputation 
MMRM 
Mixed model repeated measures model 
MNAR 
Missing not at random 
PAH 
Phenylalanine hydroxylase 
Phe 
Phenylalanine 
PK 
Pharmacokinetics 
PKU 
Phenylketonuria 
PKU-QOL 
Phenylketonuria-Quality of Life 
PP 
Per-Protocol 
PT 
Preferred Term 
QOL 
Quality of Life 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAS 
Statistical Analysis System  
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
Tyr 
Tyrosine 
ULN 
Upper Limit of Normal 
VAMS 
Volumetric Absorptive MicroSampling  
WBC 
White blood cell 


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1. 
INTRODUCTION AND OVERVIEW 
The purpose of this statistical analysis plan is to describe the procedures and the statistical 
methods to support Study PTC923-MD-003-PKU final reporting after database lock. The 
statistical methods described here are based on the analyses proposed in the Final Protocol issued 
on 24 Jun 2022, Version 5.0. 
1.1. 
Study Design 
This is a Phase 3, double-blind, randomized, multicenter efficacy study of PTC923 versus 
placebo in subjects with phenylketonuria (PKU). 
Approximately 80 subjects with PKU aged ≥2 years who achieve a ≥30% reduction from 
baseline in blood Phe levels during the responsiveness test (Part 1) will be enrolled in the 
placebo-controlled treatment period to receive either PTC923 or placebo (Part 2). Approximately 
178 subjects are expected to be enrolled in Part 1 of the study to achieve this. 
The screening period is up to 45 days. Subjects who enter the study and are receiving 
pegvaliase-pqpz (PALYNZIQ) supplementation at the Screening Visit must complete a 30-day 
washout period prior to dosing. Subjects who enter the study and are receiving 
tetrahydrobiopterin (BH4) supplementation (eg, sapropterin dihydrochloride, KUVAN) at the 
Screening Visit must complete a 7-day washout period prior to first dose with PTC923. 
Part 1 of the study tests for responsiveness to PTC923, with 14 days of open-label treatment with 
PTC923 7.5 mg/kg (subjects 0 to <6 months of age), 15 mg/kg (subjects 6 to <12 months of age), 
30 mg/kg (subjects 12 months to <2 years of age), or 60 mg/kg (subjects ≥2 years of age) 
administered orally once a day followed by a minimum of 14 days PTC923 washout. At the end 
of treatment in Part 1, the mean change in blood phenylalanine (Phe) levels over the 14-day 
treatment period for all subjects will be assessed against their pretreatment blood Phe level. The 
pretreatment blood Phe level will be the mean of Day -1 and Day 1 (predose) blood Phe levels. 
Subjects ≥2 years of age who experience a <15% reduction in blood Phe levels will be classified 
as nonresponsive and participation in the study will be terminated. Subjects (≥2 years of age) 
who experience a ≥15% reduction in blood Phe levels will continue into Part 2, which is a 
randomized, placebo-controlled, double-blind treatment period. Subjects <2 years of age who 
experience ≥15% reduction in blood Phe levels will also be classified as responsive and offered 
the option to enroll directly into an open-label extension Study PTC923-MD-004-PKU. Subjects 
<2 years of age who experience a <15% reduction in blood Phe levels will be classified as 
nonresponsive and will not be offered the option to enroll directly into the open-label extension 
study. Following the minimum 14-day PTC923 washout period, all eligible subjects ≥2 years of 
age will be randomized in Part 2 to receive either PTC923 or placebo. Subjects will be stratified 
based on their mean percent reduction in blood Phe levels (ie, subjects with mean % reduction in 
Phe levels of ≥15% to <30% and subjects with mean % reduction in Phe levels of ≥30%), and 
their baseline blood Phe concentration (ie, subjects with baseline blood Phe <600 µmol/L and 
subjects with baseline blood Phe ≥600 µmol/L). Within each stratum, subjects will be 
randomized to either PTC923 or placebo in 1:1 ratio. 
Subjects randomized to PTC923 will receive PTC923 20 mg/kg daily for Weeks 1 and 2 
(Days 1 to 14), then PTC923 40 mg/kg daily for Weeks 3 and 4 (Days 15 to 28), then PTC923 
60 mg/kg daily for Weeks 5 and 6 (Days 29 to 42). As dosing is weight-based and to maintain 
the blind, subjects randomized to placebo will receive equivalent quantities of placebo to match 


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the 20 to 40 to 60 mg/kg dose escalation of the PTC923 treatment arm. After 6 weeks of 
treatment with either PTC923 or placebo, subjects will be offered the option to enter the 
open-label PTC923-MD-004-PKU study. Approximately 45 centers will participate in this study. 
The study design is summarized in Figure 1 and the Schedule of Assessments is presented in 
Table 2 (Screening Period) and Table 3 (Parts 1 and 2). 
Figure 1: 
Study Schema for Study PTC923-MD-003-PKU 
 
Abbreviations: Phe, phenylalanine 
Note: Phe responsiveness is defined as mean Phe reduction ≥15%. 
PK Substudy Only: 
Approximately 30 subjects ≥12 years of age will participate in the PK substudy. At least 12 out 
of the 30 subjects ≥12 years of age participating in the PK substudy are expected to be female. In 
addition, up to 6 subjects from each of these age groups will be included: 1) <2 years; 2) 2 to 
5 years; and 3) 6 to 11 years. Blood samples will be collected from subjects participating in PK 
substudy to characterize the PK of sepiapterin and BH4 following an intensive schedule on Part 1 
Day 1 and Part 1 Day 2 for subjects ≥2 years. For subjects <2 years of age participating in the 
substudy, blood samples (2 on each occasion; total of 4 samples) will be collected on Part 1 Day 
1 and Part 1 Day 14. 
In addition to blood drawn for PK sampling at specified timepoints, a small amount of blood will 
be drawn to a MiniCollect tube (~0.25 mL) at the same time and applied to the VAMS device for 
blood Phe and Tyr measurement.  
For Part 2, blood samples (2 samples/occasion) will be collected from subjects in Part 2 on 
Days 1, 14, 28, and 42 visits to characterize the PK of sepiapterin and BH4 at predose 
(approximately 24 hours post the dose on prior day, except for Day 1, and prior to the dose of the 
day) and 4 hours postdose.  
1.2. 
Study Objectives 
1.2.1. 
Primary Objective 
The primary objective is to evaluate the efficacy of PTC923 in reducing blood Phe levels in 
subjects with PKU as measured by mean change in blood Phe levels from baseline to Weeks 5 
and 6 (ie, the average of each respective treatment dose 2-week period of double-blind 
treatment). 


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1.2.2. 
Secondary Objectives 
• To evaluate the proportion of subjects with baseline Phe levels ≥600 μmol/L who 
achieve Phe levels <600 μmol/L at the end of the double-blind treatment period 
• To evaluate the effect of PTC923 dose response on reducing blood Phe levels in 
subjects with PKU 
• To evaluate the PK of PTC923 in subjects with PKU 
• To assess the safety of PTC923 in subjects with PKU 
1.2.3. 
Exploratory Objective 
The exploratory objective is to evaluate changes in blood Tyr over time, including the Phe:Tyr 
ratio. 
1.3. 
Study Endpoints 
1.3.1. 
Primary Endpoint 
The primary endpoint of this study is the mean change in blood Phe levels from baseline to 
Weeks 5 and 6 in Part 2 double-blind phase. Baseline is defined as the average of Day -1 and 
Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 is calculated as the 
average of blood Phe levels collected during the Week 5-6 analysis visit window as described in 
Section 3.4.4  
1.3.2. 
Secondary Endpoints 
Proportion of Subjects with Baseline Phe levels ≥600 μmol/L who Achieve Phe Levels 
<600 μmol/L at the End of the Double-Blind Treatment Period 
For this endpoint, the baseline is defined as the average of Day -1 and Day 1 predose blood Phe 
levels in Part 2, and Phe level at the end of the double-blind treatment period is referring to the 
average of blood Phe levels collected during the Week 5-6 analysis visit window as described in 
Section 3.4.4. The binary endpoint will be calculated for all subjects with baseline Phe levels 
≥600 μmol/L: “Achieved” if Phe levels <600 μmol/L at the end of the double-blind treatment 
period, and “Not Achieved” if Phe levels still ≥600 μmol/L at the end of the double-blind 
treatment period. 
Proportion of Subjects with Baseline Phe levels ≥360 μmol/L who Achieve Phe Levels 
<360 μmol/L at the End of the Double-Blind Treatment Period 
For this endpoint, the baseline is defined as the average of Day -1 and Day 1 predose blood Phe 
levels in Part 2, and Phe level at the end of the double-blind treatment period is referring to the 
average of blood Phe levels collected during the Week 5-6 analysis visit window as described in 
Section 3.4.4. The binary endpoint will be calculated for all subjects with baseline Phe levels 
≥360 μmol/L: “Achieved” if Phe levels <360 μmol/L at the end of the double-blind treatment 
period, and “Not Achieved” if Phe levels still ≥360 μmol/L at the end of the double-blind 
treatment period. 


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PTC923 Dose Response on Reducing Blood Phe Levels in Subjects with PKU 
The mean change and percent change on blood Phe levels at each dose level from baseline will 
be calculated to evaluate the dose response of PTC923. Baseline is the average of Day -1 and 
Day 1 predose blood Phe levels in Part 2. Phe levels at each dose will be calculated by using the 
analysis visit window as described in Section 3.4.4: 
− 20 mg/kg QD: the average of blood Phe levels collected during Weeks 1 and 2 
− 40 mg/kg QD: the average of blood Phe levels collected during Weeks 3 and 4 
− 60 mg/kg QD: the average of blood Phe levels collected during Weeks 5 and 6 
PK of PTC923 in Subjects with PKU 
Besides Sepiapterin and BH4 plasma concentrations, pharmacokinetic parameters include Cmax, 
Tmax, T1/2, area under the plasma concentration-time curve from time zero to 24 hours (AUC0-
24h), area under the plasma concentration-time curve from time zero to infinity (AUC0-inf), CL/F, 
and Vz/F. 
Safety of PTC923 in Subjects with PKU 
Safety and tolerability of PTC923 will be evaluated by severity and number of treatment-
emergent adverse events (TEAEs), clinical laboratory tests, vital signs, physical examinations, 
and electrocardiograms (ECGs) over the treatment period. 
1.3.3. 
Exploratory Endpoints 
The exploratory endpoints include: 
Mean change and percent change from baseline in blood Tyr over time 
Mean change and percent change from baseline in blood Phe:Tyr ratio over time 
1.4. 
Sample Size 
All subjects ≥2 years of age with ≥15% response to PTC923 will be eligible to be randomized in 
Part 2 of the study. Subjects will be stratified in Part 2 based on their mean percent blood Phe 
reduction in Part 1 (ie, subjects with mean % reduction in blood Phe levels of ≥15% to <30% and 
subjects with mean % reduction in blood Phe levels of ≥30%). Within each stratum, subjects will 
be randomized and allocated 1:1 to receive either PTC923 or placebo. Enrollment will continue 
until approximately 80 subjects from the stratum of subjects with mean percent reduction in 
blood Phe levels of ≥30% during Part 1 have been randomized. Additionally, subjects will be 
stratified based on their baseline blood Phe concentration (ie, subjects with baseline blood Phe 
<600 µmol/L and subjects with baseline blood Phe ≥600 µmol/L) and evenly distributed to either 
PTC923 or placebo treatment arms. 
For the primary endpoint with a sample size of 80 subjects for the stratum of subjects with mean 
percent reduction in blood Phe levels of ≥30% during Part 1, the power to detect a difference in 
reduction in blood Phe between PTC923 and placebo is >95%, assuming a treatment difference 
of 250 µmol/L and a within-treatment-group standard deviation of 250 µmol/L, with a 2-sided α 
of 0.05. 


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For the primary endpoint for all subjects in Part 2, the power to detect a difference in reduction 
in blood Phe between PTC923 and placebo is >95%, assuming a treatment difference of 
200 µmol/L, a within-treatment-group standard deviation of 250 µmol/L, and a total sample size 
of 106, with a 2-sided α of 0.05. This sample size assumes approximately 60% of subjects 
≥2 years of age enrolled in Part 1 experience a ≥15% reduction in Phe levels. 
Approximately 80 subjects with PKU aged ≥2 years of age who achieve a ≥30% reduction from 
baseline in blood Phe levels during the responsiveness test (Part 1) will be enrolled in the 
placebo-controlled treatment period to receive either PTC923 or placebo (Part 2). Approximately 
178 subjects are expected to be enrolled in Part 1 of the study to achieve this. 
Subjects with classical PKU that is biochemically diagnosed (ie, blood Phe birth 
levels ≥1200 μmol/L and/or historical evidence of Phe concentrations ≥1200 μmol/L in their 
medical history) will be capped at 20% of the total study population. 
1.5. 
Randomization 
In Part 1 of the study, all subjects will receive open-label treatment with PTC923 administered 
orally once a day. Following the minimum 14-day PTC923 washout period, all eligible subjects 
will proceed to Part 2 and be randomized to receive either PTC923 or placebo. 
Part 2 of this study will be performed in a double-blinded fashion. The investigator and study 
staff (including processing laboratory personnel), the subjects, and the sponsor’s staff will 
remain blinded to the treatment until study closure. The investigational drug and its matching 
placebo are indistinguishable and will be packaged in the same way. Subjects will be randomized 
1:1 to either PTC923 or placebo using a central randomization process. The randomization will 
be stratified on two strata using a block randomization technique: one on their mean percent 
reduction in blood Phe levels in Part 1 (ie, subjects with mean % reduction in Phe levels of ≥15% 
to <30% and subjects with mean % reduction in Phe levels of ≥30%) and the other one on their 
baseline blood Phe concentration (ie, subjects with baseline blood Phe <600 μmol/L and subjects 
with baseline blood Phe ≥600 μmol/L in Part 1), and evenly distributed to either PTC923 or 
placebo treatment arms. 
The process will be established and performed centrally by an experienced contract research 
organization through an Interactive Response Technology system to maximize the integrity and 
security of the randomization and ensure appropriate access and convenience-of-use by the 
investigational sites. 
Blinding is important for validity of this clinical study, and the blind may be broken only in the 
event of a medical emergency. 


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2. 
ANALYSIS SETS 
Subject inclusion into each population for the final analysis will be determined prior to database 
lock. 
2.1. 
Full Analysis Set 
Full Analysis Set (FAS): All subjects who are randomized and take at least 1 dose of 
double-blind study drug in Part 2 will be included in the FAS. Subjects will be analyzed 
according to their randomized treatment. All efficacy analyses will be based on the FAS. 
2.2. 
Safety Analysis Set 
All subjects who receive at least 1 dose of study drug, including during Part 1, will be included 
in the Safety Analysis Set (the overall safety set). Furthermore, the Part 2 Safety Analyses Set for 
the randomized part of the study will include all subjects who are randomized and take at least 1 
dose of double-blind study drug in Part 2. Subjects will be analyzed according to actual treatment 
received for safety analysis. For the actual treatment definition, if a subject received different 
treatment from randomized treatment throughout Part 2, that treatment would be actual treatment 
as opposed to the treatment the subject was allocated to receive at randomization. 
2.3. 
Per-Protocol Analysis Set 
The Per-Protocol (PP) Analysis Set will include all subjects in the FAS who meet the study 
eligibility requirements and have no major protocol deviations that affect the validity of the 
efficacy measurements. This is a subset of the FAS. The criteria for inclusion in the PP Analysis 
Set will be finalized prior to study unblinding. Subjects who meet the following criteria will be 
excluded from the PP population: 
• Received study treatment different from the randomized treatment throughout Part 2 
• Did not have a valid blood Phe at baseline in Part 2, or a valid blood Phe at Day 42 
within the allowed analysis visit window 
• Had significant non-compliance to study drug administration 
• Had significant inclusion or exclusion criteria violations  
• Had major protocol deviations (eg, diet modification) which may impact 
effectiveness of study treatment 
The PP Analysis Set will be used for sensitivity analysis of the primary efficacy endpoint. A 
separate documentation containing the final exclusion criteria and a list of subjects in this 
population will be finalized prior to unblinding at study completion. 
2.4. 
Pharmacokinetic Analysis Set 
All subjects who have at least one measurable plasma concentration of sepiapterin or BH4 will be 
included in the Pharmacokinetic Analysis Set. 


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3. 
GENERAL CONSIDERATIONS 
3.1. 
Estimands 
The primary estimand of the study is intended to provide a population level estimate of the 
treatment difference in terms of mean change in blood Phe levels from baseline to Weeks 5 and 6 
in Part 2 double-blind phase, by a treatment policy strategy. Table 1 lists all the estimands for the 
study. 
Table 1: 
Study Endpoints and Estimands 
Endpoint 
Population 
Intercurrent 
Events 
Population Level 
Summary 
Analysis 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% 
confidence interval (CI) 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using a mixed 
model repeated measures 
(MMRM) method. 
Primary 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥15% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method. 
Secondary 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria, with no 
major protocol 
deviations (one 
stratum in PP) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method. 
 
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥15% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria, with no 
major protocol 
deviations (PP) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method. 
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
PKU subjects ≥2 
years of age with a 
reduction in blood 
a. Prohibited 
medication or diet 
modification: 
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
Sensitivity 
analysis for 


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Endpoint 
Population 
Intercurrent 
Events 
Population Level 
Summary 
Analysis 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method after multiple 
imputation (MI) assuming 
missing at random (MAR). 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥15% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method after MI assuming 
MAR. 
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method after control-based 
imputation assuming 
missing not at random 
(MNAR). 
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥15% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method after control-based 
imputation assuming 
MNAR. 
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using a tipping-
point analysis. 
 
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥15% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using a tipping-
point analysis. 
Sensitivity 
analysis for 
the primary 
endpoint 


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Endpoint 
Population 
Intercurrent 
Events 
Population Level 
Summary 
Analysis 
Data will be used 
as collected.  
 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
a. Prohibited 
medication: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected. 
c. Prohibited diet 
modification: 
Data will be set 
as missing after 
two consecutive 
weeks of change 
of diet in Part 2. 
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method.  
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥15% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (FAS) 
a. Prohibited 
medication: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected. 
c. Prohibited diet 
modification: 
Data will be set 
as missing after 
two consecutive 
weeks of change 
of diet in Part 2. 
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method. 
 
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
a. Prohibited 
medication: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected. 
c. Prohibited diet 
modification: 
Data will be set 
as missing after 
two consecutive 
weeks of change 
of diet in Part 2. 
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
method after MI assuming 
MAR.  
 
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥15% 
in Part 1, as defined 
by the protocol 
a. Prohibited 
medication: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using an MMRM 
Sensitivity 
analysis for 
the primary 
endpoint 


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Endpoint 
Population 
Intercurrent 
Events 
Population Level 
Summary 
Analysis 
and 6 in 
Part 2 
 
inclusion/exclusion 
criteria (FAS) 
Data will be used 
as collected. 
c. Prohibited diet 
modification: 
Data will be set 
as missing after 
two consecutive 
weeks of change 
of diet in Part 2. 
method after MI assuming 
MAR. 
 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using a t-test.  
Sensitivity 
analysis for 
the primary 
endpoint 
Mean 
change in 
blood Phe 
levels from 
baseline to 
Weeks 5 
and 6 in 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥15% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected. 
Treatment difference and 
corresponding 95% CI 
between PTC923 and 
placebo in the mean 
change from baseline to 
Weeks 5 and 6 will be 
estimated using a t-test. 
Sensitivity 
analysis for 
the primary 
endpoint 
Proportion 
of subjects 
with 
baseline 
Phe levels 
≥600 μmol/L 
who achieve 
Phe levels 
<600 μmol/L 
at the end of 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Odds ratio of PTC923 
versus placebo along with 
the 95% CI will be 
estimated by using a chi-
square test. 
Analysis of 
key 
secondary 
endpoint 
Proportion 
of subjects 
with 
baseline 
Phe levels 
≥600 μmol/L 
who achieve 
Phe levels 
<600 μmol/L 
at the end of 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Odds ratio of PTC923 
versus placebo along with 
the 95% CI will be 
estimated by using a 
Cochran-Mantel-Haenszel 
test stratified by 
randomization stratification 
factor (Phe reduction during 
Part 1: ≥15% to <30% or 
≥30%). 
Analysis of 
key 
secondary 
endpoint 


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Endpoint 
Population 
Intercurrent 
Events 
Population Level 
Summary 
Analysis 
Proportion 
of subjects 
with 
baseline 
Phe levels 
≥360 μmol/L 
who achieve 
Phe levels 
<360 μmol/L 
at the end of 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (one stratum 
in FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Odds ratio of PTC923 
versus placebo along with 
the 95% CI will be 
estimated by using a chi-
square test. 
Analysis of 
key 
secondary 
endpoint 
Proportion 
of subjects 
with 
baseline 
Phe levels 
≥360 μmol/L 
who achieve 
Phe levels 
<360 μmol/L 
at the end of 
Part 2 
PKU subjects ≥2 
years of age with a 
reduction in blood 
Phe levels of ≥30% 
in Part 1, as defined 
by the protocol 
inclusion/exclusion 
criteria (FAS) 
a. Prohibited 
medication or diet 
modification: 
Data will be used 
as collected. 
b. Early 
discontinuation: 
Data will be used 
as collected.  
Odds ratio of PTC923 
versus placebo along with 
the 95% CI will be 
estimated by using a 
Cochran-Mantel-Haenszel 
test stratified by 
randomization stratification 
factor (Phe reduction during 
Part 1: ≥15% to <30% or 
≥30%). 
Analysis of 
key 
secondary 
endpoint 
3.2. 
Interim Analysis 
No interim analysis is planned for this study. The DSMB will review accumulating safety data to 
ensure the safety of study subjects and provide recommendations concerning continuation, 
termination, or modification of the study. The DSMB chair will review the prespecified data 
every month (for a total of approximately 15 months), and the DSMB will review the 
prespecified data every other month and discuss in a bi-monthly scheduled meeting. 
3.3. 
Multicenter Study 
It was estimated that subjects would be screened and enrolled across approximately 45 centers 
for this study. Due to limited data from each site, no adjustment or stratification for site will be 
performed. Data from all centers will be pooled for the primary analysis. By region/country 
analysis of the primary endpoint may be explored. 
3.4. 
Data Definitions and Analysis Issues 
3.4.1. 
Baseline Definitions 
Baseline is defined for Part 1 and Part 2 respectively, unless specified otherwise. For the 
analyses in Part 1, the baseline is generally defined as the last available measurement prior to the 
first dose of PTC923 during the open-label run-in phase. For the analysis in Part 2, the baseline 
is generally defined as the last available measurement prior to the first dose of study drug 
(PTC923 or placebo) during the double-blind phase.   


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3.4.2. 
Blood Phe Data 
The American College of Medical Genetics and Genomics guidelines recommend lifelong 
treatment of PKU, with the primary goal of therapy to maintain blood Phe in the range of 120 to 
360 μmol/L (Vockley 2014). As such, blood Phe levels are universally used in the diagnosis and 
clinical management of patients with hyperphenylalaninemia due to PKU. Blood Phe levels will 
be measured at the timepoints indicated in Table 4 and Table 5. Samples should be collected 
after fasting or no earlier than 3 hours postprandial and at approximately the same time of day at 
each collection timepoint. 
The main purpose of Part 1 of the study is to test for responsiveness to PTC923. In Part 1, blood 
Phe levels will be measured on Days -1, 1 (predose), 5, 10, and 14 of the treatment period and on 
Days 19, 24, and 28 during the washout period. The mean percent reduction in Phe level will be 
calculated as mean of Part 1 Days 5, 10, and 14 against their pretreatment blood Phe level (mean 
of Part 1 Day -1 and Part 1 Day 1 predose). The calculated mean percent reduction in Phe level 
will be used to determine the responsiveness to PTC923. Phe responsiveness is defined as mean 
Phe reduction ≥15%. 
Part 2, the randomized, placebo-controlled, double-blind treatment period, is the main part of the 
study to evaluate the primary objective. Blood Phe levels will be measured in Part 2 on Days -1, 
1 (predose) 5, 10, 14, 19, 24, 28, 33, 38, and 42 for all subjects. For Part 2 blood Phe level data, 
the mean blood Phe level of Days 5, 10, and 14 is for the 2-week period of PTC923 20 mg/kg 
daily, Days 19, 24, and 28 is for the 2-week period of PTC923 40 mg/kg daily, and Days 33, 38, 
and 42 is for the 2-week period of PTC923 60 mg/kg daily. Baseline is the mean of Day -1 and 
Day 1 predose blood Phe levels in Part 2. The mean change from baseline and percent change 
from baseline in Phe levels will be calculated for each of the 2-week treatment periods for each 
of the subjects.  
VAMS clamshells containing 4 sample sticks will be used to collect blood Phe for each 
timepoint (ie, in quadruplicate). Duplicative sampling for a sample collection timepoint is being 
used to ensure that at least 1 sample contains sufficient blood volume necessary for an accurate 
measurement of blood Phe for that collection. If insufficient blood volume was sampled for 
VAMS, the analyzed blood Phe value will potentially be biased. If the central lab believes that 
there is insufficient blood volume in all 4 samples, then they will indicate that blood Phe level 
for that day is insufficient, and the blood Phe value for that study day will be treated the same as 
not evaluable. Note that if there is one or more data points for blood Phe level missing (not 
taken, not evaluable, or lost) or VAMS filled with insufficient amount of blood for all the 
samples on any assessment day, then the remaining available data on other assessment day(s) 
during the calculation period will be used to calculate the mean value. Only when all the data 
points for blood Phe levels are missing, will the mean blood Phe level for that particular period 
be considered as missing. 
3.4.3. 
Baseline Characteristics and Treatment Group Comparability 
Baseline subject characteristics will be collected prior to Part 1 dosing for the overall Safety 
Analysis Set. As subjects ≥2 years of age who experience a <15% reduction in blood Phe levels 
(will be classified as nonresponsive) or subjects <2 years of age will not be eligible to proceed to 
Part 2 randomization, the baseline characteristics will be summarized by treatment group 
(including subjects that only participated in Part 1 as a treatment group) and by the Phe reduction 


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randomization strata (≥15% to <30% or ≥30%, if participated in Part 2) using frequency tables 
for categorical variables and descriptive statistics for quantitative variables. 
During the study, several levels of treatment groups will be used to summarize data: 
• For the Safety Analysis Set, as all subjects who receive at least 1 dose of study drug 
in Part 1 will be included, the overall group represents all subjects treated in Part 1, 
but for display purposes, the treatment groups can be split into subjects who only 
participated in Part 1 and subjects who are randomized and treated in Part 2 (FAS), 
who can be further separated into PTC923 and placebo groups. Subjects who only 
participated in Part 1 include subjects ≥2 years of age non-responders (subjects 
≥2 years of age who experience a <15% reduction in blood Phe levels), subjects 
<2 years of age regardless of responsiveness to PTC923, early termination subjects 
during Part 1, and subjects who randomized but did not take any study drug during 
Part 2. 
• For the FAS, the treatment groups can be composed of PTC923 and placebo, and the 
overall includes all subjects randomized and treated in Part 2. Baseline characteristics 
tables will be further summarized by the Phe reduction randomization strata 
(≥15% to <30% or ≥30%) for the subjects who are randomized and treated in Part 2 
(FAS). 
• Further in Part 2, as subjects will proceed through a dose escalation process, data 
collected in Part 2 may be presented by the two-week intervals, aligning with the dose 
levels of 20, 40, or 60 mg/kg QD. 
3.4.4. 
Study Analysis Visit 
Study analysis visits during the study will be derived as listed in Table 2, based on study days 
from randomization date. Study analysis visits will be used in all by-visit summaries for both 
efficacy and safety assessments wherever appropriate. 
Table 2: 
Study Analysis Visit 
Analysis Visit 
Scheduled Study Day 
Analysis Window (in Study Days) 
Screening 
 
-45 days to Part 1 Day -2 
Part 1 Day -1 
Part 1 Day -1 
Part 1 Day -1 
Part 1 Day 1 
Part 1 Day 1 
Part 1 Day 1 
Part 1 Day 2 
Part 1 Day 2 
Part 1 Day [2, 3] 
Part 1 Day 5 
Part 1 Day 5 
Part 1 Day [4, 8] 
Part 1 Day 10 
Part 1 Day 10 
Part 1 Day [9, 12] 
Part 1 Day 14 
Part 1 Day 14 
Part 1 Day [13, 17] 
Washout Day 19 
Part 1 Day 19 
Part 1 Day [18, 22] 
Washout Day 24 
Part 1 Day 24 
Part 1 Day [23, 26] 
Washout Day 28 
Part 1 Day 28 
Part 1 Day [27, last day in Part 1] 
Part 2 Day -1 
Part 2 Day -1 
Part 2 Day -1 
Part 2 Day 1 
Part 2 Day 1 
Part 2 Day 1 
Part 2 Day 5 
Part 2 Day 5 
Part 2 Day [2, 7] 
Part 2 Day 10  
Part 2 Day 10 
Part 2 Day [8, 12] 
Part 2 Day 14  
Part 2 Day 14 
Part 2 Day [13, 17] 
Part 2 Day 19 
Part 2 Day 19 
Part 2 Day [18, 22] 
Part 2 Day 24 
Part 2 Day 24 
Part 2 Day [23, 26] 
Part 2 Day 28 
Part 2 Day 28 
Part 2 Day [27, 31] 


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Analysis Visit 
Scheduled Study Day 
Analysis Window (in Study Days) 
Part 2 Day 33 
Part 2 Day 33 
Part 2 Day [32, 36] 
Part 2 Day 38 
Part 2 Day 38 
Part 2 Day [37, 39] 
Part 2 Day 42 
Part 2 Day 42 
Part 2 Day [40, 14 days after the last dose in Part 2] 
Part 2 Week 1-2 
 
Part 2 Day [2, 17] 
Part 2 Week 3-4 
 
Part 2 Day [18, 31] 
Part 2 Week 5-6 
 
Part 2 Day [32, 14 days after the last dose in Part 2] 
For a given subject, if multiple assessments are within the same analysis window, the one closest 
to the scheduled study day and with non-missing value will be used for that analysis visit.  In 
case of equal number of days to the scheduled visit date, the later assessment with non-missing 
value will be used for that given analysis visit. The assessment to be used is determined by using 
the following hierarchy (in decreasing order): 
1) The assessment with non-missing value 
2) The assessment closest to the target study day 
3) The latter assessment, if >=2 observations are equally close to the target study day 
3.4.5. 
Multiplicity Control 
To control the family-wise error rate, a gatekeeping procedure will be used. 
First, the primary analysis of the mean change in blood Phe levels from baseline to Weeks 5 and 
6 in Part 2 double-blind phase will be performed in the stratum with mean percent reduction in 
blood Phe levels of ≥30% during Part 1, at the significance level of 0.05 (2-sided). If p<0.05, the 
study will be declared successful in this stratum. 
Only if the primary analysis is statistically significant, a test of the same endpoint based on the 
full analysis set (FAS) and analyses of the secondary endpoints will be performed in the 
following order:  
• Mean change in blood Phe levels from baseline to Weeks 5 and 6 in Part 2 double-
blind phase based on the FAS  
• Proportion of subjects with baseline Phe levels ≥600 μmol/L who achieve Phe levels 
<600 μmol/L at the end of the double-blind treatment period, in the stratum with 
mean percent reduction in blood Phe levels of ≥30% during Part 1 
• Proportion of subjects with baseline Phe levels ≥360 μmol/L who achieve Phe levels 
<360 μmol/L at the end of the double-blind treatment period, in the stratum with 
mean percent reduction in blood Phe levels of ≥30% during Part 1 
• Proportion of subjects with baseline Phe levels ≥600 μmol/L who achieve Phe levels 
<600 μmol/L at the end of the double-blind treatment period, based on the FAS 
• Proportion of subjects with baseline Phe levels ≥360 μmol/L who achieve Phe levels 
<360 μmol/L at the end of the double-blind treatment period, based on the FAS 
3.5. 
Changes to Protocol Specified Analysis 
Change 
Description 
1 
An additional secondary endpoint (Proportion of subjects with baseline Phe levels ≥360 
μmol/L who achieve Phe levels <360 μmol/L at the end of the double-blind treatment 
period), corresponding multiplicity control and analysis method are added. 


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4. 
PATIENT DATA 
All subjects in the Safety Analysis Set will be included in the analysis by treatment groups 
(including only participated in Part 1 as a treatment group). For subjects participating in Part 2 of 
the study, data will be further presented by the Phe reduction randomization strata 
(≥15% to <30% or ≥30%) on the FAS. Subjects will be analyzed according to the treatment 
group into which they were randomized.  
4.1. 
Patient Disposition 
The disposition of subjects, including the number of subjects screened, the number of subjects 
who received at least 1 dose of study drug in Part 1, the number of randomized subjects in Part 2, 
the number of randomized subjects who received at least 1 dose of study drug, and the number of 
subjects who prematurely discontinue study drug during Part 1 and during Part 2 (along with the 
reason for the premature termination), completed Part 2 Day 42 visit and continuing in the 
PTC923 open-label study (Study PTC923-MD-004-PKU) will be summarized. 
The number of subjects randomized will also be summarized by region, country, and site. 
Screen failures will be listed for each inclusion/exclusion criteria that were not met. 
4.2. 
Data Sets Analyzed 
A summary of the number of subjects for each analysis dataset will be provided by treatment 
groups.  
The number of subjects with major protocol deviation will be summarized for both FAS and 
Safety populations. 
4.3. 
Demographics and Baseline Characteristics 
Demographics and background disease characteristics will be summarized with descriptive 
statistics by treatment groups. Summary statistics for categorical variables will include frequency 
counts and percentages and for continuous variables will include mean, standard deviation, 
minimum, median, and maximum. 
Demographics and baseline characteristics variables include: 
• Age at screening (year) and by categories (0 to <6 months, 6 to <12 months, 
12 months to <2 years, 2-5 years, 6-11 years, 12-18 years, ≥18 years) and Pediatric 
(<18 years, ≥18 years) 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Australian Aboriginal or Torres Strait 
Islander, and Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• Screening weight 
• Screening height 
• Screening body mass index (BMI) calculated from weight and height 


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4.4. 
Disease Characteristics 
PKU history and phenylalanine hydroxylase genotype information (including newly assessed or 
previously done) will be descriptively summarized by treatment group. 
A summary will be provided by treatment groups regarding if subjects have previously received 
treatment with BH4 or pegvaliase-pqpz, if the subjects previously responded to BH4 challenge, 
and if the subjects are receiving treatment with BH4 or pegvaliase-pqpz at the time of screening. 
The data collected during the washout period (including the blood Phe data and 3-day diet 
records) will be summarized by treatment group. 
Classical PKU (ie, blood Phe birth levels ≥1200 µmol/L and or historical evidence of Phe 
concentrations ≥1200 µmol/L in their medical history) will be summarized by treatment groups. 
4.5. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Medical history information will be descriptively summarized by treatment group. 
4.6. 
Prior and Concomitant Medications and Non-Drug Treatments 
Any treatments (including nutritional supplements) and over-the-counter medications (including 
herbal medications) taken by a subject 30 days prior to the Screening Visit and during the course 
of the study and the reason for use of the medication will be recorded in the electronic case 
report form (medications and prescribed dietary supplements). Data will be coded using the 
World Health Organization Drug Dictionary. Medication stopped before Part 1 Day 1 will be 
counted as prior medications, and medication that had not stopped by Part 1 Day 1 or started on 
or post Part 1 Day 1 will be reported as concomitant medications. Prior medications and 
concomitant medications will be summarized descriptively by treatment group. 
Procedure data will be summarized descriptively by treatment group. 
4.7. 
Extent of Exposure 
The extent of exposure to study drug is defined as the last dose date minus the first dose 
date +1 day within each part of the study. Data will be summarized by treatment groups for each 
part of the study. 
The overall extent of exposure is the sum of the exposure in both parts of the study. 
4.8. 
Treatment Compliance 
Compliance will be assessed in terms of the percentage of study day that the study drug 
administrated as prescribed. 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 
𝐴𝑐𝑡𝑢𝑎𝑙 𝑑𝑎𝑦𝑠 𝑑𝑟𝑢𝑔 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 𝑎𝑠 𝑝𝑟𝑒𝑠𝑐𝑟𝑖𝑏𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑑𝑎𝑦𝑠 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑
× 100 
This will be calculated by part for each dose level and overall. Data will be summarized 
descriptively by treatment group. 


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4.9. 
Quality of Life Baseline Assessments 
Phenylketonuria Quality of Life Questionnaire 
In this study, a PKU-specific version of the quality of life (QOL) questionnaire will be 
performed at Part 2 Day 1 (predose). This will only be analyzed on FAS. Four versions of the 
Phenylketonuria Quality of Life Questionnaire (PKU-QOL) will be utilized dependent on subject 
age: Parent PKU-QOL (6 to 8 years old, 54 items), Child PKU-QOL (9 to 11 years old, 
40 items), Adolescent PKU-QOL (12 to 17 years old, 58 items), and Adult PKU-QOL 
(≥18 years, 65 items). This will be conducted using the tool in one of the following validated 
languages: English (British or American), Turkish, Dutch, German, Spanish, Italian, Portuguese, 
or French. Conduct of the PKU-QOL will not be required for subjects whose primary language is 
not one of the available validated languages. 
The PKU-QOL questionnaire comprise of 4 modules: 1) PKU symptoms, 2) PKU in general, 
3) administration of Phe-free protein supplements, and 4) dietary protein restriction. The recall 
period focuses on the past 1 week for all sections except for ‘patient’s general feeling’ where the 
recall period was ‘in general’. 
The domain scores within the 4 modules will be calculated by the three-step scoring instruction 
described in the PKU-QoL manual (Mapi 2015) in a range from 0 to 100 for each of the four 
version questionnaires. The following interpretation rules were applied for all domain scores in a 
range from 0 to 100: for symptom scores, a higher score is associated with more frequent 
symptoms; for adherence scores, a higher score is associated with a poorer adherence; for other 
scores, a higher score is associated with a greater impact (Alptekin 2018). The domain scores 
will be summarized by age categories (corresponds to the 4 versions of the PKU-QOL) and 
treatment group. 
European Quality of Life – 5 Dimensions 
The European QOL-5 dimensions (EQ-5D) questionnaire will be performed at Part 2 Day 1 
(predose). In this study, 3 versions of the EQ-5D will be used: EQ-5D-Y Proxy Version 1 
(3 to 7 years), EQ 5D-Y (8 to 15 years), and EQ-5D-5L (≥16 years) measuring 5 domains of 
health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (EuroQoL 
Research Foundation 2019, EuroQol Research Foundation 2020). Data will be summarized by 
EQ-5D versions and by treatment groups for index score which is derived based on country-
based value set and each of the five health domains (refer to Appendix 3 for detail on deriving 
index score based on country-based value set). 
For subjects aged ≥16 years, the EQ-5D-5L will be used. For the EQ-5D-5L, subjects will rate 
their own health on each dimension, with each dimension having 5 levels of severity. 
Dimensions include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
For children/adolescents aged 8 to 15 years, the EQ-5D-Y will be used. This is a child 
friendly- version of the EQ-5D-5L. Dimensions include mobility, looking after myself, doing 
usual activities, having pain or discomfort, and feeling worried, sad, or happy. The younger 
subjects will be asked to indicate his/her health state by ticking the box next to the most 
appropriate statement in each of the 5 dimensions. The instructions and wording are more 
suitable for children and adolescents. 
For children aged 3 to 7 years, a proxy version of the EQ-5D-Y will be used. This is for use 
when children or adolescents are mentally or physically incapable of reporting on their own 


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health-related QOL. For a proxy version, a caregiver who knows the child or adolescent well will 
rate the health-related QOL in their opinion. 


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5. 
EFFICACY ANALYSIS 
5.1. 
Primary Endpoint Analysis 
The primary efficacy endpoint is the mean change in blood Phe levels from baseline to Weeks 5 
and 6 (average over a 2-week period) in the Part 2 double-blind phase. 
The null hypothesis is that the mean change in blood Phe levels from baseline to Weeks 5 and 6 
is the same between PTC923 arm and placebo arm, versus the alternative that they are different, 
at the 2-sided 0.05 significance level.  
A mixed model repeated measures (MMRM) model will be used to analyze the blood Phe level 
data in the stratum with mean percent reduction in blood Phe levels of ≥30% during Part 1. The 
response variable is the change from baseline in blood Phe measured at post-baseline 
assessments for each subject.  All blood Phe measurement will be assigned to an analysis visit 
according to the analysis visit window described in Section 3.4.4. The model will include fixed 
effects for treatment, baseline blood Phe, baseline Phe level (<600 μmol/L or ≥600 μmol/L), visit 
(categorical, equivalent to the 2-week dosing periods), and visit-by-treatment interaction. In 
addition, subject will be included as random effect. An unstructured within-subject covariance 
structure will be assumed. If the model does not converge under the unstructured covariance 
matrix, the following covariance structures will be employed in order until convergence is 
reached: heterogeneous Toeplitz, heterogeneous Compound Symmetry, heterogeneous first-order 
autoregressive, Toeplitz, Compound Symmetry, and first-order autoregressive. The least squares 
(LS) mean estimate, confidence interval, and 2-sided p-value will be presented. 
If p-value from the above analysis is less than 0.05, the same MMRM model as above will be 
used on the FAS, with the addition of a fixed effect for blood Phe reduction during Part 1 
(≥15% to <30%, or ≥30%). 
5.2. 
Sensitivity Analysis 
5.2.1. 
Analysis on PP Analysis Set 
The above MMRM models in Section 5.1 for the primary endpoint will also be performed on the 
PP Analysis Set. 
5.2.2. 
Different Methods to Handle Missing Data 
For the above primary/secondary analysis, MMRM model implicitly imputes the missing data 
based on the assumption of missing at random (MAR).  In the following sensitivity analyses, the 
missing data issues will be handled explicitly through multiple imputations (MI) (Rubin 1987, 
Ouyang 2017). The details on SAS codes are provided in Appendix 2. 
• MI under an assumption of MAR 
• Control-based imputation: for patients in the PTC923 group who discontinued early, 
their response distribution after discontinuation would follow the distribution in 
control group 
• Tipping-point analysis: to assess how severe departures from MAR must be in order 
to overturn the conclusion of the primary analysis 


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5.2.3. 
Handling Subjects with Potential Change of Diet 
The study requires subjects to continue their usual diet without modification (i.e., no change in 
daily Phe consumption). To explore the impact of potential change of diet on the treatment effect 
during Part 2 double-blind phase, a subject’s change of Phe consumption (monitored by weekly 
3-day diet records), is defined as an increase of more than 100% or a decrease of more than 50% 
over any two consecutive weeks in Part 2 comparing to screening period. Note the Phe 
consumption in screening period is calculated by averaging weekly 3-day diet records collected 
during the entire screening period. If it is determined that more than 5% of subjects are 
experiencing change of diet, then the blood Phe values collected after the two consecutive weeks 
will be set as “missing” for those subjects, and the data will be analyzed by the same MMRM 
model as in primary analysis with and without MI for missing values. 
5.2.4. 
T-test with Completers 
A t-test will be used to compare the mean change from baseline in blood Phe measured to Weeks 
5 and 6 (average over a 2-week period) in Part 2 between PTC923 and placebo.  The analysis 
will only include subjects who have observations on the endpoint. 
5.2.5. 
Analysis of Phe levels at Steady State  
The same MMRM method as in primary analysis will be used to compare the mean change from 
baseline in blood Phe measured to Weeks 5 and 6, except the average over a 2-week period 
(including Weeks 1-2, 3-4 and 5-6) will be calculated by using the analysis visit window of the 
last two days in each 2-week period. 
5.3. 
Subgroup Analysis 
The change in blood Phe levels from baseline to Weeks 5 and 6 will be summarized in the 
following subgroups, in the stratum with mean percent reduction in blood Phe levels of ≥30% 
during Part 1 and FAS: 
• Gender (Male, Female) 
• Age:  
− <18 years, ≥18 years 
− 2 to 5 years, 6 to 11 years, 12 to 18 years, ≥18 years 
• Respond to BH4 challenge (Yes, No) 
• Subjects who enter the study and were receiving supplementation treatment 
(pegvaliase-pqpz, BH4, or none) 
• Biochemically diagnosed classical PKU (Yes, No) 
• Baseline Phe level of Part 2 
− ≥600 μmol/L, <600 μmol/L 
− ≥360 μmol/L, <360 μmol/L 


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• Change of diet (Yes, No) during Part 2 
− Follow the definition of “Change of Diet” in Section 5.2.3 
• Geographical region (North and Latin America, Europe, Asia Pacific) 
• Country 
For the FAS dataset, one additional subgroup analysis will be performed: 
• Phe reduction in Part 1 (≥15% to <30%, ≥30%). 
5.4. 
Secondary Endpoints Analysis 
Blood Phe levels are collected at the timepoints indicated in Table 4 and Table 5 . The 
concentration data in Part 1 (collected on Days -1, 1 (predose), 5, 10, and 14 of the treatment 
period and on Days 15, 19, 24, and 28 during the washout period), the mean baseline (mean of 
Day -1 and Day 1 predose), the mean 2-week treatment (mean of Part 1 Days 5, 10, and 14) data 
will be descriptively summarized by treatment group. The mean change and percent change from 
the mean baseline will be descriptively summarized too. The following categories (reduction 
<15%, ≥15% to <30% or ≥30%, value <360 μmol/L or ≥360 μmol/L, and value <600 μmol/L 
and ≥600 μmol/L at baseline or post-treatment period) will be summarized with number of event 
and percentage by treatment group. 
The concentration data in Part 2 (collected on Days -1, 1 (predose), 5, 10, 14, 19, 24, 28, 33, 38, 
and 42), the mean baseline (mean of Day -1 and Day 1 predose), the mean of each 2-week 
treatment of each dose level (the average blood Phe levels of Day 5, 10 and 14 is for the 2-week 
period of PTC923 20 mg/kg daily, Day 19, 24 and 28 is for the 2-week period of PTC923 
40 mg/kg daily, and Day 33, 38 and 42 is for the 2-week period of PTC923 60 mg/kg daily) will 
be descriptively summarized by treatment group, along with the mean change and percent 
change from the mean baseline in Part 2. The following categories (reduction <15%, ≥15% to 
<30% or ≥30%, value <360 μmol/L or ≥360 μmol/L, and value <600 μmol/L and ≥600 μmol/L 
at baseline or post each 2-week treatment periods) will be summarized with number of event and 
percentage by treatment group. 
Graphs will be presented to display of the mean concentration data over time by treatment 
groups. 
The Phe data collected for the PK subgroup subjects will be descriptively summarized by 
treatment group. 
Proportion of Subjects with Baseline Phe Levels ≥600 μmol/L who Achieve Phe Levels <600 
μmol/L at the end of the Double-Blind Treatment Period 
A binary variable (Achieved versus Not Achieved) will be analyzed by a chi-square test in the 
stratum with mean percent reduction in Phe levels of ≥30% during Part 1. The odds ratio of 
PTC923 versus placebo along with the 95% CI will be presented. In order to analyze the data in 
FAS, a Cochran-Mantel-Haenszel test stratified by randomization stratification factor (Phe 
reduction during Part 1: ≥15% to <30% or ≥30%) to compare PTC923 versus placebo. 
Proportion of Subjects with Baseline Phe Levels ≥360 μmol/L who Achieve Phe Levels <360 
μmol/L at the end of the Double-Blind Treatment Period 


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The same methods as above will be used for the analysis of this endpoint. The odds ratio of 
PTC923 versus placebo along with the 95% CI will be presented. 
PTC923 Dose Response on Reducing Blood Phe Levels in Subjects with PKU 
Mean change and percent change from baseline in mean blood Phe levels at each PTC923 dose 
level (ie, each 2-week period in Part 2) will be assessed using the MMRM model described for 
the primary endpoint. The LS means, treatment effect estimate, and 95% CI will be presented. 
PK Analysis for the PK SubStudy 
Descriptive statistics of plasma concentrations of sepiapterin and BH4 (n, arithmetic mean, SD, 
coefficient of variation (CV) % of arithmetic mean, median, minimum, maximum, geometric mean, 
and CV % for the geometric mean) will be presented by age group for both Part 1 and Part 2. 
The CV % for the geometric mean will be calculated using the following formula:  
𝐶𝑉 (%) = 100 ∗√𝑒𝑆𝐷2 −1 
where SD is the standard deviation of the natural-log transformed data. 
For sepiapterin (PTC923), all concentration values below the lower limit of quantification 
(LLOQ) will be set to zero.  For BH4, all BLQ concentrations will be set to ½ of LLOQ for 
predose samples and “missing” for 4 hours postdose samples.   
For Part 1, for age ≥2 years old, PK parameter estimates for sepiapterin and BH4 will be 
calculated using non-compartmental analysis (NCA) of the plasma concentration versus time 
data utilizing actual sample collection date and time. The following PK parameters, Cmax, Tmax, 
T1/2, AUC0-24h, AUC0-inf, CL/F, and Vz/F for sepiapterin, baseline corrected and uncorrected BH4 
will be descriptively summarized by age groups (2-5, 6-11, ≥12 years old). For <2 years old, PK 
parameters will not be derived.  For Part 2, the observed PK parameters such as Cmax, Tmax 
will be provided using NCA, if data permits. 
PK parameters will be summarized by age group for Part 1, and Part 2 if data permits.  
5.5. 
Exploratory Endpoints 
Tyrosine Concentrations 
Blood Tyr levels are collected at the same timepoints as blood Phe as indicated in Table 4 and 
Table 5. VAMS clamshells containing 2 sample sticks will be used to collect blood Tyr for each 
timepoint (ie, in duplicate). Duplicative sampling for a sample collection timepoint is being used 
to ensure that at least one sample contains sufficient blood volume necessary for an accurate 
measurement of blood Tyr for that collection. The Part 1 and Part 2 Tyr concentration data and 
the Phe:Tyr ratio at each timepoint will be summarized similarly to Phe concentration data, and 
the same way of calculating the mean baseline and mean 2-week treatment period data, along 
with mean change and percent change from mean baseline. Graphical illustration will be 
provided similarly as blood Phe data. 
The Tyr data collected for the PK subgroup subjects will be descriptively summarized by 
treatment group. 


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6. 
SAFETY ANALYSES 
All subjects in the Safety Analysis Set will be included in the analysis by treatment groups. 
Subjects will be analyzed according to actual treatment received. 
6.1. 
Adverse Events 
Adverse events (AEs) will be coded using MedDRA. The severity of AE will be graded using 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (refer to the study 
manual). 
Only those AEs that are treatment-emergent will be included in summary tables. Two sets of 
treatment-emergent events will be considered: 
• Part 1 TEAEs, which includes all AEs occurring after first dose in Part 1 but before 
first dose in Part 2 
• Part 2 TEAEs, which includes all AEs after first randomized dose in Part 2. For Part 2 
TEAEs, data will be further presented by each of the dose levels (2-week dosing 
period) and overall (all 6 weeks) by treatment group. 
All AEs, treatment-emergent or otherwise, will be presented in subject data listings. An overview 
table of TEAEs, including number of subjects with TEAEs, treatment-emergent serious adverse 
events (SAEs), deaths, TEAEs classified as CTCAE Grade 3 or higher, study drug related 
TEAEs, TEAEs leading to study drug withdrawal will be provided for each treatment group. The 
following summaries will be produced for the TEAEs by treatment groups: 
• Incidence of TEAEs by Preferred Term (PT) in descending order 
• Incidence of TEAEs by System Organ Class (SOC) and PT 
• Incidence of treatment-related TEAEs by SOC and PT 
• Incidence of TEAEs by SOC, PT, maximum CTCAE grade 
• Incidence of treatment-related TEAEs by SOC, PT, and maximum CTCAE grade 
In the summary tables, subjects may be counted under multiple SOCs and PTs, but for each SOC 
and PT, subjects are only counted once. If a subject has the same AE on multiple occasions, the 
highest severity (5=fatal, 4=life-threatening, 3=severe, 2=moderate, 1=mild) recorded for the 
event will be presented and the highest drug relationship (1=‘Unrelated’, 2=‘Unlikely to be 
Related’, 3=‘Possibly Related’, 4=‘Probably Related’), reclassified into Related (‘Possibly 
Related’, ‘Probably Related’) or Not Related (‘Unrelated’, ‘Unlikely to be Related’), will be 
presented on the respective tables. 
The following summaries will also be presented for the treatment-emergent SAEs: 
• Incidence of treatment-emergent SAEs by SOC and PT 
• Incidence of treatment-related treatment-emergent SAEs by SOC and PT 
In addition, the number and percentage of subjects with TEAEs and treatment-related TEAEs 
leading to discontinuation from study treatment will also be summarized by SOC and PT for 
each treatment group. 


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6.2. 
Vital Signs and Weight 
Vital signs will be collected at the Screening Visit Part 1 Day 1, Part 2 Days 1 and 42, and Early 
Termination Visit (ETV) (if applicable). Vital signs will be collected both predose and 2 hours 
postdose on Part 1 Day 1 and Part 2 Day 1; for all other timepoints, they will be taken at any 
time during the visit. Weight will be collected at the Screening Visit, Part 1 Day 1, Part 2 Days 1 
and 42, and ETV (if applicable). 
The vital signs assessments (including blood pressure, pulse, respiratory rate, and temperature) 
and weight (and BMI) will be descriptively summarized for all the specified timepoints by 
treatment group, including the change from corresponding baseline, for Part 1 and Part 2 
separately. 
6.3. 
Physical Examination 
A full physical examination will be performed predose at the Screening Visit, Part 1 Day 1, 
Part 2 Days 1 and 42, and ETV (if applicable). General appearance; dermatologic; head, eyes, 
ears, nose, and throat (HEENT); lymphatic; cardiovascular; respiratory; gastrointestinal; 
musculoskeletal; neurological; and skin parameters will be assessed. 
Physical examination results will be listed in subject listings only. 
6.4. 
Electrocardiogram 
Twelve-lead ECGs are to be performed at Part 1 Day 1 (predose) and Part 2 Day 42/EOS for all 
subjects and at the ETV (if applicable). Additional 12-lead ECGs will be performed for all 
subjects participating in the PK substudy on Part 1 Day 1 at 2, 4, 6, and 8 hours postdose. 
The ECG parameters (RR interval, PR interval, QRS interval, QT interval, and QTc interval) and 
the overall interpretation of ECG (normal, abnormal clinically significant, or abnormal not 
clinically significant) will be summarized descriptively. Part 1 Day 1 (predose) will be 
summarized for Part 1 Safety Analysis Set, and along with all the other timepoints data collected 
for PK substudy will be summarized for the PK Analysis Set. For triplicate measurements, the 
mean of the three values will be used to summarize. 
Categorical analysis of the maximum post-baseline value in QTc interval will be performed to 
summarize the number and percentage of subjects meeting or exceeding the criteria below.  
• • Absolute QTc interval prolongation: 
−  - QTc interval > 450 
−  - QTc interval > 480 
−  - QTc interval > 500  
• • Change from baseline in QTc interval:  
− - QTc interval increases from baseline >30  
− - QTc interval increases from baseline >60 
A listing of all abnormal values will be provided. 


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6.5. 
Central Laboratory Values 
Blood and urine samples for clinical chemistry, hematology, and urinalysis will be collected at 
the timepoints in Table 2 and Table 3. Laboratory parameters that will be assessed will include, 
but not be limited to: 
• Hematology: hematocrit, hemoglobin, platelet count, red blood cell count (RBC), 
white blood cell count (WBC), WBC differential, B12, and iron 
• Clinical chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, blood urea nitrogen, calcium, CO2, chloride, serum creatinine, 
gamma glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphate, 
potassium, sodium, total bilirubin, direct bilirubin, total cholesterol, total protein, and 
uric acid 
• Urinalysis: bilirubin, glucose, ketones, occult blood, pH, protein, specific gravity, 
urobilinogen, microscopic examination of WBC, RBC, and epithelial cells 
• Pregnancy testing: serum human chorionic gonadotrophin (hCG) (at Screening), urine 
hCG (at Screening and Part 2 Day 1) 
Clinical laboratory test results and laboratory marked abnormalities using pre-defined 
abnormality criteria will be descriptively summarized for all the specified timepoints by 
treatment group, for Part 1 and Part 2 separately. In addition, shift tables on abnormality for each 
laboratory parameter from corresponding baseline to each of the post-treatment visit will be 
provided, for Part 1 and Part 2 separately. 
Categorical analysis of the maximum post-baseline value in lab parameters of liver function test 
will be performed to summarize the number and percentage of subjects meeting or exceeding the 
criteria below, for Part 1 and Part 2 separately.  
 
Category 
Criteria 
Elevated Aminotransferases 
• ALT >3xULN 
• AST >3xULN 
• ALT or AST > 3 x ULN 
Elevated Bilirubin 
• Total Bilirubin >2xULN 
• ALT or AST >3xULN and Total Bilirubin >2xULN 
Elevated Alkaline Phosphatase 
• ALP >1.5xULN 
• ALT or AST >3xULN, Total Bilirubin >2xULN, and ALP 
>1.5xULN 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; 
ULN, upper limit of normal 
6.6. 
Contraception and Pregnancy Reporting 
A listing will be provided. 


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6.7. 
Diet Monitoring: 3-Day Diet Records 
Subjects will maintain 3-day diet records during the study as indicated in Table 2 and Table 3. 
The 3-day diet records will be completed over 3 consecutive days within each period and 
collected weekly. The total Phe consumption during the 3-day period calculated by the dietician 
and daily total Phe consumption (mg/day) and daily Phe consumption (mg/kg/day) will be 
descriptively summarized by week and by treatment group, including the change from baseline 
for Part 1 and Part 2 separately, where baseline will be calculated by averaging weekly 3-day 
diet records collected during the entire screening period. Graphical illustration will be provided. 


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7. 
MOCK TABLES, LISTINGS, AND GRAPHS 
The study tables, listings, and graphs shells will be provided in a separate document. 


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8. 
REVISION HISTORY 
Version Number 
Date 
Description 
1.0 
13APR2023 
Initial release 


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APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Table 3: 
Schedule of Assessments (Screening Period) 
Evaluation 
Screening Period 
Screening Visit 
Supplementation Washout Period 
(Max 30 Days) a 
Study Day 
Up to 45 days 
Pegvaliase-pqpz 
30 days 
BH4 
7 days 
Informed consent/assent 
X 
 
 
PAH genotypingb 
X 
 
 
Confirm eligibility 
X 
 
 
Demographics 
X 
 
 
Medical historyc 
X 
 
 
In-clinic visit 
X 
 
 
Vital signs, weight, and heightd 
X 
 
 
Physical examinatione 
X 
 
 
Clinical laboratory testsf 
X g 
 
 
Serum/urine pregnancy test h 
X 
 
 
Concomitant medications i 
Collected throughout the study 
Adverse events j 
Collected throughout the study 
Blood Phe/Tyr levels k 
X 
Day 1, 20, 30 
Day 1, 4, 7 
Consistent diet/diet monitoring/3-day 
diet record distribution/collection l 
X 
X 
X 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate 
aminotransferase; BH4, tetrahydrobiopterin; BUN, blood urea nitrogen; ETV, Early Termination Visit; GGT, gamma 
glutamyl transferase; HEENT, head, eyes, ears, nose, and throat; LDH, lactate dehydrogenase; PAH, phenylalanine 
hydroxylase; Phe, phenylalanine; RBC, red blood cell; SAE, serious adverse event; Tyr, tyrosine; WBC, white blood 
cells  
a BH4 treatment (eg, sapropterin dihydrochloride, KUVAN) and pegvaliase-pqpz will be discontinued 24 hours prior to 
starting the Supplementation Washout. Subjects will remain off supplementation throughout the study. 
b To be performed unless documented in subject’s medical history. 
c Includes specific information related to any prior or existing medical conditions or surgical procedures involving the 
following systems: dermatologic, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, 
neurological, and skin. Newborn Phe concentrations and the 3 most recent Phe concentrations will be collected. 
d Includes blood pressure, pulse, respiratory rate, and temperature. Obtain vital signs prior to collection of any 
laboratory samples (including Phe). Vital signs should be collected prior to blood Phe/Tyr collection at the Screening 
Visit. If feasible, subjects will rest for 5 minutes in a supine position before vital signs are assessed. Height will be 
collected only at Screening. 
e Conduct a complete physical examination of general appearance, dermatologic, HEENT, lymphatic, cardiovascular, 
respiratory, gastrointestinal, musculoskeletal, neurological, and skin parameters. 
f Includes clinical chemistry panel (albumin, AP, ALT, AST, B12, BUN, calcium, CO2, chloride, serum creatinine, 
GGT, glucose, iron, LDH, phosphate, potassium, sodium, total bilirubin, direct bilirubin, total cholesterol, total protein, 
uric acid); hematology panel (hematocrit, hemoglobin, platelet count, RBC, WBC, WBC differential); and urinalysis 
(bilirubin, glucose, ketones, occult blood, pH, protein, specific gravity, urobilinogen and microscopic examination of 
WBC, RBC, and epithelial cells). Subjects should be fasted prior to collection of samples (minimum of 4 hours for 
subjects <6 years and minimum of 8 hours for subjects ≥6 years). 
g eGFR should be calculated for all subjects. 
h Pregnancy tests required for all women of childbearing potential (Protocol Section 8.1.5); serum testing to occur at 
the Screening Visit, and urine testing to occur during all other in-clinic visits. Any positive urine pregnancy test should 
be confirmed by a serum pregnancy test. 
i Record all treatments (including nutritional supplements) and over-the-counter medications (including herbal 
medications) starting from 30 days prior to Screening through the study. 


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j AEs will be collected from the time of informed consent and/or assent (as applicable) until completion of Part 2 
Day 42 or ETV (for subjects who discontinue prematurely or are considered non-responders after Part 1, subjects will 
continue to be followed for 30 days after last dose for SAEs). Specific information related to previous use of 
sapropterin or pegvaliase-pqpz should be collected (ie, details on duration, dose, if discontinued, the reason(s) why, 
and if a subject is known to be BH4-responsive). If a subject elects not to continue into Study PTC923-MD-004-PKU, 
they should be followed up 30 days after their Day 42 visit for collection of AEs. 
k Blood Phe/Tyr levels via dried blood sample will be measured at each timepoint indicated (Protocol Table 12). 
Samples will be collected after fasting or no earlier than 3 hours postprandial and at approximately the same time of 
day. Blood Phe/Tyr samples can be collected while the subject is either in the clinic or at home. Samples obtained at 
home will be shipped to the study site. Analysis of the screening blood Phe level can be performed at the site’s local 
laboratory for determination of eligibility; however, a separate sample for blood Phe/Tyr should still be sent to the 
central lab for the screening timepoint. Vital signs should be collected prior to blood Phe/Tyr collection at the 
Screening Visit. 
l Subjects are to maintain a consistent diet (with respect to Phe intake) during the study. A dietician will monitor each 
subject’s diet to calculate Phe consumption and to have regular contact with subjects. 3-day diet records will be given 
to subjects at the screening visit and are to be completed weekly throughout the study. The 3-day diet records will be 
collected weekly throughout the study. 


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Table 4: 
Schedule of Assessments (Part 1 and Part 2 Periods) 
Evaluation 
Part 1-Open-Label Responsiveness Test 
Part 2-Randomized, Placebo-Controlled, Double-Blind 
Treatment Period 
ETV 
u 
PTC923 Open-Label Treatment 
0 to <6 months: 7.5 mg/kg 
6 to <12 months: 15 mg/kg 
12 months to <2 years: 30 
mg/kg 
≥2 years: 60 mg/kg 
14 Days 
PTC923 
Washouta 
Minimum of 
14 Days 
PTC923 
20>>40>>60 mg/kg vs Placebo) 
42 Days (6 Weeks) 
Study Day 
-1 
1 
2 
5 
10 
14 
19 
24 
28b -1 
1 
5 
10 
14 
19 
24 
28 
33 
38 
42/ 
EOS 
 
Confirm eligibility 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
In-clinic visit 
 
X 
Xd 
 
 
Xd 
 
 
 
 
X 
 
 
Xd 
 
 
Xd 
 
 
X 
X 
Virtual visit 
 
 
 
 
 
X 
 
 
Xe 
 
 
 
 
X 
 
 
X 
 
 
 
 
At home assessment/ procedure 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsf, weight  
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
X 
X 
Height h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X u 
 
ECGsi 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical examinationj 
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
X 
X 
Clinical laboratory testsk 
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
Xl 
X 
Serum/urine pregnancy test m 
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
X 
X 
Concomitant medicationsn 
Collected throughout the study 
Adverse eventso 
Collected throughout the study 
Blood Phe/Tyr levels (DBS)p 
Sample to be taken at all timepoints 
Blood for PK substudyq 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Consistent diet/diet monitoring 
/3-day diet recordr 
 
X 
 
X 
X 
QOL Assessmentss 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 


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Evaluation 
Part 1-Open-Label Responsiveness Test 
Part 2-Randomized, Placebo-Controlled, Double-Blind 
Treatment Period 
ETV 
u 
PTC923 Open-Label Treatment 
0 to <6 months: 7.5 mg/kg 
6 to <12 months: 15 mg/kg 
12 months to <2 years: 30 
mg/kg 
≥2 years: 60 mg/kg 
14 Days 
PTC923 
Washouta 
Minimum of 
14 Days 
PTC923 
20>>40>>60 mg/kg vs Placebo) 
42 Days (6 Weeks) 
Study Day 
-1 
1 
2 
5 
10 
14 
19 
24 
28b -1 
1 
5 
10 
14 
19 
24 
28 
33 
38 
42/ 
EOS 
 
Dose study drug 
 
Daily for 14 days 
 
 
 
 
Daily for 42 days (6 weeks) 
 
Dispense study drug 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Collect study drug, assess 
compliance 
 
 
 
 
 
Xt 
 
 
 
 
Xt 
 
 
Xt 
 
 
Xt 
 
 
Xt 
Xt 
Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; COVID-19, coronavirus 
disease 2019; DBS, dried blood sample; ECG, electrocardiogram; EOS, End of Study; ETV, Early Termination Visit; EQ-5D, European Quality of Life - 5 
Dimensions; EQ-5D-5L, 5-Level European Quality of Life - 5 Dimensions; EQ-5D-Y, European Quality of Life - 5 Dimensions for Youth; GGT, gamma glutamyl 
transferase; HEENT, head, eyes, ears, nose, and throat; LDH, lactate dehydrogenase; Phe, phenylalanine; PK, pharmacokinetics; PKU-QOL, Phenylketonuria-
quality of life; QOL, quality of life; RBC, red blood cell; SAE, serious adverse event; Tyr, tyrosine; VAMS, volumetric absorptive microsampling; WBC, white blood 
cells 
a PTC923 washout period consists of a minimum 14-day washout (may be longer depending on timing for determination of response). During the PTC923 
washout period, study drug will not be administered, and compliance will not be assessed.  
b Visit can occur at any point on or between Day 28 to Day 35. 
c Randomization can occur anytime during the PTC923 washout after confirmation of meeting PTC923-responsiveness of blood Phe reduction ≥15% and 
scheduling of Part 2 Day 1 in-clinic visit. 
d In-clinic visits will occur for all subjects on Part 1 Day 1, Part 2 Day 1, and Part 2 Day 42. Only for subjects participating in the PK substudy, additional in-clinic 
visits will also occur on Part 1 Day 2, Part 1 Day 14, Part 2 Day 14, and Part 2 Day 28 to obtain PK blood draws. There is a ±2-day window permitted for the Part 2 
Day 42 visit. Subject should continue treatment until the Day 42 (±2 days) Phe sample has been collected. For subjects participating in the PK sub-study, if an in-
clinic visit is scheduled for PK blood sampling, doses will be administered at the clinic with a meal. 
e Telephone call to confirm eligibility for continued participation and to schedule either Part 2 Day 1 visit or ETV. 
f Includes blood pressure, pulse, respiratory rate, and temperature. Obtain vital signs prior to collection of any laboratory samples (including Phe). If feasible, 
subjects will rest for 5 minutes in a supine position before vital signs are assessed. Vital signs will be collected both predose and 2-hours postdose on Part 1 Day 1 
and Part 2 Day 1; for all other timepoints, they will be taken at any time during the visit but prior to collection of any laboratory samples (including Phe). For 
subjects participating in the PK sub-study, windows for study days where PK samples are taken are presented in Protocol Table 17. For all other timepoints, 
Protocol Table 2 should be followed. 
g To be completed prior to initial dosing and at additional timepoints where indicated (eg, 2-hours post-dose vital signs). 
h Height should only be measured for subjects <18 years of age (at time of visit) at the indicated visits.  
i If feasible, subjects will rest for 5 minutes in a supine position before ECG is performed. Twelve-lead ECGs are to be performed at Part 1 Day 1 (predose) for all 
subjects, Part 2 Day 42/EOS, and at the ETV (if appropriate). Additional 12-lead ECGs will be performed for all subjects participating PK substudy at Part 1 Day 1 
at 2, 4, 6, and 8 hours postdose. Electrocardiograms will be performed in triplicate, with each read taken at least 1 minute apart. For subjects participating in the 
PK substudy, windows for study days where PK samples are taken are presented in Protocol Table 18. For all other timepoints, Protocol Table 2 should be 
followed. 


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j Conduct a complete physical examination of general appearance, dermatologic, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, 
musculoskeletal, neurological, and skin parameters.  
k Includes clinical chemistry panel (albumin, AP, ALT, AST, B12, BUN, calcium, CO2, chloride, serum creatinine, iron, GGT, glucose, LDH, phosphate, potassium, 
sodium, total bilirubin, direct bilirubin, total cholesterol, total protein, uric acid); hematology panel (hematocrit, hemoglobin, platelet count, RBC, WBC, WBC 
differential); and urinalysis (bilirubin, glucose, ketones, occult blood, pH, protein, specific gravity, urobilinogen and microscopic examination of WBC, RBC, and 
epithelial cells). Subjects should be fasted prior to collection of samples (minimum of 4 hours for subjects <6 years and minimum of 8 hours for subjects ≥6 years). 
l eGFR should be calculated (all subjects). 
m Pregnancy tests required for all women of childbearing potential (Protocol Section 8.1.5); serum testing to occur on Part 2 Day 1, and urine testing to occur 
during all other in-clinic visits (excluding in-clinic visits specifically for the PK substudy). Any positive urine pregnancy test should be confirmed by a serum 
pregnancy test. 
n Record all treatments (including nutritional supplements) and over-the-counter medications (including herbal medications) starting from 30 days prior to 
Screening until completion of Part 2 Day 42 or ETV (if applicable).  
o AEs will be collected from the time of informed consent and/or assent (as applicable) until completion of Part 2 Day 42 or ETV (for subjects who discontinue 
prematurely or are considered nonresponders after Part 1, subjects will continue to be followed for 30 days after last dose for SAEs). If a subject elects not to 
continue into Study PTC923-MD-004-PKU, they should be followed up 30 days after their Day 42 visit for collection of AEs. 
p Blood Phe/Tyr levels via dried blood sample are measured at each timepoint indicated. Day -1 and Day 1 (pre-dose) samples for both Part 1 and Part 2 should 
be taken predose. All other samples can be collected predose or postdose. Samples will be collected after fasting or no earlier than 3 hours postprandial and at 
approximately the same time of day. Samples obtained at home will be shipped to the study site or returned to the study site at the next clinic visit. Samples to be 
collected at home if no clinic visit is planned that day. If clinic visit is planned, sample should be collected in clinic where possible. A window ±1 day is permitted for 
samples collected after Day 1. For Day -1 and Day 1, samples must be collected on the specified day.         
q  
Blood samples will be collected for PK analysis from subjects participating PK substudy at the following timepoints.  
In Part 1, subjects ≥2 years, samples will be collected at Part 1 Day 1 (predose, and 0.5, 1, 2, 4, 6, 8, and 24 hours postdose). 
In Part 1, subjects <2 years, samples will be collected at Part 1 Day 1 (predose and 4 hours postdose), Part 1 Day 14 (2 and 6 hours postdose).  
In Part 2, samples will be collected on Days 1, 14, 28, and 42 at predose (approximately 24 hours post the dose on prior day, except for Day 1) and 4 hours 
postdose. 
In Part 1, for subjects participating in the PK substudy, additional small amount (~0.25 mL) of blood will be collected at the same time of PK sample collection and 
applied to VAMS for blood Phe and Tyr measurement.   
r Subjects are to maintain a consistent diet (with respect to Phe intake) during the study. At each in-clinic visit, a dietician will monitor each subject’s diet to 
calculate Phe consumption and to have regular contact with subjects. The 3-day diet records will be collected weekly throughout the study. 
s Phenylketonuria quality of life (Parent PKU-QOL [6 to 8 years]; Child PKU-QOL [9 to 11 years]; Adolescent PKU-QOL [12 to 17 years]; Adult PKU-QOL 
[≥18 years]) will be conducted using the tool in one of the following validated languages: English (British or American), Turkish, Dutch, German, Spanish, Italian, 
Portuguese, or French. Conduct of the PKU-QOL will not be required for subjects whose primary language is not one of the available validated languages. EQ-5D 
(EQ-5D-Y Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 15 years]; and EQ-5D-5L [≥16 years]) will also be conducted. 
t If feasible, study drug should be dispensed and returned at the study site. In the event that a subject cannot go into the study site (ie, due to COVID-19 
restrictions, inability to make visit), study drug may be shipped directly to the subject’s home/study site. In the event that a subject cannot go into the study site, 
unused study drug can be shipped directly back to the study site per local guidance.  
u An ETV will be performed on or between Day 28 to Day 35 for all subjects who are determined to be non-responders in Part 1, or within 2 days for any subject 
who discontinues the study prematurely during Part 1 or Part 2 for any other reason. If eGFR calculation is desired, subjects <18 years of age should have their 
height and serum creatinine measured and subjects ≥18years of age should have their serum creatinine measured. Additionally, a phone follow-up visit will occur 
30 (±3) days after the last dose of study drug to assess for SAEs. 
Note: If any unscheduled visits are performed when eGFR calculation is desired, alongside any assessments/procedures considered appropriate by the 
Investigator (or designee), subjects <18 years of age should have their height and serum creatinine measured and subjects ≥18years of age should have their 
serum creatinine measured. 


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Table 5: 
Phenylalanine/Tyr Sample Collection (Screening Period) a 
Evaluation 
Screening Period (up to 45 days) 
Screening Visit 
Supplement Washout Period (Max 30 Days) 
Study Day 
Up to 45 Days 
Pegvaliase-pqpz 
30 Days 
BH4 
7 Days 
DBS 
X 
Day 1, 20, 30 
Day 1, 4, 7 
Abbreviations: BH4, tetrahydrobiopterin; DBS, dried blood sample; Tyr, tyrosine 
a Analysis of the screening blood Phe level can be performed at the site’s local laboratory for determination of eligibility; however, a separate sample for blood 
Phe/Tyr should still be sent to the central lab for the screening timepoint.  
Table 6: 
Phenylalanine/Tyr Sample Collections (Part 1 and Part 2) a 
Evaluation 
Part 1 - Open-Label Responsiveness Test 
Part 2 - Randomized, Placebo-Controlled, Double-Blind 
Treatment Period 
PTC923 Open-Label Treatment 
14 Days 
PTC923 Washout 
Minimum 14 Days 
PTC923 20>>40>>60 mg/kg vs Placebo) 
42 Days (6 Weeks) 
Study Day 
-1 
1 
2b 
5 
10 
14 
19 
24 
28 
-1 
1 
5 
10 
14 
19 
24 
28 
33 
38 
42 
DBS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: DBS, dried blood sample; ETV, Early Termination Visit; Tyr, tyrosine  
Note: If a subject discontinues the study early, an additional DBS should be taken at the ETV. 
Samples will be collected after fasting or no earlier than 3 hours postprandial at approximately the same time of day at each collection timepoint. 
Day -1 and Day 1 samples for both Part 1 and Part 2 should be taken pre-dose. All other samples can be collected pre-dose or post-dose.  
a A window ±1 day is permitted for samples collected after Day 1. For Day -1 and Day 1, samples must be collected on the specified day. 
b For subjects participating in the PK substudy only.


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Table 7: 
Vital Signs Sampling Times (±Permitted Windows) for Subjects in PK Substudy on 
PK Sampling Days 
Scheduled Sample Time 
Permitted Time Window 
Predose 
Within 1 hour prior to dose 
Postdose 
±15 minutes 
Note: This table relates to study days where PK samples are taken. For all other timepoints, vital signs 
measurements should be taken as outlined in Table 2. 
Table 8: 
Electrocardiogram Sampling Times (±Permitted Windows) 
Scheduled Sample Time 
Permitted Time Window 
Predose 
Within 1 hour prior to dose 
≤4 hours after study drug administration 
±15 minutes 
>4 hours and ≤24 hours after study drug administration 
±30 minutes 
Note: This table relates to study days where PK samples are taken. For all other timepoints, ECGs should be 
performed as outlined in Table 2. 
Table 9: 
Pharmacokinetic Sampling Times (±Permitted Windows) for Plasma Samples for 
Part 1 
 
 
Day 1 (Hours)* 
Day 14 (Hours) 
Predose 
Postdose 
Predose 
Postdose 
0.5 
1 
2 
4 
6 
8 
24 
2 
4 
6 
Age 
(Years) 
Window 
≤60 Min 
of Dose 
±5 Min 
±10 Min 
±30 Min 
≤60 Min 
±5 Min ±10 Min 
<2 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
≥2 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Note: Additionally, a small amount (~ 0.25 mL) blood will be collected at the same time of PK sample collection and 
applied to VAMS for blood Phe/Tyr measurement. 
Table 10: 
Pharmacokinetic Sampling Times (±Permitted Windows) for Plasma Samples for 
Part 2 
 
Day 1, 14, 28, 42 
 
Predose 
Postdose (4 hours) 
Window 
Within 60 min prior to dose of the day and 
approximately 24 hours post dose of the prior day 
(except for Day 1) 
±15 min 
 


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APPENDIX 2. 
DETAILS ON SENSITIVITY ANALYSIS ON MISSING 
DATA – MULTIPLE IMPUTATION 
First, the multiple imputation will be generated using SAS PROC MI under missing at random 
(MAR). 100 imputations sets of the study data will be generated using the following variables to 
model the blood Phe values: treatment group, gender, age, classical PKU, region, the average of 
daily Phe consumption of the 3-day period at screening, and multiple Phe levels in Part 2 which 
include mean baseline Phe level, mean 2-week treatment Phe level at 20 mg/kg daily, mean 2-
week treatment Phe level at 40 mg/kg daily, Part 2 mean 2-week treatment Phe level at 60 mg/kg 
daily. 
 
PROC MI DATA=xxx OUT=xxx SEED=1275 NIMPUTE=100 
    ROUND = . . . . . .10 .10 .10 .10 .10 .10 ; 
    CLASS TRTPG1N REGION1N SEX cPKU; 
    FCS REG (P2BASE P2W1W2 P2W3W4 P2W5W6); 
    VAR TRTPG1N REGION1N SEX AGE cPKU PHECON P2BASE P2W1W2 P2W3W4 P2W5W6; 
RUN; 
Each of the simulated data will be analyzed as described in Section 3.1 for the primary endpoint. 
Then the results will be combined by SAS PROC MIANALYZE to produce the final analysis 
result. This result should be consistent with MMRM model result, indicating the robustness of 
the results from primary analysis. 
Furthermore, multiple imputation under an assumption of missing not at random (MNAR) will 
be examined. In these analyses, the multiple imputation approach will be expanded to allow for 
varying impact of missing data by: 
1) imputation completely based on the control group (ie, control-based imputation), for 
patients who discontinued the study drug. 
 
PROC MI DATA=xxx OUT=xxx SEED=1275 NIMPUTE=100 
    ROUND = . . . . . .10 .10 .10 .10 .10 .10 ; 
    CLASS TRTPG1N REGION1N SEX cPKU; 
    FCS REG (P2BASE P2W1W2 P2W3W4 P2W5W6); 
    mnar model(P2BASE P2W1W2 P2W3W4 P2W5W6 / modelobs= (TRTPG1N='Placebo')); 
    VAR TRTPG1N REGION1N SEX AGE cPKU PHECON P2BASE P2W1W2 P2W3W4 P2W5W6; 
RUN; 
2) incorporating a shift parameter in the imputation model. The range of values for the shift 
parameter will be explored to assess how severe departures from MAR must be in order 
to overturn the conclusion from the primary analysis. 
 
PROC MI DATA=&data OUT=impute&sj SEED=1275 NIMPUTE=100 
    ROUND = . . . . . .10 .10 .10 .10 .10 .10 ; 
    VAR TRTPG1N REGION1N SEX AGE cPKU PHECON P2BASE P2W1W2 P2W3W4 P2W5W6; 
    CLASS TRTPG1N REGION1N SEX cPKU; 
    FCS REG (P2BASE P2W1W2 P2W3W4 P2W5W6); 
    mnar adjust( P2BASE /shift=# adjustobs=(TRTPG1N='PTC923')); 
    mnar adjust( P2W1W2 /shift=# adjustobs=(TRTPG1N='PTC923')); 
    mnar adjust( P2W3W4 /shift=# adjustobs=(TRTPG1N='PTC923')); 
    mnar adjust( P2W5W6 /shift=# adjustobs=(TRTPG1N='PTC923')); 


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Page 43 of 45 
RUN; 
# is the shift parameter, which can range from min value to max value by increment; 
min, max and increment values will be determined based on the tipping point that 
reverses the conclusion from the primary analysis.  
 


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Page 44 of 45 
APPENDIX 3. 
EQ5D INDEX SCORE DERIVATION 
3 versions of the EQ-5D will be used: EQ-5D-Y Proxy Version 1 (3 to 7 years), EQ 5D-Y (8 to 
15 years), and EQ-5D-5L (≥16 years) measuring 5 domains of health: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. 
EQ-5D-Y Proxy Version 1 (3 to 7 years) and EQ 5D-Y (8 to 15 years) will be derived using the 
same value set, and will be derived based on Spain value set:  
• SAS_Syntaxis Spanish_eq5dY3l_value_set.sas 
For EQ-5D-5L, below are the list of documents to be used to derive the domain scores based on 
US value set: 
• US EQ-5D-5L Value Set.xlsx 
• US EQ-5D-5L SAS calculation by 5L Health State Profile.xlsx 
• US EQ-5D-5L SAS Value Set Calculation by 5L Dimension.sas 
• US EQ-5D-5L SAS Value Set Calculation by 5L Health State Profile.sas 


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Page 45 of 45 
9. 
REFERENCES 
Alptekin, IM, Koc, N, Gunduz, M and Cakiroglu, FP. The impact of phenylketonuria on PKU 
patients' quality of life: Using of the phenylketonuria-quality of life (PKU-QOL) questionnaires. 
Clin Nutr ESPEN 2018;27:79-85. 
EuroQoL Research Foundation (2019). EQ-5D-5L User Guide. 
EuroQol Research Foundation (2020). EQ-5D-Y User Guide. 
Mapi (2015). PKU-QoL Questionnaires-User Manual NX6423. 
Ouyang, J, Carroll, KJ, Koch, G and Li, J. Coping with missing data in phase III pivotal 
registration trials: Tolvaptan in subjects with kidney disease, a case study. Pharm Stat 
2017;16(4):250-266. 
Rubin, DB (1987). Multiple Imputation for Nonresponse in Surveys; John Wily & Sons, Inc. 
van Wegberg, AMJ, MacDonald, A, Ahring, K, Bélanger-Quintana, A, Blau, N, Bosch, AM, et 
al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J 
Rare Dis 2017;12(1):162. 
Vockley, J, Andersson, HC, Antshel, KM, Braverman, NE, Burton, BK, Frazier, DM, et al. 
Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med 
2014;16(2):188-200. 


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