Conditions: BH4 Deficiency Hyperphenylalaninemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8
Healthy volunteers: no

Brief summary:
This study has been designed to demonstrate the safety, pharmacokinetics (PK) and preliminary efficacy of PTC923 (CNSA-001) in reducing blood phenylalanine concentrations in participants with hyperphenylalaninemia due to primary BH4 deficiency (PBD).

Detailed description:
BH4 is an essential cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, fatty acid glycerylether oxygenase, and nitric oxide (NO) synthase. The PBD is caused by deficiency of GTP cyclohydrolase I (GTP-CH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), or sepiapterin reductase (SR) that impairs the biosynthesis of BH4 or by defects in BH4 recycling (pterin-4a-carbinolamine dehydratase \[PCD\] or dihydropteridine reductase \[DHPR\] deficiency).

Participants will be randomized into one of 2 cohorts, with each cohort assessing 2 dose levels of PTC923 via intra-participant escalation.

Arms:
arm 1: Participants will receive PTC923 suspension 2.5 milligrams (mg)/kilogram (kg)/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, undergo a 3 (±1) day washout period, then escalate to a dose of 10 mg/kg/day (dose divided in 2 for twice daily administration) administered orally for 7 days in Period 2 (14 days total treatment). arm 2: Participants will receive PTC923 suspension 5 mg/kg/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, undergo a 3 (±1) day washout period, then escalate to a dose of 20 mg/kg/day (dose divided in 2 for twice daily administration) administered orally for 7 days in Period 2 (14 days total treatment).

Interventions: intervention 1: PTC923
Intervention descriptions: intervention 1: PTC923 will be administered per dose and schedule specified in arm description.

Protocol document:
Prot_000.pdf: 
CNSA-001 (sepiapterin) Amendment 5 
Censa Pharmaceuticals 
Clinical Trial Protocol: PBD-001 
Page 1 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
Study Title: 
A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra-patient Dose 
Escalation Study to Evaluate the Safety, Pharmacokinetics and Preliminary 
Efficacy of CNSA-001 (Sepiapterin) in Primary Tetrahydrobiopterin 
Deficient Patients with Hyperphenylalaninemia 
Study Number: 
PBD-001 
Study Phase: 
1/2 
Product Name: 
CNSA-001 (sepiapterin)  
Dosage Form:  
oral powder for suspension 
IND Number: 
132575 
Indication: 
Treatment of Hyperphenylalaninemia in Primary Tetrahydrobiopterin 
Deficient patients with PTPS or recessive GTP-CH deficiencies  
Investigators: 
Multicenter trial 
Sponsor: 
Censa Pharmaceuticals Inc. 
65 William Street 
Suite #200 
Wellesley, MA 02481 
Sponsor Contact: 
 
Medical Monitor: 
 
Date 
Original Protocol: 
14 August 2017 
Amendment 1: 
01 November 2017 
Amendment 2: 
01 March 2018 
Amendment 3: 
08 October 2018 
Amendment 4: 
10 May 2019 
Amendment 5: 
13 May 2020 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorization from the Sponsor.  
NCT #NCT03519711


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SPONSOR SIGNATURES 
Study Title: 
A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra-patient Dose 
Escalation Study to Evaluate the Safety, Pharmacokinetics and 
Preliminary Efficacy of CNSA-001 (Sepiapterin) in Primary 
Tetrahydrobiopterin Deficient Patients with Hyperphenylalaninemia 
Study Number: 
PBD-001 
Final Date: 
14 August 2017 
Amendment 1 Date: 
01 November 2017 
Amendment 2 Date: 
01 March 2018 
Amendment 3 Date: 
08 October 2018 
Amendment 4 Date: 
10 May 2019 
Amendment 5 Date: 
13 May 2020 
 
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor. The following personnel contributed to writing and/or approving this protocol: 
 
Signed: 
 
 
Date:  
 
 
 
Censa Pharmaceuticals, Inc. 
 
Signed: 
 
 
Date:  
 
 
 
Censa Pharmaceuticals 
 


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INVESTIGATOR’S SIGNATURE 
Study Title: 
A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra-patient Dose 
Escalation Study to Evaluate the Safety, Pharmacokinetics and 
Preliminary Efficacy of CNSA-001 (Sepiapterin) in Primary 
Tetrahydrobiopterin Deficient Patients with Hyperphenylalaninemia 
Study Number: 
PBD-001 
Final Date: 
14 August 2017 
Amendment 1 Date: 
01 November 2017 
Amendment 2 Date: 
01 March 2018 
Amendment 3 Date: 
Amendment 4 Date: 
Amendment 5 Date: 
08 October 2018 
10 May 2019 
13 May 2020 
 
 
 
 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
Date:  
 
 
 
 


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PROTOCOL AMENDMENT 5 (MAY 13, 2020) 
Protocol PBD-001 is amended primarily for the following reasons: 
• Included exploratory measure to assess changes in movement and sleep for 
euphenylalaniemic and hyperphenylalaninemic states and as assessed by an accelerometer 
device (GeneActiv, Activinsights Ltd.).  
• Included exploratory measure to evaluate changes from baseline in cognitive assessments 
for children and adolescents ages 3-17 via the NIH Toolbox. 
• Included a parent rated sleep assessment tool, the Child and Adolescent Sleep 
Checklist. 
Major changes to the protocol are as follows: 
• Synopsis, Section 2.3, Section 7.1.1, Section 7.2.1, Section 7.2.4, Section 7.6, Section 
9.5. Appendix 1: Added language and activities specific to two new exploratory 
measures GENEActiv accelerometer device, the NIH Toolbox, and the Child and 
Adolescent Sleep Checklist. 
• Sections 6.8.4, 6.8.5and 6.8.6 were added to describe the GENEActiv accelerometer 
device, the NIH Toolbox, and the Child and Adolescent Sleep Checklist, respectively. 
• References were updated.  
 


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PROTOCOL AMENDMENT 4 (MAY 10, 2019) 
Protocol PBD-001 is amended primarily for the following reasons: 
 
• Included children above 12-months of age.  
• Modified exclusion criteria for tachycardia rates and systolic blood pressure for 
children. 
• Clarified discrepancy between inclusion criterion 2 and various sections regarding 
genetic testing not being required for inclusion into the study. 
• Modified the laboratory value for hypophenylalaninemia to be consistent across 
patient ages. 
• Modified the Abnormal Movement Seizure Journal to distinguish and collect both 
seizures and abnormal movement (dystonia).   
• Urine sample collection for urinalysis and for the exploratory biomarkers 
(Sepiapterin, BH4 and Neopterin) will not be collected from toddlers (unless toilet 
trained and able to provide sample). 
• Updated the Schwartz formula for estimating creatinine clearance in children to the 
Schwartz-Lyon formula. 
Major changes to the protocol are as follows: 
• Synopsis, Section 2.1, Section 3.1, Section 4.2, Section 10.3: Decreased inclusion age 
to above 12-months based on DSMB and FDA feedback.   
• Synopsis, Section 4.3, Section 11: Modified Exclusion Criterion No.13, adjusted the 
heart rate bpm and systolic blood pressure for children.   
• Synopsis, Section 3.1, Section 4.2, Section 6.2, Section 7.1.1: Modified Inclusion 
Criterion No.2, clarified discrepancy between inclusion criterion 2 and section 6.2 
and 7.1.1 regarding genetic testing.   
• Section 6.13.1, Section 6.8.1: Modified early discontinuation for the occurrence of 
hypophenylalaninemia defined as < 30 μmol/L for all patients. 
• Section 6.14: Modified the Abnormal Movement Seizure journal to distinguish and 
collect seizures and abnormal movement separately within the journal.  
• Section 6.61, Section 6.82: Collection of urine samples from toddlers (unless toilet 
trained and able to provide sample) is not required.  


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• Appendix 2: changed the Schwartz Formula to the Schwartz-Lyon Formula for 
estimation of creatinine clearance. 
 


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PROTOCOL AMENDMENT 3 (OCTOBER 8, 2018) 
Protocol PBD-001 is amended primarily for the following reasons: 
1. Shortened the BH4 Washout Period from 7 to 3 days duration and removed Inclusion 
Criterion #3: Blood Phenylalanine (Phe) level >360 µmol/L during the Screening or BH4 
Washout Periods. This change is being made for patient safety and ease of study conduct. 
2. Made the Washout Period 3 Days ± 1 Day to better accommodate clinic hours of 
operations. 
3. Corrected the title to more accurately reflect the trial design. 
4. Removed the requirement for the Day 7 trough single PK draw and changed the 12-hour 
draw to 8 hours for ease of collection. 
5. Clarified Inclusion Criteria 4, 5 and 8. 
6. Added summary of safety data from completed Phase 1 single- and multiple-dose 
escalation study in healthy volunteers, Study PKU-001, inclusive of food effect data. 
7. Added a new section describing rationale for selection of doses. 
8. Added a new section describing the risk and benefits of study participation.  
9. Added a new section describing Sponsor clinical trial insurance. 
 
Major changes to the protocol are as follows: 
• Synopsis, Section 3.1, Figure 1, Section 6.6.1, Section 6.8.1, Section 7.1.1, Section 7.1.2 
and Appendix 1: Shortened the BH4 Washout from 7 to 3 days duration. 
• Synopsis and Section 4.2: Removed Inclusion Criterion # 3. 
• Title Page, Sponsor’s Signature, Investigator’s Signature, Synopsis, Section 3.1 and 
Section 3.2: Title was changed to better reflect the actual design of intra-patient dose 
escalation versus intra-patient dose titration. 
• Synopsis, Section 3.1, Section 6.9, Section 7.2.4, Section 7.4.4, Appendix 1 and 
Appendix 3: Removed the Day 7 trough single PK draw.  Following data from a recently 
completed Phase 1 Study wherein accumulation was not observed and following 
feedback from investigational sites, this single blood draw was deemed unnecessary. The 
12-hour collection was moved to 8 hours to ease collection. 
• Synopsis, Section 4.2, and Appendix 2: Modified Inclusion Criteria 4, 5, and 8 to clarify 
that assent applied to adolescents and/or mentally impaired secondary to disease, 2 
methods of contraception include a highly effective method plus barrier contraception, 
and creatinine clearance for adolescents will now use the Schwartz formula. 
• Section 1.3, Section 1.4, Section 3.3 and Section 3.4: Added data from completed Phase 1 
single- and multiple dose study in healthy volunteers, Study PKU-001.  Inserted new 
dose rationale and risk benefit sections. 


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• Section 6.4, Section 7.1.1 and Appendix 1: Collection of height was added for Screening 
Period. 
• Section 10.15: Statement of Sponsor Insurance provided. 
 
 


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PROTOCOL AMENDMENT 2 (MARCH 1, 2018)  
Protocol PBD-001 is amended primarily for the following reasons: 
1. Expanded geographic scope to include Germany. 
2. Corrected the central bioanalytical laboratory sampling schedule in Appendix 3 and 
removed the sample tube summaries as these are in the Laboratory Manual. 
3. Included local bioanalytical phenylalanine (Phe) monitoring by sites for safety. 
4. Clarified that for patients taking tetrahydrobiopterin (BH4) pre-study, the BH4 Washout 
will last the full 7 days regardless of when Phe concentrations become elevated above 
360 µmol/L. 
5. Clarified inclusion criterion requiring confirmation of mutation via medical history. 
6. Extended the duration of male contraception inclusion criterion from 30 to 90 days post-
study to cover full cycle of spermatogenesis. 
7. Adverse event grading was changed to use the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) criteria throughout the study. 
8. Corrected several typographical errors and inconsistencies. 
Major changes to the protocol are as follows: 
• Section 1.4: Added Kuvan® as an approved treatment of HPA in adults and pediatric 
patients with PBD in Europe. 
• Synopsis, Section 3.1, Section 6.8.1, and Section 7.1.2: Clarified that all patients washing 
out of BH4 will complete the full 7-day BH4 Washout prior to being randomized into the 
study and patients may continue the BH4 Washout until the Day -1 Phe concentration 
results have been obtained. 
• Section 4.1: Germany added as a geographic region in which study will be conducted. 
• Synopsis, Section 4.2, Section 6.2, Section 7.1.1, and Appendix 1: Modified Inclusion 
Criterion No. 2 to indicate that documentation of mutation could be obtained as part of 
medical history. Clarified no genetic testing or retesting is required. 
• Synopsis and Section 4.2: Modified Inclusion Criterion No. 6 to indicate the duration of 
required contraception for males is 90 days after the last dose of study drug. 
• Synopsis and Section 4.3: Modified Exclusion Criterion No. 7 to indicate the Investigator 
will determine if the patient has any condition or history that would interfere with the 
patient’s ability to participate or increase the risk of participation for the patient. 
• Synopsis and Section 4.3: Modified Exclusion Criterion No. 17 to indicate pregnant 
females are excluded from the study. 
• Section 6.6.1, Section 6.8.1, Section 7, and Appendix 1: Included local measurement of 
Phe for safety monitoring of HypoPhe and HyperPhe and indicated those that are 
monitored by the bioanalytical laboratory for preliminary efficacy. 


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• Section 6.10, Section 6.10.6.2, Section 10.2, Section 10.3: Removed reference to Code of 
Federal Regulations (CFR). 
• Section 6.10.1: Revised reporting timelines for serious adverse events (SAEs), 
pregnancies, and deaths, and clarified reporting of pregnancies. 
• Section 6.10.2: Replaced adverse event severity grading with NCI CTCAE Version 4.03 
criteria. 
• Section 6.10.4: Revised adverse event (AE) and SAE expectedness to indicate all will be 
considered unexpected in this study. 
• Section 6.10.5: Deleted section on determination of clinical significance by the 
Investigator. 
• Section 6.10.6.1: Adverse event definitions updated. 
• Section 6.13.2: Added subjects may be withdrawn from the study for AEs or SAEs. 
• Section 10.2, Section 10.4, Section 10.5, Section 10.10: Added reference to the 
Independent Ethics Committee. 
• Appendix 3: Table updated to accurately reflect tubes and samples, and to indicate 
tyrosine will be measured on Day 4 and EOS with Phe; summary was removed and 
placed into the Laboratory Manual. 
Editorial changes to the protocol are as follows: 
• Title Page: Added EudraCT Number. 
• Corrected typographical errors and inconsistencies throughout. 
 


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PROTOCOL AMENDMENT 1 (NOVEMBER 1, 2017)  
Protocol PBD-001 is amended primarily for the following reasons: 
1. To add the use, collection and review of an abnormal movement seizure journal starting 
at Screening through End of Study visits. 
2. To include a lower limit of normal for Phe concentrations and provide appropriate rescue 
therapy and the ability to obtain an unscheduled Phe collection. 
3. To include an age-based stopping rule for hypophenylalaninemia. 
4. To ensure all blood Phe samples collected for preliminary efficacy assessment during 
Period 1 and Period 2 are analyzed by the Bioanalytical Laboratory, Medical 
Neurogenetics Laboratories. 
5. To add a provision to permit adjusting PK sampling timepoints/duration once the PK data 
become available from the Period 1 treatment. 
6. To permit Study Day 4 to occur ±1 Day.  This permits sites that are closed on weekends 
to accommodate Day 4 visits on either Day 3 or Day 5 in order to be within the 
requirements of the protocol. 
7. To permit the use of filter paper for Phe collection on Study Days -5 and -3 during the 
BH4 Washout Period in an effort to minimize burden placed on patients’ participation in 
the study. 
8. Appendix 3, “Study Drug Preparation and Dispensing Instructions,” was removed from 
the protocol in an effort to remove confusion on how to prepare and dose CNSA-001 
Powder for Oral Suspension.  A separate Pharmacy Manual and Patient Instruction Guide 
for dose preparation will be provided. 
Major changes to the protocol are as follows: 
• Synopsis, Section 3.1, Section 6.14, Section 7.1.1, Section 7.1.2, Section 7.2.1, 
Section 7.2.2, Section 7.2.3, Section 7.2.4, Section 7.3, Section 7.4.1, Section 7.4.2, 
Section 7.4.3, Section 7.4.4, Section 7.6 and Appendix 1:  Added 
dispensing/collection/review of abnormal movement seizure journal. 
• Section 6.8.1, Section 6.13.1, and Appendix 1: Added lower limit of Phe and rescue 
therapy for hypophenylalaninemia (Section 6.8.1), unscheduled Phe collection 
(Appendix 1), and criteria for discontinuation of study drug to hypophenylalaninemia 
(Section 6.13.1).  
• Section 6.8.1, Section 7.2.2, Section 7.2.3, Section 7.4.2, Section, 7.4.3, Appendix 1 and 
Appendix 3: Added ±1 day variance for Day 4 visit to permit sites to avoid weekend 
visits. 
• Synopsis, Section 3.1, Section 6.6.1, Section 6.8.1, Section 7.1.2, and Appendix 1 
footnote: Added potential for Day -5 and Day -3 Phe collections to be obtained using 
filter paper. 


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• Section 5.2, Section 6.7 and Appendix 3 (original protocol): Clarified that details on 
preparation of study drug and dosing guidelines will be provided in a Pharmacy Manual 
separate from the protocol and deleted this information in Appendix 3.   
• Synopsis, Section 3.1, Section 6.9, Section 7.4.1, Section 7.4.2, Section 7.4.4, 
Appendix 1, and Appendix 3 (formerly Appendix 4): Clarified that pharmacokinetic 
sampling timepoints/duration may be adjusted once the PK data are available from 
Treatment Period 1.   
• Section 6.6.2.1, Section 7.2.1, Section 7.2.2, Section 7.2.3, Section 7.2.4, Section 7.4.1, 
Section 7.4.2, Section 7.4.3, Section 7.4.4, Section 7.6, Appendix 1, and Appendix 3 
(formerly Appendix 4): Clarified that blood Phe levels collected during treatment Period 
1 and Period 2 will be analyzed by the bioanalytical laboratory.  
Editorial Changes to the Protocol are as follows: 
• Revised text in Section 5.9 to include only the total amount of the active ingredient 
(sepiapterin). 
• Renamed Appendix 4 (Pharmacokinetic Samples) as Appendix 3 (Pharmacokinetic, 
Efficacy, and Exploratory Biomarker Samples).   
• Renamed Table 6 (PK Sampling Time for Plasma/Whole Blood and Urine Samples) to 
Table 2 (PK, Preliminary Efficacy, Biomarker, and Exploratory Biomarker Sampling 
Times for Plasma/Whole Blood and Urine Samples) 
• Deleted original protocol Tables 2, 3, 4, and 5 when Appendix 3 content was deleted. 
 


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SYNOPSIS 
Sponsor: 
Censa Pharmaceuticals 
Name of Finished Product: 
CNSA-001 
Name of Active Ingredient: 
sepiapterin 
Name of Inactive Ingredient(s): 
microcrystalline cellulose, colloidal silicon dioxide, croscarmellose, and ascorbic acid 
Study Title: 
A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra-patient Dose Escalation Study to 
Evaluate the Safety, Pharmacokinetics and Preliminary Efficacy of CNSA-001 (Sepiapterin) in 
Primary Tetrahydrobiopterin Deficient Patients with Hyperphenylalaninemia 
Study Number: 
PBD-001 
Study Phase: 1/2 
Primary Objective(s): 
• 
To assess the safety and tolerability of 4 dose levels of CNSA-001 in primary 
tetrahydrobiopterin deficiency (PBD) patients with 6-pyruvoyl-tetrahydropterin synthase 
(PTPS) or recessive guanosine triphosphate cyclohydrolase 1 (GTP-CH) deficiency 
Secondary Objective(s): 
The secondary objective(s) of this study are: 
• 
To assess the pharmacokinetic profile of CNSA-001 and its effect on tetrahydrobiopterin 
(BH4), phenylalanine (Phe), and tyrosine (Tyr) in PBD patients with PTPS or recessive GTP-
CH deficiency. 
• 
To evaluate the preliminary efficacy of CNSA-001 in reducing blood Phe levels in PBD 
patients with PTPS or recessive GTP-CH deficiency after 7 days of treatment. 
Exploratory Objective: 
• 
To assess the change from baseline in other exploratory biomarkers of this disease such as 
serum prolactin, whole blood serotonin, and urine sepiapterin, BH4, and neopterin levels. 
• 
To assess the change from baseline in Cambridge Neuropsychological Test Automated Battery 
(CANTAB) tests, including the Reaction Time (RTI), the Spatial Span (SSP), the Spatial 
Working Memory (SWM) and Rapid Visual Information Processing (RVP). 
• 
To assess changes in movement and sleep for euphenylalaniemic and hyperphenylalaninemic 
states as assessed by an accelerometer device (GeneActiv, Activinsights Ltd.). 
• 
To evaluate changes from baseline in cognitive assessments via the NIH Cognition Toolbox. 
• 
To evaluate changes from baseline in the Child and Adolescent Sleep Checklist (CASC). 
Study Design: 
This is a Phase 1/2, multicenter, randomized, open-label, intra-patient dose escalation study 
designed to evaluate the safety, pharmacokinetics, and preliminary evidence of efficacy of CNSA-
001 in male and female patients with PBD. This Phase 1/2 study will enroll patients with 
confirmed defects in de novo biopterin biosynthesis due to PTPS or recessive GTP-CH genes, 
abnormal enzyme activity of the PTPS or GTP-CH enzymes, or a CSF biochemical profile 
indicative of PTPS or GTP-CH deficiencies. Genetic testing is not required. Approximately 6 to 
10 patients will be enrolled in this study at 5 to 6 study centers. 
The study design is summarized in the study schema. A schedule of study events and assessments 


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to be performed is provided in Appendix 1. 
 
 
Screening Period (Day -14 to Day -4): 
An informed consent or assent (if applicable) form must be signed before any study-related 
procedures are performed. After consenting to the study, PBD patients will undergo Screening 
procedures which include medical/surgical history, demographics, vital signs, ECG, physical 
examination, and clinical laboratory tests (chemistry, hematology, urinalysis). Blood Phe levels 
will be measured at Screening and compared to the 3 most recent historical Phe concentrations. 
Patients who are eligible based on Screening tests will proceed to the BH4 Washout Period. 
Patients will be asked to keep an abnormal movement seizure journal while on study. 
BH4 Washout Period (Day -3 to Day -1): 
Eligible patients who are taking BH4 [Kuvan® (sapropterin dihydrochloride)] will discontinue the 
medication during the BH4 Washout Period and will remain off this medication during the entire 
study. Patients will be instructed to maintain a consistent diet (with respect to protein and Phe 
intake) and 3-day diet records will be collected during BH4 Washout and throughout the study. On 
Days -3 and -1 during the BH4 Washout Period, blood will be collected for determination of Phe 
concentrations. To minimize burden on patients, Phe collection on Days -3 and -1 may be obtained 
via filter paper with overnight shipping to the site’s designated laboratory.  
Treatment Period 1 and Period 2: 
Patients will receive treatment with CNSA-001 for a total of 14 days [i.e., two 7-day treatment 
periods separated by a 3 (±1) day washout]. Patients will be randomized into one of 2 cohorts, with 
each cohort assessing 2 dose levels of CNSA-001 via intra-patient dose escalation. 


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• 
Cohort 1, patients will receive 2.5 mg/kg/day for 7 days in Period 1, undergo a 3 (±1) day 
washout period, then escalate to 10 mg/kg/day for 7 days in Period 2 (14 days total treatment) 
• 
Cohort 2, patients will receive 5 mg/kg/day for 7 days in Period 1, undergo a 3 (±1) day 
washout period, then escalate to 20 mg/kg/day for 7 days in Period 2 (14 days total treatment). 
Patients will be eligible for dose escalation during Period 2 only if they meet the criteria for intra-
patient dose escalation (see Section 6.12). 
Initially, only adult patient(s) (≥18 years) will be enrolled. The first adult patient will be enrolled 
into Cohort 1 and then a second adult patient will be enrolled into Cohort 2 of the study, with 
subsequent patients being randomized into either cohort. After the first adult patient(s) have 
completed the study, the Data Safety Monitoring Board (DSMB) will review safety and 
pharmacokinetic/ pharmacodynamic (PK/PD) data, including preliminary efficacy, for the adult 
patient(s). If the data display no safety issues and provide for the prospect of clinical benefit in 
patients ≥12 months to <18 years old, then the eligibility criterion for age at time of enrollment will 
be expanded to include children (≥12 months). The safety, pharmacokinetic, and pharmacodynamic 
data on the dosed adult patient(s) will be submitted for review to the United States (US) Food and 
Drug Administration for review prior to enrolling patients <18 years old. 
During the study, patients will continue receiving their other current medications for PBD 
(including L-dopa/carbidopa, 5HTP, melatonin, MAO inhibitors, and dopamine receptor agonists 
as prescribed) except for BH4 supplementation (if they were taking BH4) and will be monitored 
clinically as per standard of care for PBD to optimize treatment. 
Safety and tolerability will primarily be assessed by adverse events (AEs), vital signs, and clinical 
laboratory tests (including chemistry, hematology, and urinalysis), physical examinations, and 
12 lead electrocardiograms (ECGs).  
Preliminary efficacy will be assessed by the reduction in plasma Phe levels. Other secondary 
measures will include whole blood serotonin, serum prolactin and BH4, and urine sepiapterin, BH4 
and neopterin. 
Blood samples will be collected to characterize the pharmacokinetics of sepiapterin and its effect 
on serum BH4, Phe, and Tyr at the following time points for each dose level: on Day 1 at pre-dose 
(within 30 min of dosing), +0.5 hr (±3 min), +1 hr (±5 min), +2 hr (±6 min), +4 hr (±20 min), +6 hr 
(±30 min), +8 hr (±60 min, prior to Day 1 evening dose), and +24 hours (±2 hr, prior to Day 2 
morning dose) after the first dose of study drug.  
Patients will receive treatment with CNSA-001 for a total of 14 days [i.e., two 7-day treatment 
periods separated by a 3 (±1) day washout], unless they meet criteria for discontinuing CNSA-001 
treatment. Permanent discontinuation of CNSA-001 treatment may be triggered by safety reasons 
or lack of efficacy (see Section 6.13.1). 
Patients who discontinue CNSA-001 treatment early will complete the End of Study (EOS) 
assessments. After completion of the EOS assessments, patients should immediately revert to 
pre-study standard of care for their PBD, including BH4 if they were taking it previously. 
Phone follow-up visits to assess for AEs and serious adverse events (SAEs) will occur 7 to 10 days 
and 30 (±3) days after the last dose of study drug. 
Study Population: 
Approximately 6 to 10 patients will be enrolled in this study and treated with CNSA-001  
(3 to 5 patients per arm).  
Diagnosis and Main Criteria for Inclusion and Exclusion: 
Individuals eligible to participate in this study include patients with PBD who meet all the 
following inclusion criteria: 


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1. Male or Female patients 18 years old and above and 12 months old and above for the 
remaining patients (age reduction pending analysis of safety, PK, and response, in the adult 
patient(s) by the DSMB and FDA) 
2. Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic 
mutations in PTPS or recessive GTP-CH genes, abnormal enzyme activity of the PTPS or 
GTP-CH enzymes, or a CSF biochemical profile indicative of PTPS or GTP-CH 
deficiencies. Genetic testing is not required. 
3. Informed consent and assent [if necessary (i.e., for children and/or patients that are mentally 
impaired secondary to disease)] with parental consent 
4. Females must be either postmenopausal for ≥1 year, or surgically sterile (tubal ligation, 
hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing 
potential and not abstinent, willing to use at least 2 of the following methods of 
contraception (including adolescents 12 to 18 years old) from Screening through 30 days 
after the last dose of study drug: 
o Hormonal contraception (stable dose for 3 months) or 
o IUD/IU Hormone-releasing System, plus 
o Barrier contraceptive method (diaphragm, cervical cap, contraceptive sponge, 
condom) with spermicidal foam/gel/cream/suppository 
Males and females who are abstinent will not be required to use a 2nd contraceptive method 
unless they become sexually active. 
5. Males with female partners of childbearing potential must agree to use barrier contraceptive 
(i.e., condom) with spermicidal foam from Screening through 90 days after the last dose of 
study drug. Males must also refrain from sperm donations during this time period. 
6. Females with a negative pregnancy test at Screening and on Day 1 prior to dosing 
7. Creatinine clearance (CrCl) >90 mL/min as estimated using the Cockcroft-Gault equation 
(≥18 years) or Schwartz-Lyon equation (≥ 12 months < 18 years) (Appendix 2) 
8. The patient is clinically stable on therapy for management of their signs and symptoms of 
PBD as determined by the Investigator 
9. The patient is willing and able to comply with the protocol 
10. No tobacco use (e.g., cigarettes, e-cigarettes, cigars, smokeless tobacco) for 2 weeks prior to 
the Screening visit and willingness to abstain from these products through the last dose of 
study drug  
Individuals are not eligible to participate in this study if they have or meet any of the following 
exclusion criteria: 
1. PBD caused by biallelic pathogenic mutations in pterin-4a-carbinolamine dehydratase 
(PCD), sepiapterin reductase (SR), dihydropteridine reductase (DHPR), or single dominant 
mutations in GTP-CH 
2. Significant chronic medical illness other than PBD, as determined by the Investigator 
3. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, 
chronic gastritis, peptic ulcer disease, etc.) that could affect the absorption of study drug 
4. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy 
with vagotomy, or gastrectomy 
5. Inability to tolerate oral medication 
6. History of allergies or adverse reactions to BH4 or related compounds, or any excipients in 
the study drug formulation  
7. Any clinically significant medical or psychiatric condition or medical history, that in the 
opinion of the Investigator, would interfere with the patient’s ability to participate in the 
study or increase the risk of participation for that patient 


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8. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or 
hepatitis C virus (HCV) 
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) laboratory values 
>2 × the upper limit of normal (ULN) 
10. Any other clinically significant laboratory abnormality unrelated to PBD at the Screening 
visit or prior to the administration of the first dose of study drug, as determined by the 
Investigator 
11. Clinically significant cardiac arrhythmia at Screening or prior to the first dose of study drug 
12. QTcF (QT with Fredericia’s correction) ≥460 msec in males and ≥480 msec in females 
(based on the mean of triplicate measurements taken at Screening) 
13. Resting heart rate ≤40 or ≥110 bpm for ages 12 and older, ≥ 130 bpm for ages 3 to 12, ≥ 150 
bpm for ages 1-2 years or resting blood pressure <85/40 mmHg or >150/90 mmHg at 
Screening or prior to the first administration of study drug 
14. Current participation in any other investigational drug study or participation within 30 days 
prior to Screening 
15. History of alcohol or drug abuse within last 6 months prior to Screening or current evidence 
of substance dependence as determined by the Investigator 
16. Currently taking an antifolate including, but not limited to, methotrexate, pemetrexed, or 
trimetrexate 
17. A female who is nursing or who is pregnant or planning to become pregnant 
18. The patient, in the opinion of the Investigator, is unwilling or unable to adhere to the 
requirements of the study 
Test Product; Dose; and Mode of Administration: 
The test product is CNSA-001 (sepiapterin) oral powder for suspension. Patients will be 
randomized to one of 2 cohorts that will test 2 doses each, adjusted for body weight (i.e., either oral 
doses of 2.5 and 10 mg/kg/day CNSA-001 in Cohort 1 or 5 and 20 mg/kg/day CNSA-001 in 
Cohort 2). All dosing will be divided and administered twice daily with breakfast and dinner.   
Reference Therapy; Dose; and Mode of Administration: None 
Duration of Treatment: 
Patients will receive CNSA-001 during the treatment period for a duration of 7 days during Period 
1 followed by a 3 (±1) day washout and then intra-patient escalation to a second dose level for an 
additional 7 days during Period 2 (i.e., 14 days of total treatment). 
Safety Assessments: 
Safety and tolerability of CNSA-001 will be measured by assessing the incidence of treatment-
emergent adverse events (TEAEs), including assessment of severity of TEAEs, clinical laboratory 
tests, vital signs, and 12-lead electrocardiograms (ECGs).  
Pharmacokinetic Variables: 
The blood concentrations of sepiapterin, BH4, Phe, and Tyr will be summarized and listed. The 
following non-compartmental PK parameters for sepiapterin, BH4, Phe, and Tyr will be estimated 
and summarized along with graphical presentation of the concentration data: 
Parameter 
Definition 
AUC0-inf 
Area under the curve from time 0 to infinity using trapezoidal method 
(linear-up/log-down method) and extrapolation to infinite time 
AUC0-last 
Area under the curve from time 0 to the time of the last quantifiable 
concentration using linear-up/log-down method trapezoidal method 
Cmax 
Maximum observed concentration 
Tmax 
Time to Cmax 
t1/2 
Half-life 


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Ke 
Elimination rate constant 
Efficacy Variables: 
The preliminary efficacy measure will be reduction in plasma Phe levels as defined by the change 
of plasma Phe concentrations from baseline (Day 1, pre-dose). All changes from baseline will be 
calculated from Day 1 of the treatment period to Day 7 of the treatment period. 
Secondary measures may include the following summary statistics (at each visit) as well as 
summary statistics changes from baseline to Day 7: 
• 
Percent of patients with Phe concentrations in acceptable treatment range of 130 to 
360 µmol/L at Day 7 
• 
Percent of patients with Phe concentrations <130 µmol/L at Day 7 
Exploratory Measures Include: 
• 
Urine sepiapterin, neopterin, and BH4 
• 
Serum prolactin 
• 
Whole blood serotonin 
• 
Computerized testing (CANTAB) at Screening and Day 1 (pre-dose) and Day 7 of each 
treatment period 
• 
Changes in movement and sleep as assessed by an accelerometer device (GeneActiv, 
Activinsights Ltd.). 
• 
Cognitive assessments via the NIH Cognition Toolbox. 
• 
Sleep assessment via the CASC. 
Statistical Methods: 
Three study populations will be assessed: 
1. Safety population: all patients who receive any amount of study drug 
2. The Efficacy population: all patients who were randomized, received any amount of study 
drug, and had available pre-dose Phe Concentrations on Day 1 and at least one post-Day 1 
visit within a period. All efficacy analyses will be conducted in this population. 
3. PK Population: all patients who received at least one dose of study drug and had at least 
1 blood sample collected for analysis of sepiapterin, BH4, Phe, or Tyr concentrations. 
Safety will be assessed in the Safety population. AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA®). The number and percentage of patients with TEAEs (events 
that begin after first dose of study drug) will be tabulated by dose cohort, period, system organ 
class, and MedDRA preferred term. The dose cohort for each AE is identified based on the last 
dose of study drug taken at or before the start of the AE. Severity of AEs and SAEs will be 
summarized similarly. AEs leading to premature discontinuation from the study drug and serious 
TEAEs will be presented in a table or a listing. Clinical laboratory test results and vital signs will 
be summarized at each visit as well as changes from baseline within each cohort and period. 
Efficacy will be assessed in the Efficacy population. Phe concentrations at each visit and changes 
from baseline will be summarized using summary statistics (number of patients, mean, standard 
deviation, median, range) within each dose cohort and period. Treatment induced Phe level is not 
powered for this study and caution is needed in the interpretation of results. 
Secondary and exploratory outcome measures will also be summarized using descriptive statistics 
in the Efficacy population. 
All PK variables will be summarized by dose and will also be listed. Concentration time plots will 
be created as well for sepiapterin, BH4, Phe, and Tyr in the PK Population. 
Details of the statistical analysis will be provided in a separate Statistical Analysis Plan. 
Date of Original Protocol: 14 August 2017 
Date of Most Recent Protocol Amendment (if applicable):  13 May 2020 


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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ..............................................................................................1 
SPONSOR SIGNATURES ........................................................................................................2 
INVESTIGATOR’S SIGNATURE ...........................................................................................3 
PROTOCOL AMENDMENT 5 (MAY 13, 2020) ....................................................................4 
PROTOCOL AMENDMENT 4 (MAY 10, 2019) ....................................................................5 
PROTOCOL AMENDMENT 3 (OCTOBER 8, 2018) .............................................................7 
PROTOCOL AMENDMENT 2 (MARCH 1, 2018) .................................................................9 
PROTOCOL AMENDMENT 1 (NOVEMBER 1, 2017) .......................................................11 
SYNOPSIS ...............................................................................................................................13 
TABLE OF CONTENTS .........................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................23 
1 
INTRODUCTION .................................................................................................26 
1.1 
Primary Tetrahydrobiopterin Deficiency .........................................................26 
1.2 
Current Treatment of PBD ...............................................................................27 
1.3 
CNSA-001 (Sepiapterin) ..................................................................................28 
1.4 
Rationale for Study ..........................................................................................29 
2 
STUDY OBJECTIVES ..........................................................................................31 
2.1 
Primary Objective(s) ........................................................................................31 
2.2 
Secondary Objective(s) ....................................................................................31 
2.3 
Exploratory Objective ......................................................................................31 
3 
INVESTIGATIONAL PLAN ................................................................................32 
3.1 
Overall Study Design and Plan ........................................................................32 
3.2 
Rationale for Study Design and Control Group ...............................................35 
3.3 
Rationale for Selection of Doses......................................................................35 
3.4 
Risks and Benefits for Participating in Study PBD-001 ..................................36 
3.5 
Study Duration and Dates ................................................................................37 
4 
STUDY POPULATION SELECTION .................................................................38 
4.1 
Study Population ..............................................................................................38 
4.2 
Inclusion Criteria .............................................................................................38 
4.3 
Exclusion Criteria ............................................................................................39 
5 
STUDY TREATMENT(S) ....................................................................................41 
5.1 
Description of Treatment(s) .............................................................................41 
5.1.1 
Study Drug ...........................................................................................41 
5.1.2 
Placebo or Control ...............................................................................41 
5.2 
Treatment(s) Administered ..............................................................................41 
5.3 
Selection and Timing of Dose for Each Patient ...............................................41 
5.4 
Method of Assigning Patients to Treatment Groups........................................42 


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5.5 
Blinding............................................................................................................42 
5.6 
Concomitant Therapy.......................................................................................42 
5.7 
Restrictions ......................................................................................................42 
5.7.1 
Prior Therapy .......................................................................................42 
5.7.2 
Fluid and Food Intake ..........................................................................42 
5.7.3 
Total Blood Volume ............................................................................43 
5.7.4 
Patient Activity Restrictions ................................................................43 
5.8 
Treatment Compliance .....................................................................................43 
5.9 
Packaging and Labeling ...................................................................................43 
5.10 
Storage and Accountability ..............................................................................43 
5.11 
Investigational Product Retention at Study Site ..............................................43 
6 
STUDY PROCEDURES .......................................................................................44 
6.1 
Informed Consent.............................................................................................44 
6.2 
Medical History and Demographic Data .........................................................44 
6.3 
Physical Examination.......................................................................................44 
6.4 
Vital Signs ........................................................................................................44 
6.5 
ECGs ................................................................................................................45 
6.6 
Clinical Laboratory Tests .................................................................................45 
6.6.1 
Local Laboratory Parameters ...............................................................45 
6.6.2 
Bioanalytical Laboratory Parameters ...................................................47 
6.7 
Dispensing Study Drug ....................................................................................47 
6.8 
Efficacy Assessments.......................................................................................48 
6.8.1 
Blood Phenylalanine Levels ................................................................48 
6.8.2 
Other Biomarker Levels .......................................................................48 
6.8.3 
Cambridge Neuropsychological Test Automated Battery 
(CANTAB) Test Battery ......................................................................49 
6.8.4 
GENEActiv Accelerometer Device .....................................................49 
6.8.5 
The NIH Toolbox – Cognition Domain ...............................................49 
6.8.6 
Child and Adolescent Sleep Checklist (CASC) ...................................51 
6.9 
Pharmacokinetic Assessments .........................................................................51 
6.10 
Adverse Events Assessments ...........................................................................52 
6.10.1 
Reporting Timelines.............................................................................52 
6.10.2 
Severity ................................................................................................53 
6.10.3 
Relationship .........................................................................................54 
6.10.4 
Expectedness ........................................................................................55 
6.10.5 
Clinical Laboratory Adverse Events ....................................................55 
6.10.6 
Serious Adverse Events .......................................................................56 
6.10.7 
Treatment-Emergent Adverse Events ..................................................57 


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6.11 
Prior and Concomitant Medication Assessments ............................................57 
6.12 
Intra-Patient Dose Escalation Criteria .............................................................58 
6.13 
Removal of Patients from the Trial or Study Drug ..........................................58 
6.13.1 
Early Discontinuation from Study Drug Administration .....................58 
6.13.2 
Withdrawal from the Study ..................................................................59 
6.13.3 
Study Halting Criteria ..........................................................................59 
6.14 
Abnormal Movement Seizure Journal .............................................................60 
6.15 
Appropriateness of Measurements ...................................................................60 
7 
STUDY ACTIVITIES ...........................................................................................61 
7.1 
Screening Visit (Days –14 to -1) .....................................................................61 
7.1.1 
Screening Procedures (Day -14 to Day -4) ..........................................61 
7.1.2 
BH4 Washout (Day -3 to Day -1) .........................................................62 
7.2 
Treatment Period 1 (Day 1 to Day 7)...............................................................63 
7.2.1 
Period 1, Day 1 Procedures ..................................................................63 
7.2.2 
Period 1, Day 2 Procedures ..................................................................64 
7.2.3 
Period 1, Day 4 (±1 Day) Procedures ..................................................65 
7.2.4 
Period 1, Day 7 Procedures ..................................................................66 
7.3 
Washout Period [3 (±1) Days] .........................................................................67 
7.4 
Treatment Period 2 (Day 1 to Day 7)...............................................................67 
7.4.1 
Period 2, Day 1 Procedures ..................................................................67 
7.4.2 
Period 2, Day 2 Procedures ..................................................................69 
7.4.3 
Period 2, Day 4 (±1 Day) Procedures ..................................................70 
7.4.4 
Period 2, Day 7 Procedures ..................................................................70 
7.5 
Early Termination Procedures .........................................................................71 
7.6 
End of Study Visit ............................................................................................71 
7.7 
Phone Follow-up Visits....................................................................................72 
7.7.1 
Phone Follow-up 7 to 10 Days After Last Dose ..................................72 
7.7.2 
Phone Follow-up 30 (± 3) Days after Last Dose .................................73 
8 
QUALITY CONTROL AND ASSURANCE .......................................................74 
9 
PLANNED STATISTICAL METHODS ..............................................................75 
9.1 
General Considerations ....................................................................................75 
9.2 
Determination of Sample Size .........................................................................75 
9.3 
Analysis Populations ........................................................................................75 
9.4 
Demographics and Baseline Characteristics ....................................................75 
9.5 
Statistical Analysis of Efficacy Variables ........................................................75 
9.6 
Safety Analysis ................................................................................................76 
9.7 
Statistical Analysis of Pharmacokinetic Variables ..........................................76 
10 
ADMINISTRATIVE CONSIDERATIONS ..........................................................78 


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10.1 
Investigators and Study Administrative Structure ...........................................78 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .......78 
10.3 
Ethical Conduct of the Study ...........................................................................78 
10.4 
Patient Information and Consent .....................................................................79 
10.5 
Confidentiality .................................................................................................79 
10.6 
Study Monitoring .............................................................................................80 
10.7 
Case Report Forms and Study Records ...........................................................80 
10.8 
Data Monitoring Committee ............................................................................81 
10.9 
Protocol Violations/Deviations ........................................................................81 
10.10 
Access to Source Documentation ....................................................................81 
10.11 
Data Generation and Analysis .........................................................................81 
10.12 
Retention of Data .............................................................................................82 
10.13 
Financial Disclosure.........................................................................................82 
10.14 
Publication and Disclosure Policy ...................................................................82 
10.15 
Clinical Trial Insurance....................................................................................82 
11 
REFERENCE LIST ...............................................................................................83 
 
LIST OF TABLES 
Table 1: 
Severity Grading of Adverse Events (NCI CTCAE Criteria version 
4.03) ...........................................................................................................53 
Table 2 
Administrative Structure for PBD-001 Study ............................................78 
Table 3 
PK, Preliminary Efficacy Biomarker, and Exploratory Biomarker 
Sampling Times for Plasma/Whole Blood and Urine Samples .................92 
 
LIST OF FIGURES 
Figure 1. 
Study Schema.............................................................................................34 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................88 
Appendix 2 
Cockcroft-Gault Formula (Adults, ≥ 18) and Schwartz-Lyon Formula 
(Children < 18 Years) for Creatinine Clearance ........................................91 
Appendix 3 
Pharmacokinetic, Efficacy and Exploratory Biomarker Samples..............92 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AM 
Morning 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the time-concentration curve 
BH4 
Tetrahydrobiopterin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CASC 
Child and Adolescent Sleep Checklist 
CANTAB 
Cambridge Neuropsychological Test Automated Battery  
CBC 
Complete blood count 
Cmax 
Maximum plasma drug concentration 
Cmin 
Minimum plasma drug concentration 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMP  
Clinical Monitoring Plan 
COMT 
catechol-O-methyl transferase 
CRF 
Case report form 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal fluid 
CV 
Coefficient of variation 
DHPR 
Dihydropteridine reductase 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


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GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practices 
GTP-CH 
Guanosine triphosphate cyclohydrolase 1 
HCT 
Hematocrit 
HGB 
Hemoglobin 
HCB 
Human chorionic gonadotropin 
HEENT 
Head, eyes, ears, nose and throat 
HIPAA 
Health Information Portability and Accountability Act 
HPA 
Hyperphenylalaninemia 
IB 
Investigator’s Brochure 
IBS 
Irritable bowel syndrome  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IQ 
Intelligence Quotient 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LAR 
Legally Authorized Representative 
LDH 
lactic dehydrogenase 
MAO 
Monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIH 
National Institutes of Health 
PBD 
Primary tetrahydrobiopterin deficiency 
PCD 
Pterin-4a-carbinolamine dehydratase 
PCr 
Plasma Creatinine 
PD 
Pharmacodynamic 
PE 
Physical examination 


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Phe 
Phenylalanine 
PK 
Pharmacokinetic 
PKU 
Phenylketonuria 
PTPS 
6-pyruvoyl-tetrahydropterin synthase 
QC 
Quality control 
RBC 
Red blood cell (count) 
RTI 
Reaction time 
RVP 
Rapid visual information processing 
SAE 
Serious adverse event 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SSP 
Spatial span 
SR 
Sepiapterin reductase 
SWM 
Spatial working memory 
Tmax 
Time to maximum plasma concentration 
t1/2 
Half-life 
Tyr 
Tyrosine 
US 
United States 
WBC 
White blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 


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1 
INTRODUCTION 
1.1 
Primary Tetrahydrobiopterin Deficiency 
Primary tetrahydrobiopterin deficiency (PBD) is caused by deficiency of GTP 
cyclohydrolase I (GTP-CH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), or sepiapterin 
reductase (SR) that impair the biosynthesis of tetrahydrobiopterin (BH4) or by defects in BH4 
recycling (pterin-4a-carbinolamine dehydratase [PCD] or dihydropteridine reductase [DHPR] 
deficiency) (Tada et al, 1969; Tada et al, 1980; Bartholome, 1974; Abeling et al, 2006). PBD 
accounts for 1 to 3% of all cases of hyperphenylalaninemia (HPA), with virtually all of the 
remaining cases due to phenylalanine hydroxylase deficiency. HPA occurs in 1:10,000 to 
1:15,000 live births (Dhondt, 1991; Hardelid et al, 2008; Donlon et al, 2004). The estimated 
frequency of PTPS deficiency is 1:320,000 while GTP-CH deficiency affects <1:1,000,000 
newborns (http://www.orpha.net/consor/cgi-bin/index.php) accessed 8/29/16). 
A worldwide registry started more than 20 years ago contains data on approximately 1,118 
patients with primary BH4 deficiency (BioDefDb at BIOPKU.org accessed 2/16/17). Based 
on this evidence, currently there are approximately 100 patients with PTPS or GTP-CH 
deficiency in the United States (US). 
BH4 is an essential cofactor for phenylalanine hydroxylase (Kaufman, 1958), tyrosine 
hydroxylase (Nagatsu et al, 1964), tryptophan hydroxylase (Ichiyama et al, 1970), 
(Loyenberg, 1967), fatty acid glycerylether oxygenase (Tietz et al, 1964), and nitric oxide 
(NO) synthase (Kwon et al, 1989), (Mayer et al, 1991). 
In PBD, impaired hydroxylation of Phenylalanine (Phe) to Tyrosine (Tyr) results in HPA. 
The reduced synthesis of Tyr and impaired activities of Tyr and tryptophan hydroxylases 
results in reduced formation of neurotransmitters and consequent neuromotor deficits 
(Butler et al, 1981). A synthetic form of BH4, sapropterin dihydrochloride (Kuvan®; NDA 
022181 and NDA 205065; Biomarin Pharmaceutical, Inc.), has been successful in addressing 
HPA, but not the neurotransmitter deficiency in the brain (Ohashi A et al, 2016). 
Phenotypically, BH4 deficiency presents with HPA and deficiency of the neurotransmitter 
precursors, L-dopa and 5-hydroxytryptophan, and thus may be detected through newborn 
screening programs which measure Phe in order to detect phenylalanine hydroxylase 
deficiency (the exception being SR deficient patients who have normal Phe concentrations). 
Untreated patients with PBD typically present with developmental delay and other severe 
neurological symptoms early in life (Smith et al, 1975; Danks et al, 1975). Infants affected by 
PTPS deficiency, the most common form of BH4 deficiency, are usually small for gestational 
age (Smith and Dhont, 1985) and can have poor sucking, impaired tone and microcephaly in 
the neonatal period. Later they present characteristic extrapyramidal symptoms due to 
deficiency of dopamine in the basal ganglia including truncal hypotonia, increased limb tone, 
postural instability, hypokinesia, choreatic or dystonic limb movements, gait difficulties, 
hypersalivation due to swallowing difficulties, and oculogyric crises. Ataxia, hyperreflexia, 
hypothermia as well as episodes of hyperthermia (in the absence of infections), drowsiness, 
irritability, disturbed sleep patterns, and convulsions (grand mal or myoclonic) are often seen 


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(Nyan and Ozand, 1998; Blau and Dhondt, 1996). The clinical course of illness in DHPR 
deficiency is similar to that seen in severe forms of PTPS deficiency with the addition of 
brain calcifications in the cortex, basal ganglia, and thalamus (Kaufman, 1975). 
PBDs are screened in all infants with HPA by measuring pterins in urine and DHPR activity 
in blood spots. A BH4 loading test in vivo is sometimes performed in European Countries 
(Dhondt JL, 1991; Blau, 2006). 
1.2 
Current Treatment of PBD 
Treatment of BH4 deficiency consists of reducing Phe concentrations in blood either by oral 
administration of BH4 (in GTP-CH and PTPS deficiency) and/or low Phe diet (mainly in 
DHPR deficiency) and administration of the neurotransmitter precursors L-dopa and 
5-hydroxytryptophan (5HTP) (Ponzone, 2006). Folinic acid is given to DHPR-deficient 
patients and also in some PTPS-deficient patients with low 5-methyltetrahydrofolate 
(5MTHF) concentrations in cerebrospinal fluid (CSF). Monoamine oxidase (MAO) or 
catechol-O-methyl transferase (COMT) inhibitors are sometimes added to the therapeutic 
regimen (Jaggi et al, 2008), and more recently dopamine receptor agonists are sometimes 
utilized (Porta et al, 2015). A synthetic form of BH4, sapropterin dihydrochloride, is 
approved (Kuvan®; NDA 022181 and NDA 205065; Biomarin Pharmaceutical, Inc.) for the 
treatment of HPA due to BH4-responsive phenylketonuria (PKU) but is not approved for 
PBD in the US. Therapy with BH4, alone or in combination with neurotransmitter precursors 
and folinic acid, has been shown to decrease blood Phe concentrations and improve 
neuromotor function in patients with PBD (Shintaku, 2002; Kitagawa et al, 1990). Reports of 
long-term follow-up of patients with BH4 deficiency are scarce (Dudesek et al, 2001; 
Chien et al, 2001; Wang et al, 2006). Therapeutic strategies vary by treating physician and 
clinic, are far from clinically based evidence, and include pharmacologic agents none of 
which have marketing approval for this indication in the US (Shintaku, 2002). 
Although there is no approved treatment for PBD in the US, in Japan a formulation of BH4 
(Biopten®, Asubio Pharma) has been marketed for this indication since 1992. In Europe, BH4 
Deficiency was included as part of the labeled indication for Kuvan® (sapropterin 
dihydrochloride) when it was approved to treat PKU in 2008. 
Two clinical trials have evaluated the safety and efficacy of sapropterin in BH4 deficient 
patients. The first study evaluated the effectiveness of sapropterin 2.5% granules (Biopten) to 
decrease blood Phe concentrations in patients with BH4 deficiency (PTPS, DHPR, or 
GTP-CH deficiency). This open-label trial which was used to support Biopten (sapropterin 
2.5% granules) registration in Japan, was conducted between 1987 and 1989, and enrolled 
and treated 16 patients with BH4 deficiency. For all 16 patients, blood Phe concentrations 
were lower after treatment with sapropterin and were maintained within the normal range 
during the treatment period (Kitigawa et al, 1990). A post-marketing surveillance study of 
the use of Biopten in the treatment of BH4 deficiency was conducted in Japan over a 10-year 
data collection period, from March 1992 to March 2002. Global improvement based on blood 
Phe concentrations and physical/mental development before and during Biopten treatment 
was assessed as an efficacy endpoint. Ninety-three percent (93%; 25/27) of patients were 
described as having a global improvement of “markedly improved”, “improved”, or “slightly 


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improved.” One patient with DHPR deficiency was described as having a global 
improvement of “unchanged” and another was classified as “exacerbated.” These 2 patients 
had also developed neurological symptoms before treatment with sapropterin, and symptoms 
of epilepsy increased during the surveillance period. 
A second study evaluating the effects of Kuvan® in PBD was conducted: Safety and Efficacy 
Study of Phenoptin in Patients with Hyperphenylalaninemia Due to BH4 Deficiency, 
ClinicalTrials.gov Identifier NCT00355264. Wasserstein et al, 2008 reported interim results 
of presumably the same study at the American Society of Human Genetics 2008 meeting: 
Interim results of a Phase II, multicenter, open-label study of sapropterin dihydrochloride in 
patients with hyperphenylalaninemia related to primary BH4 deficiency. Sapropterin was 
well tolerated. There were no deaths, serious adverse events (SAEs) or withdrawals caused 
by the drug, and blood Phe concentrations remained stable. 
1.3 
CNSA-001 (Sepiapterin) 
CNSA-001 contains the new molecular entity, sepiapterin. Sepiapterin is 
 with a molecular weight of 237.2 and a 
molecular formula of C9H11 N5O3. 
The chemical structure is: 
Sepiapterin is a natural precursor of BH4 via the pterin salvage pathway (Curtius et al, 1979; 
Mayer, 1995). The major goals of treatment for PBD are to impact signs and symptoms by 
elevating tissue levels of BH4, lowering Phe levels, and replacing potentially deficient 
neurotransmitters. Support for the use of sepiapterin for the treatment of PBD comes from 
experience with BH4. Sepiapterin is converted intracellularly to BH4. The use of BH4 for the 
treatment of PBD has been well documented in the literature and is approved for BH4 
Deficiency in Japan (Biopten) and the European Union (Kuvan®). Sepiapterin is expected to 
function as well as or better than BH4, however, until now, manufacturing sepiapterin at a 
scale to conduct appropriate clinical studies has been prohibitive. 
CNSA-001 is the first viable formulation of sepiapterin, shown to increase intracellular BH4, 
and intended for the treatment of HPA in patients with PBD. CNSA-001 was studied in a 
single and multiple ascending-dose study in healthy volunteers, the Phase 1 study, Study 
PKU-001 (Smith et al, 2019). A total of 60 subjects were exposed to single or multiple doses 
of CNSA-001. Part A of this study assessed the safety and pharmacokinetics of CNSA-001 at 
6 dose levels inclusive of an assessment of food effect (i.e., 2.5 mg/kg, 7.5 mg/kg, 20 mg/kg, 
40 mg/kg, 80 mg/kg, and 10 mg/kg [to assess food effect]). Additionally, Kuvan was 
administered at equivalent doses for the first 3 dose levels (2.5 mg/kg, 7.5 mg/kg, and 20 


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mg/kg). Dose-dependent correlations between CNSA-001 and plasma BH4 concentrations 
were observed with each successive dose level. Administration with a standard high-fat 
(approximately 50 percent of total caloric content of the meal) and high calorie 
(approximately 800 to 1000 calories) meal resulted in approximately 80% higher plasma BH4 
concentrations (area under the concentration time curve from 0 to the last measurement 
[AUC0-last] and maximum concentration [Cmax]) than in subjects who had fasted before 
receipt of CNSA-001. Treatment-emergent adverse events (TEAEs) in Part A of Study PKU-
001 were reported in 26 subjects (44.1%, 26/59). The TEAEs for CNSA-001 were generally 
mild and consistent with reported adverse events (AEs) for Kuvan® and placebo. The 
frequency of TEAEs did not appear to increase with increasing dose. The TEAEs that were 
judged to be related to study treatment were reported in 17 subjects: 11 subjects (26.2%, 
11/42) who received CNSA-001, 4 subjects (44.4%, 4/9) who received Kuvan®, and 2 
subjects (25.0%, 2/8) who received placebo. No TEAEs were severe or serious or led to 
discontinuation of study drug. Headache and dizziness were the most common TEAEs, but 
these TEAEs occurred at a similar frequency as with placebo. 
Part B of Study PKU-001 assessed multiple ascending doses CNSA-001 in healthy 
volunteers. Data indicate CNSA-001 was well tolerated following daily doses of 5, 20, and 
60 mg/kg/day for 7 days and that TEAEs were reported in 14 subjects (58.3%, 14/24). The 
TEAEs in subjects who received CNSA 001 were mild or moderate and consistent with the 
TEAEs in subjects who received placebo: TEAEs were experienced by 10 subjects (55.6%, 
10/18) who received CNSA-001 at doses from 5 mg/kg to 60 mg/kg daily for 7 days and by 4 
subjects (66.7%, 4/6) who received placebo. No TEAEs were severe, serious, or led to 
discontinuation. Of the 10 TEAEs reported in subjects who received CNSA-001, only 4 were 
judged to be related to study drug, and, of the 4 TEAEs reported in subjects who received 
placebo, only 1 was judged to be related to study drug. Somnolence, fatigue, headache, and 
procedural pain (secondary to performance of 2 sequential lumbar punctures 7 days apart) 
were the most common TEAEs reported, and they occurred at a similar frequency when 
compared with placebo with the exception of fatigue and headache, which were each 
reported in 2 subjects who received CNSA-001 (11.1%, 2/18). 
There have been 5 published case reports of PBD patients that received sepiapterin and 
demonstrated similar positive effects on blood Phe concentrations as seen with BH4 treatment 
(Niederwieser et al, 1982; Curtius et al, 1979; Hase et al, 1982; Dhondt et al, 1985; Giudici et 
al, 1991). 
1.4 
Rationale for Study 
Primary BH4 deficiency is an ultra-rare, genetically-linked disease that affects approximately 
100 to 200 patients in the US. Of these, 70% are associated with defects in the PTPS and 
GTP-CH enzymes that are responsible for the de novo synthesis of BH4. As CNSA-001 is 
part of the salvage pathway for BH4 synthesis, it is anticipated that patients with PTPS or 
recessive GTP-CH defects will produce BH4 via the salvage pathway when administered 
CNSA-001. Both in vitro and in vivo data suggest that exogenous administration of 
sepiapterin demonstrates preferential uptake into various tissues resulting in superior BH4 
production versus BH4 supplementation (Sawabe et al, 2008).  


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Although Kuvan® (sapropterin dihydrochloride) is approved in Europe for the treatment of 
HPA in adults and pediatric patients of all ages with PBD who have been shown to be 
responsive to such treatment, there is a need for additional treatment options. There is 
currently no approved treatment for HPA in PBD in the US and, therefore, represents an 
unmet medical need. The excellent safety record of sapropterin as well as the completed 
Phase 1 study of CNSA-001, Study PKU-001, and human case studies of sepiapterin 
demonstrating Phe lowering justify this study (Niederwieser et al, 1982; Curtius et al, 1979; 
Hase et al, 1982; Dhondt et al, 1985; Giudici et al, 1991). 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
The primary objective of this study is: 
• To assess the safety and tolerability of 4 dose levels of CNSA-001 in PBD patients with 
PTPS or recessive GTP-CH deficiency. 
2.2 
Secondary Objective(s) 
The secondary objective(s) of this study are: 
• To assess the pharmacokinetic profile of CNSA-001 and its effect on BH4, Phe, and Tyr 
in PBD patients with PTPS or recessive GTP-CH deficiency. 
• To evaluate the preliminary efficacy of CNSA-001 in reducing blood Phe levels in PBD 
patients with PTPS or recessive GTP-CH deficiency after 7 days of treatment. 
2.3 
Exploratory Objective 
• To assess the change from baseline in other exploratory biomarkers of this disease such 
as serum prolactin, whole blood serotonin, and urine sepiapterin, BH4, and neopterin 
levels. 
• To assess the change from baseline in a CANTAB test battery including the Reaction 
Time (RTI), the Spatial Span (SSP), the Spatial Working Memory (SWM) and Rapid 
Visual Information Processing (RVP). 
• To assess changes in movement and sleep for euphenylalaniemic and 
hyperphenylalaninemic states as assessed by an accelerometer device (GeneActiv, 
Activinsights Ltd.). 
• To evaluate changes from baseline in cognitive assessments via the NIH Cognition 
Toolbox. 
• To evaluate changes form baseline in sleep via the CASC. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 1/2, multicenter, randomized, open-label, intra-patient dose escalation study 
designed to evaluate the safety, pharmacokinetics, and preliminary evidence of efficacy of 
CNSA-001 in male and female patients with PBD. This Phase 1/2 study will enroll patients 
with confirmed defects in de novo biopterin biosynthesis due to PTPS or recessive GTP-CH 
genes, abnormal enzyme activity of the PTPS or GTP-CH enzymes, or a CSF biochemical 
profile indicative of PTPS or GTP-CH deficiencies. Genetic testing is not required. Six (6) to 
10 patients will be enrolled in this study at 5 to 6 study centers. 
Screening Period (Day -14 to Day -4): 
An informed consent or assent (if applicable) form must be signed before any study-related 
procedures are performed. After consenting to the study, PBD patients will undergo 
Screening procedures which include medical/surgical history, demographics, vital signs, 12-
lead electrocardiogram (ECG), physical examination, and clinical laboratory tests (chemistry, 
hematology, urinalysis). Blood Phe levels will be measured at Screening and compared to the 
3 most recent historical Phe concentrations. Patients who are eligible based on Screening 
tests will proceed to the BH4 Washout Period.  Patients will be asked to keep an abnormal 
movement seizure journal while on study. 
BH4 Washout Period (Day -3 to Day -1): 
Eligible patients who are taking BH4 [Kuvan® (sapropterin dihydrochloride)] will 
discontinue the medication during the BH4 Washout Period and will remain off this 
medication during the entire study. Patients will be instructed to maintain a consistent diet 
(with respect to protein and Phe intake) and 3-day diet records will be collected during BH4 
Washout Period and throughout the study. On Days -3, and -1 during the BH4 Washout 
Period, blood will be collected for determination of Phe concentrations. To minimize burden 
on patients, Phe collection on Days -3 and -1 may be obtained via filter paper with overnight 
shipping to the site’s designated laboratory.  
Treatment Period 1 and Period 2: 
Patients will receive treatment with CNSA-001 twice daily for a total of 14 days [i.e., two 
7-day treatment periods separated by a 3 (±1) day washout]. Patients will be randomized into 
one of 2 cohorts, with each cohort assessing 2 dose levels of CNSA-001 via intra-patient 
dose escalation. 
• Cohort 1, patients will receive 2.5 mg/kg/day for 7 days in Period 1, undergo a 3 (±1) 
day washout period, then escalate to 10 mg/kg/day for 7 days in Period 2 (14 days total 
treatment) 
• Cohort 2, patients will receive 5 mg/kg/day for 7 days in Period 1, undergo a 3 (±1) day 
washout period, then escalate to 20 mg/kg/day for 7 days in Period 2 (14 days total 
treatment). 


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Patients will be eligible for dose escalation during Period 2 if they meet the criteria for 
intra-patient dose escalation (see Section 6.12). 
Initially, only adult patient(s) (≥18 years) will be enrolled. The first adult patient will be 
enrolled into Cohort 1 and then a second adult patient will be enrolled into Cohort 2 of the 
study, with subsequent patients being randomized into either cohort. After the first adult 
patient(s) have completed the study, the Data Safety Monitoring Board (DSMB) (see 
Section 10.8) will review safety and PK/PD data, including preliminary efficacy, for the adult 
patient(s). If the data display no safety issues and provide for the prospect of clinical benefit 
in patients ≥12 months to <18 years old, then the eligibility criterion for age at time of 
enrollment will be expanded to include children (≥12 months). The safety, pharmacokinetic, 
and pharmacodynamic data on the dosed adult patient(s) will be submitted for review to the 
US FDA for review prior to enrolling patients <18 years old.   
During the study, patients will continue their other current medications for PBD (including 
L-dopa/carbidopa, 5HTP, melatonin, MAO inhibitors, and dopamine receptor agonists as 
prescribed) except for BH4 supplementation (if they were taking BH4) and will be monitored 
clinically as per standard of care for PBD to optimize treatment. 
Evaluations while in the study will include safety and tolerability, PK, and preliminary 
efficacy evaluation. Safety and tolerability will primarily be assessed by adverse events 
(AEs), vital signs, clinical laboratory tests (including chemistry, hematology), physical 
examinations, and urinalysis, and 12-lead ECGs. Preliminary efficacy will be assessed by the 
reduction in plasma Phe levels. Other secondary measures will include whole blood 
serotonin, serum prolactin and BH4, and urine sepiapterin, BH4 and neopterin. 
Sampling for pharmacokinetic analysis (with evaluation of sepiapterin and its effect on serum 
BH4, Phe, and Tyr levels) will occur at the following time points for each dose level: on 
Day 1 at pre-dose (within 30 min of dosing), +0.5 hr (±3 min), +1 hr (±5 min), +2 hr 
(±6 min), +4 hr (±20 min), +6 hr (±30 min), +8 hr (±60 min, prior to Day 1 evening dose), 
and +24 hours (±2 hr, prior to Day 2 morning dose) after the first dose of study drug. 
Patients will receive treatment with CNSA-001 for a total of 14 days [i.e., two 7-day 
treatment periods separated by a 3 (±1) day washout], unless they meet criteria for 
discontinuing CNSA-001 treatment. Permanent discontinuation of CNSA-001 treatment may 
be triggered by safety reasons or lack of efficacy (see Section 6.13.1). 
Patients who discontinue CNSA-001 treatment early will complete the End of Study (EOS) 
assessments. After completion of the EOS assessments, patients should immediately revert to 
pre-study standard of care for their PBD, including BH4 if they were taking it previously. 
Phone follow-up visits to assess for AEs and SAEs will occur 7 to 10 days and 30 (± 3) days 
after the last dose of study drug. 
A schedule of study events and assessments to be performed is provided in Appendix 1. The 
study design is summarized in Figure 1. 


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Figure 1. 
Study Schema 
 


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3.2 
Rationale for Study Design and Control Group 
Primary BH4 deficiency is an ultra-rare, genetically-linked disease that affects approximately 
100 to 200 patients in the US. Of these, 70% are associated with defects in the PTPS and 
GTP-CH enzymes that are responsible for the de novo synthesis of BH4. As CNSA-001 is 
part of the salvage pathway for BH4 synthesis, it is anticipated that patients with PTPS or 
recessive GTP-CH defects will produce BH4 via the salvage pathway when administered 
CNSA-001. Because of the extremely small numbers of available patients, effort to maximize 
the data obtained from each individual patient was considered. Accordingly, an intra-patient 
dose escalation will be employed to obtain safety, tolerability, PK and preliminary efficacy at 
4 different dose levels while utilizing a minimum number of patients. 
Patients will be asked to stop taking BH4 supplementation while participating in this study. 
HPA is anticipated for a short period of time during Screening and in between dosing 
periods. Short-term increases in plasma Phe will be closely monitored. Phe >360 µmol/L 
represents the lower limit of acceptable Phe concentrations in patients with HPA. If patients 
experience an increase in their Phe of more than 360 µmol/L from baseline (Day 1 pre-dose 
value) within the initial 48 hours of treatment, then they will be removed from the study and 
immediately placed back on pre-study treatment for HPA. Because of the concern for 
prolonged HPA, a placebo control will not be used in this study. 
3.3 
Rationale for Selection of Doses 
Results from completed Phase 1 study (Study PKU-001) entitled, “A Phase 1 Exploratory 
Placebo and Active-Controlled, Double-Blind, Single- and Multiple-Dose Escalation, 
Pharmacokinetic, Pharmacodynamic and Food Effect Study of CNSA-001 in Healthy 
Volunteers” indicate that CNSA-001 is safe and well tolerated at doses ranging from 2.5 to 
80 mg/kg/day as single doses and 5 to 60 mg/kg/day as multiple daily dosing over 7 days 
(Section 1.3; Smith et al. 2019). In total, 60 subjects received either single (n = 42) or 
multiple doses (n = 18) of CNSA-001 in Study PKU-001.  This study also assessed 
pharmacokinetic properties of CNSA-001 and Kuvan® (sapropterin dihydrochloride).  Both 
sepiapterin and BH4 were assessed as PK analytes in plasma.  Following oral administration 
of CNSA-001, sepiapterin was rapidly converted to BH4. Plasma concentrations of BH4 
following CNSA-001 treatment were 1.5 to 3.6 times higher (AUC0-last and Cmax) on a 
dose/dose equivalency when compared with Kuvan.  Based on these data, it is anticipated 
that the starting dose of 2.5 mg/kg/day will produce sufficient quantity of BH4 to demonstrate 
efficacy in this patient population. Subsequent doses of 5, 10 and 20 mg/kg/day were selected 
as half-log increases in doses, a typical practice in early phase 1 studies and may aid in 
assessing dose response.  Additionally, this range of doses represents the same range of doses 
used commercially by Kuvan. Lastly, these doses were found to be safe and well tolerated in 
the completed Phase 1 study PKU-001. 
In nonclinical studies conducted in mice, rats, and marmoset monkeys, rapid conversion of 
CNSA-001 to BH4 intracellularly in liver, kidney, and brain was observed.  In two 14-day 
GLP toxicology studies conducted in rat and marmoset monkey with CNSA-001 at doses of 
100, 300 and 1000 mg/kg/day, no adverse effect was observed on any assessment and the 
No-Observed-Adverse-Effect-Level (NOAEL) for both species was 1000 mg/kg/day.  This 


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correlates to a Human Equivalent Dose of 161.3 mg/kg/day and reflects a safety margin of 
approximately 64.5 based on a minimum expected therapeutic dose of 2.5 mg/kg in humans, 
the starting dose for healthy volunteers in Study PKU-001 and for patients with PBD in study 
PBD-001. 
3.4 
Risks and Benefits for Participating in Study PBD-001 
Results from completed Phase 1 study (Study PKU-001) are summarized in Section 1.3. 
Administration of CNSA-001 was found safe and well tolerated at single doses ranging from 
2.5 to 80 mg/kg/day and following multiple doses ranging from 5 to 60 mg/kg/day for 7 days.  
In this study, safety was evaluated by adverse events (AEs) reporting, vital signs and 12-lead 
ECGs, physical examination and weight, medical and laboratory assessments. Headache, 
dizziness and fatigue were the most common TEAEs reported but occurred at a similar 
frequency when compared with placebo. Shifts in liver function enzyme parameters from 
baseline observed during the study were small, either from grade 1 to no grade or vice versa.  
All post baseline vital signs were normal or slightly below normal for heart rate (<50 bpm) 
and diastolic blood pressure (<50 mm Hg).  No clinically significant increases in heart wave 
interval between Q and T with Fridericia’s correction (QTcF) values were observed. 
As indicated in Section 3.2, patients will be asked to stop taking BH4 supplementation while 
participating in this study and will likely experience associated increases in phenylalanine.  
All other treatments for their primary BH4 deficiency will remain unchanged.  For two brief 
periods, patients will not have access to any pharmacological treatment for HPA [BH4 
washout Period: 3 days duration, and CNSA-001 Washout between Treatment Periods 1 and 
2: 3 (±1) days duration].  Major clinical/neurological signs of HPA such as effects in 
coloration of the skin, hair, and eyes, psychomotor function, and mental retardation are long-
term observations. As these patients will only be off of BH4 supplementation for a short 
period of time, the concern for significant clinical/neurological effects will be minimized.  
Over short-term periods, HPA may result in slowed reaction time or impaired mental acuity, 
similar to the effects following alcohol consumption.  Accordingly, this study has 
incorporated very short-term periods for washout of BH4 to minimize potential long-term 
effects of HPA.  Additionally, patients will be requested to maintain an abnormal movement 
seizure diary throughout the study to assist with monitoring patient safety and reporting of 
potential adverse events (Section 6.14).  Rescue therapy with BH4 has also been incorporated 
should patients experience lack of efficacy with CNSA-001 treatment. 
Another potential risk is hypophenylalaninemia as a result of CNSA-001 treatment.  
Hypophenylalaninemia is extremely rare.  However, the Kuvan prescribing information 
states, “in clinical trials, some patients have experienced low blood Phe levels. Children 
younger than 7 years treated with Kuvan doses of 20 mg/kg per day are at increased risk for 
low levels of blood Phe compared with patients 7 years and older” congestion (Kuvan 
Prescribing Information, BioMarin 07/2015).”  Long term deficit of phenylalanine may result 
in poor mental and physical development.  To ensure that no long-term deficit in 
phenylalanine results with study treatment in Study PBD-001, a rescue meal will be 
provided.   


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As indicated in Sections 3.3, oral administration of CNSA-001 in Study PKU-001 resulted in 
rapid conversion or sepiapterin to BH4 with subsequent plasma concentrations of BH4 
following CNSA-001 treatment being 1.5 to 3.6 times higher (AUC0-last and Cmax) on a 
dose/dose equivalency when compared with Kuvan.  Based on these data, it is anticipated 
that all of the proposed dose levels in PBD-001 will produce enough BH4 to demonstrate 
efficacy in this patient population.   
There have been 5 published case reports of Primary BH4 Deficiency patients that received 
sepiapterin, the active ingredient of CNSA-001 (Niederwieser et al, 1982; Curtius et al, 1979; 
Hase et al, 1982; Dhondt et al, 1985; Giudici et al, 1991). These case reports demonstrated 
rapid and sustained reduction in serum Phe levels within 2–4 hours following oral 
administration of sepiapterin. Each patient received a single dose of sepiapterin ranging 
between 0.6 and ~3.3 mg/kg, with no noted adverse events. The ages of patients treated were 
between 0 (i.e., several days postnatal) and 3.5 years of age.  
CNSA-001 has been administered to 60 subjects in a phase 1 study, PKU-001 and was 
determined to be safe and well tolerated.  CNSA-001 represents a potential new treatment for 
HPA in PBD patients.  
 
3.5 
Study Duration and Dates 
The study is expected to begin enrollment in October 2018. The study duration for each 
patient is anticipated to be approximately 10 weeks. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Six (6) to 10 PBD patients will be enrolled in this study and treated with CNSA-001 (3 to 
5 patients per arm). It is expected that 5 to 6 study sites will be required to enroll patients for 
this orphan population. The study will be conducted globally. 
4.2 
Inclusion Criteria 
Individuals eligible to participate in this study include patients with PBD who meet all of the 
following criteria: 
1. 
Male or Female patients 18 years old and above and 12 months old and above for the 
remaining patients (age reduction pending analysis of safety, PK, and response, in the 
adult patient(s) by the DSMB and FDA) 
2. 
Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic 
mutations in PTPS or recessive GTP-CH genes, abnormal enzyme activity of the 
PTPS or GTP-CH enzymes, or a CSF biochemical profile indicative of PTPS or GTP-
CH deficiencies. Genetic testing is not required. 
3. 
Informed consent and assent [if necessary (i.e., for children and/or patients that are 
mentally impaired secondary to disease)] with parental consent 
4. 
Females must be either postmenopausal for ≥1 year, or surgically sterile (tubal 
ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of 
childbearing potential and not abstinent, willing to use at least 2 of the following 
methods of contraception (including adolescents 12 to 18 years old) from Screening 
through 30 days after the last dose of study drug: 
o 
Hormonal contraception (stable dose for 3 months) or 
o 
IUD/IU Hormone-releasing System, plus 
o 
Barrier contraceptive method (diaphragm, cervical cap, contraceptive sponge, 
condom) with spermicidal foam/gel/cream/suppository 
Males and females who are abstinent will not be required to use a 2nd contraceptive 
method unless they become sexually active. 
5. 
Males with female partners of childbearing potential must agree to use barrier 
contraceptive (i.e., condom) with spermicidal foam from Screening through 90 days 
after the last dose of study drug. Males must also refrain from sperm donations during 
this time period. 
6. 
Females with a negative pregnancy test at Screening and on Day 1 prior to dosing 
7. 
Creatinine clearance (CrCl) >90 mL/min as estimated using the Cockcroft-Gault 
equation (≥18 years) or Schwartz-Lyon equation (≥ 12 months < 18 years) (Appendix 
2) 
8. 
The patient is clinically stable on therapy for management of their signs and 
symptoms of PBD as determined by the Investigator 


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9. 
The patient is willing and able to comply with the protocol 
10. 
No tobacco use (e.g., cigarettes, e-cigarettes, cigars, smokeless tobacco) for 2 weeks 
prior to the Screening visit and willingness to abstain from these products through the 
last dose of study drug 
4.3 
Exclusion Criteria 
Individuals are not eligible to participate in this study if they have or meet any of the 
following criteria: 
1. 
PBD caused by biallelic pathogenic mutations in PCD, SR, DHPR, or single dominant 
mutations in GTP-CH 
2. 
Significant chronic medical illness other than PBD, as determined by the Investigator 
3. 
Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel 
disease, chronic gastritis, peptic ulcer disease, etc.) that could affect the absorption of 
study drug 
4. 
History of gastric surgery, including Roux-en-Y gastric bypass surgery or an 
antrectomy with vagotomy, or gastrectomy 
5. 
Inability to tolerate oral medication 
6. 
History of allergies or adverse reactions to BH4 or related compounds, or any 
excipients in the study drug formulation 
7. 
Any clinically significant medical or psychiatric condition or medical history, that in 
the opinion of the Investigator, would interfere with the patient’s ability to participate 
in the study or increase the risk of participation for that patient 
8. 
Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) 
or hepatitis C virus (HCV) 
9. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) laboratory 
values >2 × the upper limit of normal (ULN) 
10. 
Any other clinically significant laboratory abnormality unrelated to PBD at the 
Screening visit or prior to the administration of the first dose of study drug, as 
determined by the Investigator 
11. 
Clinically significant cardiac arrhythmia at Screening or prior to the first dose of study 
drug 
12. 
QTcF (QT with Fredericia’s correction) ≥460 msec in males and ≥480 msec in females 
(based on the mean of triplicate measurements taken at Screening) 
13. 
Resting heart rate ≤40 or ≥110 bpm for ages 12 and older, ≥ 130 bpm for ages 3 to 12, 
≥ 150 bpm for ages 1-2 years or resting blood pressure <85/40 mmHg or >150/90 
mmHg at Screening or prior to the first administration of study drug 
14. 
Current participation in any other investigational drug study or participation within 
30 days prior to Screening 


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15. 
History of alcohol or drug abuse within last 6 months prior to Screening or current 
evidence of substance dependence as determined by the Investigator 
16. 
Currently taking an antifolate including, but not limited to, methotrexate, pemetrexed, 
or trimetrexate 
17. 
A female who is nursing or who is pregnant or planning to become pregnant 
18. 
The patient, in the opinion of the Investigator, is unwilling or unable to adhere to the 
requirements of the study 
 


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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Study Drug 
CNSA-001 contains the new chemical entity, sepiapterin. Sepiapterin is 
 with a molecular weight of 237.2 and a 
molecular formula of C9H11 N5O3. 
The chemical structure is: 
The test product is CNSA-001 (sepiapterin) oral powder for suspension. 
5.1.2 
Placebo or Control 
There is no placebo or control product. 
Patients will be randomized to one of 2 cohorts that will test 2 dose levels each, adjusted for 
body weight:  
• Cohort 1, patients will receive 2.5 mg/kg/day for 7 days in Period 1, undergo a 3 (±1) 
day washout period, then escalate to 10 mg/kg/day for 7 days in Period 2 (14 days total 
treatment) 
• Cohort 2, patients will receive 5 mg/kg/day for 7 days in Period 1, undergo a 3 (±1) day 
washout period, then escalate to 20 mg/kg/day for 7 days in Period 2 (14 days total 
treatment). 
All dosing will be divided and administered twice daily with breakfast and dinner.   
Details on preparation of study drug (i.e. suspension for oral administration) and dosing 
guidelines will be provided in a pharmacy manual for the site and an instruction guide for 
patients. 
5.3 
Selection and Timing of Dose for Each Patient 
Patients will receive CNSA-001 twice daily during the treatment period for a duration of 
7 days followed by a 3 (±1) day washout and then intra-patient escalation to a second dose 
level for an additional 7 days (i.e., 14 days of total treatment).  Patients will be allowed to 


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dose-escalate during Period 2, only if none of the criteria in Section 6.12 are met.  If a patient 
meets any of the criteria prohibiting dose escalation, the patient will discontinue further study 
treatment and will complete the EOS assessments (See Section 7.6).   
5.4 
Method of Assigning Patients to Treatment Groups 
Patients who fulfill the eligibility criteria, provide informed consent, and complete the BH4 
Washout Period, will be enrolled into the study and randomized to study treatment. Patients 
will be randomized to one of 2 cohorts, both receiving active treatment (see Figure 1). 
5.5 
Blinding 
This Phase 1/2 study is an open-label study; therefore, neither patients nor the Investigator 
are blinded to study treatment. 
5.6 
Concomitant Therapy 
Patients will continue their other current medications for PBD (including L-dopa/carbidopa, 
5HTP, melatonin, MAO inhibitors, and dopamine receptor agonists as prescribed) except for 
BH4 supplementation (if they were taking BH4) and will be monitored clinically as per 
standard of care for PBD to optimize treatment. 
Patients will not be permitted to take any drugs known to inhibit folate synthesis (e.g., 
methotrexate, pemetrexed, trimetrexate). 
During the study, the Investigator can prescribe additional medications as long as they are 
not prohibited medications (as described above). Study staff will record on the case report 
form (CRF) all prescription and over-the-counter medications that a patient takes during the 
study (from the time of informed consent until the EOS visit). 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
Study staff will record on the CRF all prescription and over-the-counter medications that a 
patient took during the 30-day period before Screening. Any patients taking BH4 therapy 
prior to study entry will undergo a “washout” period during Screening before they can 
qualify for randomization. 
5.7.2 
Fluid and Food Intake 
Patients will be instructed to maintain a consistent diet, with respect to protein and Phe 
intake, and 3-day diet records will be obtained throughout the study. Diet records will be 
reviewed by a qualified dietician at each site. Total Phe concentrations for the 3-day period 
will be calculated by the dietician and entered in the electronic CRF (eCRF). 


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5.7.3 
Total Blood Volume 
The total volume of blood obtained from an individual study participant is expected to be 
approximately 125 mL, including pharmacokinetic and biomarker samples and clinical 
laboratory tests. 
5.7.4 
Patient Activity Restrictions 
Patients will not be confined during the study and will not require any activity restrictions. 
5.8 
Treatment Compliance 
Study staff will instruct patients to return all used and unused study drug bottles at each study 
visit. Compliance with the dosing regimen will be assessed by reconciliation of used and 
unused study drug bottles and study drug vials (prior to reconstitution). The quantities 
dispensed, returned, used, and lost will be recorded on the dispensing log provided for the 
study. 
5.9 
Packaging and Labeling 
CNSA-001 drug product packaging consists of CNSA-001 vials (vials sufficient for each 
dose level), 1 bottle of Medisca® Oral Mix, (473mL), an empty vial with cap for suspending 
CNSA-001 in Medisca Oral Mix, and a dosing syringe. CNSA-001 Oral Powder for 
Suspension is packaged in 10 mL amber glass vials with black child proof caps. Each glass 
vial contains 175 mg of the active ingredient, sepiapterin. The suspending agent, Medisca® 
Oral Mix (473 mL), is included. A dosing syringe is included for accurate measurement of 
dose volumes. 
Each vial of CNSA-001 Oral Powder for Suspension will contain the product name, strength, 
content, and company name. Each vial label will contain the words, “Caution: New Drug—
Limited by Federal (or US) law to investigational use.’’ 
5.10 
Storage and Accountability 
All drug product required for completion of this study will be provided by Censa 
Pharmaceuticals. 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 
accountability records must be readily available for inspection by the study monitor and are 
open to inspection at any time by applicable regulatory authorities. 
5.11 
Investigational Product Retention at Study Site 
Upon the completion of the study and once inventoried by the study site and the Sponsor’s 
clinical research monitor, all used vials of drug product will be destroyed. Any unused vials 
of drug product may be either destroyed or returned to the Sponsor following discussion with 
the Sponsor. If drug product is destroyed, a certificate of destruction will be provided to the 
Sponsor by the appropriate facility performing the destruction. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Consent forms describing in detail the study agent, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to conducting 
study-related procedures. 
For pediatric participants, full informed consent should be obtained from the legal guardian 
in accordance with regional laws or regulations. Where appropriate, pediatric participants 
should assent to enroll in a study (age of assent to be determined by Institutional Review 
Boards (IRBs)/ Independent Ethics Committees (IECs) or be consistent with local legal 
requirements). 
See Section 10.4 for more information on the informed consent process. 
6.2 
Medical History and Demographic Data 
A detailed medical history will be obtained at Screening. The history includes 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; and neurological. 
The number and reasons for hospitalizations during the previous year should be recorded. 
The 3 most recent historical Phe concentrations will be collected as part of the medical 
history. Documentation by medical history of biallelic pathogenic mutations in PTPS or 
recessive GTP-CH genes, abnormal enzyme activity of the PTPS or GTP-CH enzymes, or a 
CSF biochemical profile indicative of PTPS or GTP-CH deficiencies should also be recorded 
as part of the medical history. No genetic testing or retesting is required. 
Demographic data will include age, gender, and self-reported race/ethnicity. 
6.3 
Physical Examination 
A physical examination will be performed at Screening and on the Day 1 and Day 7 study 
visits during treatment Periods 1 and 2, and at the EOS visit. On Day 1 of each treatment 
period, a physical examination will be performed before the patient receives the first dose of 
study drug. The examination will assess general appearance, as well as dermatologic, 
HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, and 
neurological parameters. 
6.4 
Vital Signs 
Vital signs, including blood pressure, pulse, respiratory rate, and oral temperature, will be 
measured at Screening and on Day 1, Day 2 and Day 7 during each period, and at the EOS 
visit. Patients will have a 5-minute rest in a supine position before vital signs are assessed. 
On Day 1 of each treatment period, vital signs will be performed before the patient receives 
the first dose of study drug and post-dose at 2 hours (before 2-hour blood collection for PK). 
Weight will only be collected at Screening and on Day 1 of each treatment period.  Height 
will only be collected at Screening. 


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6.5 
ECGs  
Twelve-lead ECGs will be obtained at the Screening visit, and on Day 1 (pre-dose) and Day 
7 of each treatment period. ECGs will be performed in triplicate, with each read taken 1 
minute apart. The following parameters will be collected and recorded in the e-CRF: 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. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Local Laboratory Parameters 
Clinical laboratory tests will be performed by a qualified local laboratory. Blood and urine 
samples for clinical chemistry, hematology, and urinalysis will be collected at Screening and 
on Day 1 (before the morning dose) and Day 7 study visits of each period and at EOS if early 
termination. Patients should be fasted prior to collection of samples (minimum of 8 hours 
prior to sample collection. Urine samples will not be collected from toddlers unless they are 
toilet trained and a sample can be obtained.   
 


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The following laboratory parameters will be analyzed by the local laboratory: 
Hematology: 
- 
Hematocrit (HCT) 
- 
Hemoglobin (HGB) 
- 
Platelet count 
- 
Red blood cell (RBC) count 
- 
White blood cell (WBC) count with 
differential (neutrophils, eosinophils, 
basophils, lymphocytes, and 
monocytes) 
Urinalysis: 
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Microscopic examination of sediment 
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Urobilinogen 
Pregnancy Testing: 
- 
Serum human chorionic gonadotropin 
(HCG) at Screening 
- 
Urine human chorionic gonadotropin 
(HCG) prior to Periods 1 and 2 and 
EOS 
Serum Chemistry: 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (AP) 
- 
Alanine aminotransferase (ALT; 
SGPT) 
- 
Aspartate aminotransferase (AST; 
SGOT) 
- 
Blood urea nitrogen (BUN) 
- 
Calcium (Ca) 
- 
Carbon dioxide (CO2) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Gamma glutamyl transferase (GGT) 
- 
Glucose 
- 
Lactate dehydrogenase (LDH) 
- 
Phosphorus 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total bilirubin 
- 
Direct bilirubin 
- 
Total cholesterol 
- 
Total protein 
- 
Uric acid 
Exploratory Biomarker: 
- 
Prolactin 
 
Blood Phe levels will be analyzed by a local laboratory at the Screening visit and during the 
BH4 Washout Period (Days -3, and -1), and during Treatment Period 1 and Period 2 on Day 1 
(pre-dose), Day 2 (pre-dose), Day 4 (±1 day), Day 7, and EOS to monitor for safety (see 
Section 6.8.1). To minimize burden on patients, Phe collection on Days -3 and -1 during the 
BH4 Washout Period may be obtained via filter paper with overnight shipping to the site’s 
designated laboratory. 


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6.6.2 
Bioanalytical Laboratory Parameters 
6.6.2.1 
Sample Collection, Storage, and Shipping 
The following pharmacokinetic, preliminary efficacy (i.e., Phe), and secondary biomarkers 
will be analyzed by a qualified bioanalytical laboratory. Blood, plasma and urine samples for 
analysis will be sent to Medical Neurogenetics Laboratories. Urine samples will not be 
collected from toddlers unless they are toilet trained and a sample can be obtained.  See 
Appendix 3 for details on sample collection and shipping for bioanalytical samples. 
Analyte 
Source  
 
Endpoint 
Sepiapterin 
Plasma 
Pharmacokinetic  
BH4 
Plasma 
Pharmacokinetic  
Phenylalanine 
Plasma 
Pharmacokinetic/Preliminary Efficacy  
Tyrosine 
Plasma 
Pharmacokinetic  
Serotonin 
Whole blood 
Exploratory Biomarker 
Sepiapterin 
Urine 
Exploratory Biomarker 
BH4 
Urine 
Exploratory Biomarker 
Neopterin 
Urine 
Exploratory Biomarker 
 
Blood Phe levels collected during treatment Period 1 and Period 2 on Days 1 (pre-dose), 
2 (pre-dose), 4 (±1), 7 and EOS visit will be analyzed by the bioanalytical laboratory upon 
completion of the study (see Section 6.8.1).   
6.7 
Dispensing Study Drug 
Dosing of CNSA-001 is based on the patient’s weight. When dispensing CNSA-001, the 
patient’s weight obtained on Day 1 of each dosing period will be used to calculate the exact 
mg of active ingredient, sepiapterin, required for each patient’s daily dose. For example, if 
the patient’s weight was 70 kg on Day 1 of dosing, and this patient was randomized to 
receive 2.5 mg/kg/day, then the total mg/day required of active ingredient, sepiapterin, would 
be 175 mg or one vial of CNSA-001.  
Patients will take both doses of CNSA-001 on Day 1 and the morning dose of CNSA-001 on 
Day 2 while in the clinic; for all other dosing days, patients should take their morning dose 
prior to coming to the clinic for assessments.  
Study drug will be dispensed at each Day 2 study visit and will include enough study drug 
for dosing until the Day 7 study visit. This will include enough CNSA-001 for the remainder 
of the treatment period plus one additional day (e.g., to account for holidays, weekends, or 
difficulties in scheduling study visits). Patients will be instructed on how to mix CNSA-001 
powder for oral suspension and how much volume to take.   


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Details on preparation of study drug and dosing guidelines will be provided in a pharmacy 
manual for the site and an instruction guide for patients. 
6.8 
Efficacy Assessments 
6.8.1 
Blood Phenylalanine Levels 
Phe levels will be measured at Screening and compared to the 3 most recent historical Phe 
concentrations. These values will be recorded as part of the patient’s medical history. 
Eligible patients who are taking BH4 [Kuvan® (sapropterin dihydrochloride)] will stop 
taking BH4 following the Screening visit and 3 days prior to randomization. On Days -3 and -
1, blood will be collected for determination of Phe concentrations. To minimize burden on 
patients, Phe collection on Days -3 and -1 may be obtained via filter paper with overnight 
shipping to the site’s designated laboratory.  
During the treatment periods, blood Phe levels will be measured at each study visit (Day 1 
and Day 2 [pre-dose], Day 4 (±1) and Day 7 [after the morning dose]), and at the EOS visit. 
Analysis of Phe levels during the treatment periods will be conducted at the site’s designated 
laboratory in real-time to monitor for safety, and at the bioanalytical laboratory for 
assessment of preliminary efficacy and may use the same sample collected for 
pharmacokinetic Phe concentrations. If blood Phe concentrations have increased from 
baseline by >360 µmol/L after the initial 48 hours of treatment, patients should discontinue 
CNSA-001 treatment and will be withdrawn from the study. Patients who are withdrawn 
from the study will have EOS assessments collected (see Section 7.6). If blood Phe 
concentrations have decreased below the lower limit of normal defined as <30 μmol/L 
anytime while on treatment, patients will be asked to provide an unscheduled blood Phe 
sample.  Immediately following this sample, they will be asked to consume a rescue therapy 
consisting of extra protein starting at 0.25 g/kg per day given as eggs, meat or cheese, etc. 
depending on patient preference. If a patient experiences hypophenylalaninemia as defined 
above, stopping rules may apply (see Section 6.13.1). 
Blood samples for Phe as a measure of preliminary efficacy should be collected as pre-fed or 
no earlier than 3 hours following the patient’s last meal and at approximately the same time 
of day at each visit (after the morning dose). The bioanalytical laboratory will analyze 
samples for blood Phe levels collected for efficacy (see Section 6.6.2.1). 
6.8.2 
Other Biomarker Levels 
Exploratory biomarkers to be measured during the study will include serum prolactin, whole 
blood serotonin, and urine sepiapterin, BH4 and neopterin levels. Urine collection should be 
the first void of the day.  Urine samples will not be collected from toddlers unless they are 
toilet trained and a sample can be obtained.   
Serum prolactin samples will be analyzed by a local laboratory and urine sepiapterin, BH4 
neopterin, and whole blood serotonin samples will be analyzed by the bioanalytical 
laboratory, MNG Laboratories. Directions for sample collections for those samples sent to 
the bioanalytical laboratory will be provided in Appendix 3. 


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6.8.3 
Cambridge Neuropsychological Test Automated Battery (CANTAB) Test 
Battery 
Phenylalanine accumulation has been demonstrated to cause impairments in psychomotor 
processing and executive functions (Palermo et al, 2017). The Cambridge 
Neuropsychological Test Automated Battery (CANTAB) is a highly sensitive set of 
cognitive assessments designed to detect impairments in executive cognitive functioning. 
Cognitive assessments to explore the potential effects of CNSA-001 on specific brain 
functions will be administered during Screening and on Day 1 (pre-dose) and Day 7 of each 
treatment period. The CANTAB test battery will include 4 short assessments designed to 
measure key cognitive domains of reaction time, memory and attention. The CANTAB test 
battery will include the RTI, the SSP, the SWM, and the RVP. 
• The CANTAB RTI task is a processing and psychomotor speed task that will take on 
average 6 minutes to complete. 
• The CANTAB SSP task is a measure of visual working memory and executive 
function and will take on average 8 minutes to complete. 
• The CANTAB SWM task is a simultaneous measure of executive functioning (more 
specifically strategic thinking), alongside working memory and will take on average 6 
minutes to complete. 
• The CANTAB RVP task is a measure of sustained attention, requiring participants to 
continually scan an array of flashing digits and identify specific target sequences and 
will take on average 8 minutes to complete. 
6.8.4 
GENEActiv Accelerometer Device 
The wrist-worn GENEActiv accelerometer is a highly sensitive device that records changes 
in physical activity and sleep patterns of behavior.  It is postulated that data from the 
GENEActiv device may support valid comparisons in patient’s changes of behavior, physical 
activity and sleep when patients are on and off CNSA-001 therapy.   
Patients will be asked to wear a GENEActiv accelerometer continuously for up to two 14-day 
periods starting no earlier than Day -7 during screening through to the End of Study visit.   
6.8.5 
The NIH Toolbox – Cognition Domain 
The NIH Toolbox® for Assessment of Neurological and Behavioral Function (NIH Toolbox) 
is an open-sourced set of computerized tests (http://www.healthmeasures.net/explore-
measurement-systems/nih-toolbox/intro-to-nih-toolbox/cognition) (Weintraub et al. 2013).  
The Toolbox was specifically designed to measure neuropsychological and behavioral 
functions over time and to measure key constructs across developmental stages.  This 
facilitates the potential evaluation of treatment effectiveness of CNSA-001, as well.  This 
study will use an age-based battery of assessments from the Cognitive Domain of the NIH 


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Toolbox.  All tests will be administered via an iPad on either Day-1 or Day 1 predose (i.e., at 
baseline) and on Day 7 of each Treatment Period. 
The following tests comprise the Fluid Cognition Composite Score. 
For children and adolescents ages 3-17, the following subtests will be administered: 
6.8.5.1 
NIH Toolbox Flanker Inhibitory Control and Attention Test (3 minutes) 
The Flanker task measures both a participant’s attention and inhibitory control (Zelazo et al. 
2013). The test requires the participant to focus on a given stimulus while inhibiting attention 
to stimuli (arrows for ages 8-85) flanking it. Sometimes the middle stimulus is pointing in the 
same direction as the “flankers” (congruent) and sometimes in the opposite direction 
(incongruent). Scoring is based on a combination of accuracy and reaction time. 
6.8.5.2 
NIH Toolbox Picture Sequence Memory Test (7 minutes) 
Picture Sequence Memory Test assesses episodic memory (Bauer et al. 2013). It measures 
cognitive processes involved in the acquisition, storage, and retrieval of new information. It 
involves recalling increasingly lengthy series of illustrated objects and activities that are 
presented in a particular order on the computer screen. The participants are asked to recall the 
sequence of pictures that is demonstrated over two learning trials; sequence length varies 
from 6-18 pictures, depending on age.  
6.8.5.3 
NIH Toolbox Picture Vocabulary Test (4 minutes)  
The Picture Vocabulary Test measures receptive vocabulary administered in a computer-
adaptive test (CAT) format (Gershon et al. 2013). Respondents select the picture that most 
closely matches the meaning of the word. 
6.8.5.4 
NIH Toolbox Dimensional Card Sort (4 minutes) 
The Dimensional Change Card Sort Test is a measure of cognitive flexibility. Two target 
pictures are presented that vary along two dimensions (e.g., shape and color).  The task 
involves deciding whether the two pictures are the same or different (depending on whether 
the “rule” is to sort by color or shape). This task measures the capacity to plan, organize, and 
monitor the execution of behaviors that are strategically directed in a goal-oriented manner.  
Errors and reaction time are recorded (Zelazo et al. 2013). 
For children and adolescents ages 7-17 the following additional tests will be 
administered:  
6.8.5.5 
NIH Toolbox List Sorting Working Memory Test (7 minutes)  
The List Sorting Working Memory Test assesses working memory and requires the 
participant to sequence different visually- and orally-presented stimuli (Tulsky et al. 2013). 
Pictures of different foods and animals are displayed with both a sound clip and written text 
that name the item. The task has two different conditions: 1-List and 2-List. In the 1-List 


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condition, participants are required to order a series of objects (either food or animals) in size 
order from smallest to largest. In the 2-List condition, participants are presented both food 
and animals and are asked to report the food in size order, followed by the animals in size 
order.  
6.8.5.6 
NIH Toolbox Pattern Comparison Processing Speed Test (3 minutes)  
The Pattern Comparison Processing Speed Test measures speed of processing by asking 
participants to discern whether two side-by-side pictures are the same or not (Carlozzi et al. 
2013). Participants’ raw score is the number of items correct in a 90-second period. The 
items are designed to be simple to most purely measure processing speed.  
6.8.6 
Child and Adolescent Sleep Checklist (CASC) 
The Child and Adolescent Sleep Checklist is a 24-item parent questionnaire to identify sleep 
problems in children, ages 3-18 years (Oka et al. 2009).  Parents or caregivers are asked to 
recall the child’s sleep during the last 7 days when providing responses to questions. 
Responses to the questions about sleep habits are scored from 0 (never or don’t know) to 3 
(always), yielding an overall score of 0-72.  Scores above 18 indicate sleep problems.  In 
addition, there are four categories of scores:  Bedtime problems (Q1-Q6; 6 questions), sleep 
breathing and unstable sleep (Q7-Q12; 6 questions), parasomnia and sleep movement (Q13-
Q18; 6 questions), and daytime problems (Q19-Q24; 6 questions).  The CASC takes about 10 
minutes to complete. 
A parent or caregiver of patients between the ages of 3-18 years will be asked to complete 
the CASC at Day 1 and Day 7 or each treatment period.  
6.9 
Pharmacokinetic Assessments 
Sampling for pharmacokinetic analysis (with evaluation of sepiapterin and its effect on BH4, 
Phe and Tyr levels) will occur at the following time points for each dose level: on Day 1 at 
pre-dose (within 30 min of dosing), +0.5 hr (±3 min), +1 hr (±5 min), +2 hr (±6 min), +4 hr 
(±20 min), +6 hr (±30 min), +8 hr (±60 min, prior to Day 1 evening dose), and +24 hours 
(±2 hr, prior to Day 2 morning dose) after the first dose of study drug. 
The concentration of CNSA-001 (sepiapterin), BH4, Phe, and Tyr in plasma samples will be 
analyzed by MNG Laboratories using a validated LC/MS/MS method. The following 
non-compartmental PK parameters will be estimated and summarized along with graphical 
presentation of the concentration data: 
Parameter 
Definition 
AUC0-inf 
Area under the curve from time 0 to infinity using trapezoidal method 
(linear-up/log-down method) and extrapolation to infinite time 
AUC0-last 
Area under the curve from time 0 to the time of the last quantifiable 
concentration using linear-up/log-down method trapezoidal method 
Cmax 
Maximum observed concentration 


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Parameter 
Definition 
Tmax 
Time to Cmax 
t1/2 
Half-life 
Ke 
Elimination rate constant 
6.10 
Adverse Events Assessments 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
The occurrence of an AE or SAE (see Section 6.10.6) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical 
care, or upon review by a study monitor. All AEs including local and systemic reactions not 
meeting the criteria for SAEs will be captured on the appropriate CRF. Information to be 
collected includes, but not limited to, the event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All 
treatment-related AEs or AEs leading to discontinuation will be followed to adequate 
resolution as determined by the Investigator. 
Any medical condition that is present at the time that the participant is screened will be 
considered as medical history and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
6.10.1 
Reporting Timelines 
The Investigator will record all reportable events with start dates occurring any time after 
informed consent and continue through clinical trial completion or, in the case of withdrawal, 
until the outcome is determined. AEs will be assessed at each visit and/or through telephone 
contact with the patient. A neutral question, such as “How have you been feeling since your 
last visit?” may be asked.  
All SAEs should be reported after the patient signs the informed consent and followed until 
resolution, stabilization or until the Investigator provides sufficient evidence that no further 
information can be obtained. 
All SAEs and pregnancies occurring while the patient is on the study or within 30 (±3) days 
after the patient received their last dose of study drug must be reported within 24 hours of 
knowledge of the event by study personnel whether or not considered to be related to study 
drug. 


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Deaths that occur ≥ 30 (±3) days after the patient’s last study dose must be reported within 
24 hours of knowledge of the event if deemed related to study drug by the Investigator  
Although pregnancy is not always considered an AE or SAE by regulatory definition, for this 
study pregnancies must be processed following SAE timelines (e.g., within 24 hours of 
knowledge of the pregnancy) for data transmission purposes. In the event that a pregnancy 
complication occurs or elective termination of a pregnancy is required for medical reasons, 
then the complication will be recorded as an AE or SAE, as appropriate. 
While elective and uncomplicated induced abortion not required for medical reasons does not 
constitute an AE or SAE (even if the patient is hospitalized to undergo abortion), 
spontaneous abortion is considered a fatal event and must be reported as an AE and SAE as 
appropriate. 
Any pregnancy and/or suspected pregnancy that occurs during the study in a female patient 
should be reported using Pregnancy Reporting Form within 24 hours of knowledge of the 
event by study personnel. Any pregnancy and/or suspected pregnancy will be followed for 
outcome. 
The Investigator must notify the Sponsor after the pregnancy is confirmed following SAE 
reporting timelines. If the patient has received the investigational drug prior to becoming 
pregnant, the patient will continue the efficacy assessment and follow-up periods and 
measures of safety and efficacy will be obtained. 
The patient will be followed until the outcome of the pregnancy is determined. It is the 
responsibility of the Investigator to obtain and document pregnancy information on the most 
recent Pregnancy Report Form. Furthermore, any SAE occurring as outcome of the 
pregnancy must be reported according to the procedures outlined for SAE reporting. 
6.10.2 
Severity 
Adverse events will be graded using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03 (NCI, 2010) severity grading scheme 
as defined in Table 1. 
Table 1: 
Severity Grading of Adverse Events (NCI CTCAE Criteria version 4.03) 
Grade 
Severity 
Definitions 
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL* 
3 
Severe 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL** 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE 
* 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 


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** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
ADL = activities of daily living; AE = adverse event; NCI CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events  
Medical conditions/diseases present before consenting the patient are only considered 
adverse events if they worsen after receiving any study drug. All laboratory values are to be 
reviewed by the Investigator and medically relevant abnormal values will be graded 
according to the CTCAE Version 4.03 as well (NCI, 2010). 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity; however, an AE of severe intensity need not necessarily be considered serious. For 
example, nausea that persists for several hours may be considered severe nausea but may not 
be considered an SAE. Alternatively, a stroke that results in only a limited degree of 
disability may be considered only a mild stroke but would be considered an SAE. 
6.10.3 
Relationship 
The Investigator’s assessment of causality must be provided for all AEs (serious and non-
serious). An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the study drug caused or contributed to an AE. For purposes of 
consistency, guidelines for assessing causality are provided below: 
Not Related 
The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There 
must be an alternative, definitive etiology documented by the clinician. 
No relationship between the experience and the administration of study 
drug; related to other etiologies such as concomitant medications or 
patient’s clinical state. 
Unlikely to be 
Related 
A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after 
administration of the trial medication) and in which other drugs or chemicals 
or underlying disease provides plausible explanations (e.g., the participant’s 
clinical condition, other concomitant treatments). 
Possibly 
Related 
There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., 
the participant’s clinical condition, other concomitant events). Although an 
AE may rate only as “possibly related” soon after discovery, it can be 
flagged as requiring more information and later be upgraded to “probably 
related” or “definitely related,” as appropriate. 
Probably 
Related 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the drug, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, 


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and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.  
Definitely 
Related 
There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an 
abnormal laboratory test result, occurs in a plausible time relationship to 
drug administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the drug (dechallenge) 
should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary.  
 
These criteria, in addition to good clinical judgment, should be used as a guide for 
determining the causal assessment. If the event is believed to be unrelated to study drug 
administration, then an alternative explanation should be provided, if available. 
6.10.4 
Expectedness 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the 
Investigators’ Brochure (IB) or is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the protocol. 
The drug safety medical reviewer (or designee) will be responsible for determining whether 
an AE or SAE is expected or unexpected. An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent (e.g., IB). 
6.10.5 
Clinical Laboratory Adverse Events 
Laboratory abnormalities should not be recorded as AEs or SAEs unless they are associated 
with clinical signs or symptoms or require medical intervention. However, each laboratory 
abnormality (e.g., clinically significant changes detected in hematology, serum chemistry 
panel, urinalysis, and urine microscopic evaluations) independent from any underlying 
medical condition that requires medical or surgical intervention, or that leads to study drug 
interruption or discontinuation, must be recorded as an AE, or SAE if applicable. If the 
laboratory abnormality is part of a clinical condition or syndrome, it should be recorded as 
the syndrome or diagnosis rather than as the individual laboratory abnormality. In addition, 
laboratory abnormalities or other abnormal test assessments (e.g., vital signs) performed that 
are associated with signs or symptoms must be recorded as AEs or SAEs if they meet the 
definition of an AE (or SAE) as described below. 


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6.10.6 
Serious Adverse Events 
6.10.6.1 
Definition 
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of 
either the Investigator or sponsor, it results in any of the following outcomes: death, life 
threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity or a substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect. 
An adverse event or suspected adverse reaction is considered ‘‘life-threatening’’ if, in the 
view of either the Investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in these other situations. 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
‘‘reasonable possibility’’ means there is evidence to suggest a causal relationship between 
the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a 
drug. 
For countries outside of the US, the associated ICH adverse and serious adverse event 
guidelines will be followed, and local regulatory guidance will apply. 
6.10.6.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
The Sponsor must report in an IND safety report any suspected adverse reaction to study 
treatment that is both serious and unexpected. Before submitting an IND safety report, the 
Sponsor needs to ensure that the event meets all 3 of the definitions: 
• Suspected adverse reaction 
• Serious 
• Unexpected 
If the AE does not meet all 3 of the definitions, it should not be submitted as an IND safety 
report. 


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6.10.6.3 
Reporting Serious Adverse Events 
The Investigator will report all SAEs within 24 hours of knowledge of the event whether or 
not considered to be related to study drug to the designated drug safety team using the SAE 
Report Form provided (following timelines included in Section 6.10.1). 
Although not all information required for a complete SAE Report Form may be readily 
available at the time of the event, the Investigator must include sufficient information on the 
SAE Report Form to allow for a complete medical assessment. This should include at a 
minimum the patient number, site number, detailed description of the event, seriousness 
criteria, causality/relationship to study drug, and Investigator signature. 
The designated drug safety team will acknowledge the receipt of the SAE via email to the 
clinical site. After submission of the initial report, the Investigator will provide follow-up 
information to the drug safety team as requested (e.g., concomitant medications, hospital 
discharge summary) to further evaluate the event and assure that all appropriate information 
is received. Once all information is received and the SAE has been deemed appropriate for 
closure, the SAE Report Form must be signed and dated by the Investigator. 
The Investigator is responsible for informing the IRB/IEC of the SAE in accordance with 
institutional policies and procedures including relevant initial and follow-up information 
about the SAE. 
Treatment-related SAEs or events leading to discontinuation will be followed for outcome 
information until resolution or stabilization. Other supporting documentation of the event 
may be requested by Censa Pharmaceuticals or designee and should be provided as soon as 
possible. The Medical Monitor should be contacted when the Investigator considers an SAE 
to be treatment-related. 
6.10.7 
Treatment-Emergent Adverse Events 
Treatment-emergent AEs (TEAEs) are AEs that start at the time of or after the first dose of 
study drug. AEs that worsen at or after the time of first dose of study drug are also 
considered treatment-emergent. All AEs that occur on or after the informed consent form has 
been signed, including all treatment-emergent AE, through 7 days after the last dose of study 
drug (30 days after last dose of study drug for SAEs) will be recorded in the eCRF. 
6.11 
Prior and Concomitant Medication Assessments 
All prescription and over-the-counter medications taken by a patient starting from the 30-day 
period before Screening through the last study visit will be recorded. Any concomitant 
medications added or discontinued during the study will be recorded at each visit. 


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6.12 
Intra-Patient Dose Escalation Criteria 
A determination regarding intra-patient dose escalation will be made in consultation by the 
Investigator with the Sponsor and the Medical Monitor if either of the following criteria are 
met: 
• The presence of any Grade 3 or greater AE (per Common Terminology Criteria for AEs 
[CTCAE] v4.03) or SAE, regardless of relationship to study drug, which occurs prior to 
Day 1 of Dosing Period 2. 
• The presence of any Grade 3 or greater (per CTCAE v4.03) laboratory abnormality, 
regardless of Investigator assessment of clinical significance or relationship to study 
drug, which occurs prior to Day 1 of Dosing Period 2, including any unscheduled 
laboratory results. 
If neither of the above criteria are met, if no study halting rules have been met, and if none of 
the criteria in Section 6.13.1 for premature discontinuation of study drug have been met, dose 
escalation for the patient may continue as per the protocol. 
6.13 
Removal of Patients from the Trial or Study Drug 
6.13.1 
Early Discontinuation from Study Drug Administration 
Premature discontinuation of study drug administration is defined as the discontinuation of 
study drug for an individual patient 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 eCRF and may include, but are not limited to the 
following: 
• Safety reasons: 
- 
Occurrence of an AE, SAE, or clinically significant laboratory abnormality that, in 
the opinion of the Investigator, warrants the patient’s permanent discontinuation from 
study drug administration. 
- 
Occurrence of hypophenylalaninemia defined as <30 μmol/L that cannot be corrected 
with a rescue therapy consisting of extra protein starting at 0.25 g/kg per day given as 
eggs, meat or cheese, etc., depending on patient preference, and in the opinion of the 
Investigator warrants the patient’s permanent discontinuation from study drug 
administration. 
- 
In the judgment of the Investigator, the patient experiences a general or specific 
change(s) that renders the patient unsuitable for continued study drug administration. 
- 
There is a need for concomitant medication that makes the patient ineligible for 
further study drug administration. 
- 
Pregnancy 


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• Reasons Specific to Underlying PBD 
- 
Symptoms or findings that, in the opinion of the Investigator, indicate a worsening of 
the patient’s underlying PBD that renders continued study drug administration 
inadvisable. 
- 
Increase of > 360 µmol/L in Phe concentration from baseline after the initial 48 hours 
of treatment and prior to the end of the dosing period. 
Given the requirement for testing for pregnancy in women of childbearing potential at 
Screening and the requirement for highly effective methods for 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 nursing during the study 
drug administration period occur. 
Patients who discontinue study treatment early due to any of the above reasons should 
immediately revert to pre-study standard of care for their PBD. 
6.13.2 
Withdrawal from the Study 
Patients may withdraw from the study for any reason or be withdrawn at the request of the 
Investigator or Sponsor. The reason for a patient’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 
• Adverse events or SAEs 
• Significant patient noncompliance, defined as refusal or inability to adhere to the protocol 
requirements 
• The Investigator determines that it is in the best interest of the patient to withdraw from 
study participation, due to a reason other than safety 
Each patient who withdraws from the study after receipt of any amount of study drug will be 
asked to undergo EOS assessments. However, patients may withdraw consent to participate 
in this study at any time without penalty. Withdrawn patients will not be replaced. 
6.13.3 
Study Halting Criteria 
Dosing of patients randomized in the study and randomization of additional patients will be 
halted if any of the following occur: 
• The presence of an SAE in 1 patient that is considered to be related to the study drug by 
the Investigator. 
• The presence of the same system organ class (e,g., gastrointestinal, cardiac) Grade 3 or 
greater AE or laboratory abnormality for which no other alternative etiology can be 
identified (per CTCAE v4.03), considered related to study drug, in 2 or more patients, 
regardless of dose group or period. 


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• The presence of ALT or AST ≥3 × ULN, alkaline phosphatase (AP) ≥2 × ULN, AND 
bilirubin ≥2 × ULN (Hy’s Law criteria) in 1 patient if no alternative etiology can be 
identified. 
• Any other clinical observation that the Investigator or the Medical Monitor considers a 
safety issue such that additional doses of CNSA-001 should not be administered to 
subsequent patients. 
Randomization and dosing of subsequent patients can be restarted if, after an assessment of 
any of the above findings by the DSMB, it is determined that there is no additional safety risk 
to the study patients. 
6.14 
Abnormal Movement Seizure Journal 
Seizures and dystonic movements (abnormal movements) can occur in PBD but are difficult 
to distinguish clinically.  Upon signing informed consent, patients will be required to keep a 
seizure journal to indicate date and time of abnormal dystonic movement and seizures.  
Patients will be required to record the duration (i.e., start and stop) of each abnormal 
movement and seizure in the journal.  The journal will be reviewed at every visit. 
6.15 
Appropriateness of Measurements 
Safety will be measured by routine clinical and laboratory procedures, physical examination, 
collection of vital signs, and recording of AEs and SAEs. 
The measure of preliminary efficacy, blood Phe level, was selected as the endpoint measure 
for assessing response to a 1-week course of oral CNSA-001 treatment. The choice was 
based on consultation with the US FDA and data associating blood Phe with intelligence 
quotient (IQ) testing and the National Institutes of Health (NIH) consensus statement 
indicating that metabolic control of blood Phe is necessary across the lifespan of individuals 
with PBD (NIH 2000). 


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7 
STUDY ACTIVITIES 
7.1 
Screening Visit (Days –14 to -1) 
7.1.1 
Screening Procedures (Day -14 to Day -4) 
The following assessments will be performed/collected during the Screening Period from 
Day -14 to Day -4: 
• Before performing any study-related procedures, obtain informed consent/pediatric assent 
and a properly signed Informed Consent Form (ICF) (Section 10.4) 
• Confirm patient meets inclusion/exclusion criteria (see Section 4.2 and Section 4.3) 
• Obtain/confirm gene mutation analysis, enzyme activity analysis, or CSF biochemical 
profile consistent for PBD and record as part of the Medical History (no genetic testing or 
retesting is required) 
• Obtain demographic data (age, gender, race/ethnicity) 
• Obtain medical history: Include the 3 most recent historical Phe concentrations. Also 
include specific information related to any prior or existing medical conditions or surgical 
procedures involving the following systems: dermatologic; HEENT; lymphatic; 
cardiovascular; respiratory; gastrointestinal; musculoskeletal; and neurological. 
• Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature). Patients 
will have a 5-minute rest in a supine position before vital signs are assessed. Obtain 
patient weight and height. 
• Obtain 12-lead ECG in triplicate. Each read can be taken 1 minute apart 
• Conduct a complete physical examination, including assessments of the skin, head, eyes, 
ears, nose, throat, neck, thyroid, lungs, heart, abdomen, lymph nodes, extremities 
• Collect blood sample for clinical chemistry panel (albumin, alkaline phosphatase [AP], 
alanine amino transferase [ALT], aspartate aminotransferase [AST], blood urea nitrogen 
[BUN], calcium, carbon dioxide [CO2], chloride, creatinine, gamma glutamyl transferase 
[GGT], glucose, lactate dehydrogenase [LDH], phosphorus, potassium, sodium, total 
bilirubin, direct bilirubin, total cholesterol, total protein, uric acid), and prolactin 
• Collect blood sample for hematology panel (hematocrit, hemoglobin, platelet count, red 
blood cell [RBC], white blood cell [WBC], and WBC differential) 
• Collect urine sample for urinalysis (appearance, bilirubin, color, glucose, ketones, 
microscopic examination of sediment, occult blood, pH, protein, specific gravity, 
urobilinogen) 
• Obtain serum pregnancy test for all women who are not postmenopausal and for 
adolescents who have started menstruation 


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• Record all prior prescription and over-the-counter medications (including herbal 
medications) taken within 30 days before the Screening visit 
• Assess AEs from the time of informed consent 
• Collect blood samples for Phe concentration (prior to BH4 Washout) to be analyzed by 
the site’s local laboratory. 
• Collect urine sample for exploratory biomarkers (sepiapterin, BH4, and neopterin) to be 
sent to bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3). Urine 
collection should be the first void of the day. 
• Collect blood samples for exploratory biomarker whole blood serotonin to be sent to 
bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3) 
• Perform CANTAB test battery 
• Provide an GENEActive accelerometer for the patient to wear continuously (i.e., 24 
hours/day) for 14 days no earlier than Day-7 (see Section 6.8.4 and Appendix 1) 
• Provide patients with abnormal movement seizure journal and ask to record any seizures. 
• Instruct patients to stop BH4 treatment 24 hours prior to returning for BH4 Washout 
Period 
7.1.2 
BH4 Washout (Day -3 to Day -1) 
The following assessments will be performed/collected during the BH4 Washout Period 
before randomization  
(Day -3 to Day -1) for patients found eligible during Screening and who are taking BH4: 
• Collect blood samples for Phe concentrations during the BH4 Washout Period at 
approximately the same time each day on Day -3 and Day -1. Blood sample collection 
should be performed pre-fed or at least 3 hours following last meal. To minimize burden 
on patients, Phe collection on Days -3 and -1 may be obtained via filter paper with 
overnight shipping to the site’s designated laboratory. Blood Phe levels during the BH4 
Washout period should be analyzed by the site’s local laboratory.  
• Instruct patient to maintain a consistent diet (with respect to protein and Phe intake) 
throughout the study. Ask patient to record 3-day diet records during the BH4 Washout 
Period. 
• Assess AEs since the last visit 
• Instruct patient to complete the abnormal movement seizure journal and to return it on 
their Day 1 visit. 
• Record all prescription and over-the-counter medications taken by the patient 
• Administer the NIH Toolbox Cognitive Domain test battery (on Day -1) or wait to 
administer on Day 1 of Treatment Period 1 (see Section 6.8.5) 


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7.2 
Treatment Period 1 (Day 1 to Day 7) 
7.2.1 
Period 1, Day 1 Procedures 
• The following assessments are to be collected prior to dosing on Day 1: 
- 
Confirm patient continues to meet inclusion/exclusion criteria 
- 
Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) and 
patient weight 
- 
Obtain 12-lead ECG in triplicate. Each read can be taken 1 minute apart. 
- 
Conduct a complete physical examination 
- 
Perform CANTAB test battery 
- 
Administer the NIH Toolbox Cognitive Domain test battery unless already completed 
on Day -1 (see Section 6.8.5) 
- 
Collect blood sample for clinical chemistry and prolactin 
- 
Collect blood sample for hematology panel 
- 
Collect urine sample for urinalysis 
- 
Obtain urine pregnancy test for all women who are not postmenopausal and for 
adolescents who have started menstruation 
- 
Collect pre-dose blood samples for safety monitoring of Phe to be sent to the site’s 
local laboratory for analysis (see Section 6.8.1). Phe collection should be performed 
pre-fed or at least 3 hours following last meal. 
- 
Collect pre-dose urine sample for exploratory biomarkers (sepiapterin, BH4, and 
neopterin) to be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3). Urine collection should be the first void of the day, if possible. 
- 
Collect pre-dose blood samples for exploratory biomarker whole blood serotonin to 
be sent to the bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3) 
- 
Collect pre-dose blood samples (within 30 min of dosing) for pharmacokinetic 
parameters (sepiapterin, BH4, Phe, and Tyr) to be sent to the bioanalytical laboratory 
for analysis (see Section 6.6.2 and Appendix 3). Phe concentrations for preliminary 
efficacy parameter may be obtained from the Phe pharmacokinetic sample.  
• Determine patient’s cohort and assigned treatment based on the randomization list: 
- 
Cohort 1: sepiapterin 2.5 mg/kg/day in Period 1 and 10 mg/kg/day in Period 2 
- 
Cohort 2: sepiapterin 5 mg/kg/day in Period 1 and 20 mg/kg/day in Period 2 
• Administer first dose of Period 1 study drug to patient 
• Collect post-dose blood samples for pharmacokinetic parameters (sepiapterin, Phe, BH4, 
and Tyr) to be sent to the bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3) at the following timepoints: +0.5 hr (±3 min), +1 hr (±5 min), +2 hr 


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(±6 min), +4 hr (±20 min), +6 hr (±30 min), and +8 hr (±60 min) after the first dose of 
study drug. NOTE: +8-hour sample should be prior to the evening dose on Day 1.  
• Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) 2 hours 
after the first dose of study drug in Period 1 (prior to the Hour 2 PK sample collection) 
• Administer evening dose of Period 1 study drug to patient (after +8-hour PK sample has 
been collected) 
• Provide the CASC for the parent or caregiver to complete and collect (see Section 6.8.6) 
• Collect/review the 3-day diet record for the BH4 Washout (dietician to review and record 
calculated Phe values consumed during washout) 
• Collect/review the abnormal movement seizure journal and provide patients with a new 
abnormal seizure journal.  
• Record all prescription and over-the-counter medications (including herbal medications) 
taken since the last visit 
• Assess AEs since the last visit 
7.2.2 
Period 1, Day 2 Procedures 
• The following assessments are to be collected prior to the morning dose on Day 2: 
- 
Collect pre-dose blood sample for pharmacokinetic parameters (sepiapterin, BH4, 
Phe, and tyrosine) to be sent to the bioanalytical laboratory for analysis (see 
Section 6.6.2 and Appendix 3). NOTE: Sample should be collected 24 (± 2) hr from 
the time of the first dose of study drug. Phe concentrations for preliminary efficacy 
parameter may be obtained from the Phe pharmacokinetic sample. 
- 
Collect pre-dose blood samples for safety monitoring of Phe to be sent to the site’s 
local laboratory for analysis (see Section 6.8.1). Phe collection should be performed 
pre-fed or at least 3 hours following last meal. 
- 
Collect pre-dose urine sample for exploratory biomarkers (sepiapterin, BH4, and 
neopterin) to be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3). Urine collection should be the first void of the day, if possible. 
- 
Collect pre-dose blood samples for exploratory biomarker whole blood serotonin to 
be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3) 
• Administer morning dose of study drug to patient 
• Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) 
• Dispense sufficient study drug for dosing until the Day 7 study visit and instruct patient 
on how to administer study drug (see Section 5.2) 
• Dispense dosing diary and instruct patient on how to complete it 
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• Record all prescription and over-the-counter medications (including herbal medications) 
taken since the last visit 
• Assess/record AEs since last visit 
• Collect/review the abnormal movement seizure journal and provide patients with a new 
abnormal seizure journal. 
• Set up time for patient to have blood and urine samples for preliminary efficacy and 
exploratory biomarkers on Day 4 (± 1 day) 
• Instruct patient to take their morning dose of study drug prior to the Day 4 (±1 day) 
laboratory visit, and to not eat another meal for at least 3 hours prior to the visit.  
• Set up time for patient to return to the clinic on Day 7 and ask them to bring all diaries 
and study drug supplies with them to the visit 
• Instruct patient to take their morning dose of study drug prior to the Day 7 visit 
7.2.3 
Period 1, Day 4 (±1 Day) Procedures 
• Collect post-dose blood sample for pharmacokinetic parameters (Phe and Tyr) to be sent 
to the bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3). Phe 
concentrations for preliminary efficacy parameter may be obtained from the Phe 
pharmacokinetic sample. 
• Collect post-dose blood samples for safety monitoring of Phe to be sent to the site’s local 
laboratory for analysis (see Section 6.8.1). Phe collection should be performed pre-fed or 
at least 3 hours following last meal. 
• Collect post-dose urine sample for exploratory biomarkers (sepiapterin, BH4, and 
neopterin) to be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3). Urine collection should be the first void of the day, if possible. 
• Collect post-dose blood samples for exploratory biomarker whole blood serotonin to be 
sent to bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3). 
• Record all prescription and over-the-counter medications (including herbal medications) 
taken since the last visit 
• Assess/record AEs since last visit 
• Collect/review the abnormal movement seizure journal and provide patients with a new 
abnormal seizure journal. 
• Instruct patient to continue taking study drug twice daily until Day 7 visit 
• Remind patient to take their morning dose of study drug prior to the Day 7 visit and to 
bring their dosing diary and diet record to the Day 7 visit 


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7.2.4 
Period 1, Day 7 Procedures 
• Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) 
• Obtain 12-lead ECG in triplicate. Each read can be taken 1 minute apart 
• Conduct a complete physical examination 
• Collect blood sample for clinical chemistry and prolactin 
• Collect blood sample for hematology panel 
• Collect urine sample for urinalysis 
• Perform CANTAB test battery 
• Administer the NIH Toolbox Cognitive Domain test battery (see Section 6.8.5) 
• Provide the CASC for the parent or caregiver to complete and collect (see Section 6.8.6) 
• Collect post-dose blood sample for Phe concentrations for preliminary efficacy. Phe 
collection should be performed pre-fed or at least 3 hours following last meal.  
• Collect post-dose blood samples for safety monitoring of Phe to be sent to the site’s local 
laboratory for analysis (see Section 6.8.1). Phe collection should be performed pre-fed or 
at least 3 hours following last meal. 
• Collect post-dose urine sample for exploratory biomarkers (sepiapterin, BH4, and 
neopterin) to be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3).  
• Collect post-dose blood samples for exploratory biomarker whole blood serotonin to be 
sent to bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3) 
• Record all prescription and over-the-counter medications (including herbal medications) 
taken since the last visit 
• Assess/record AEs since last visit 
• Collect the dosing diaries for the treatment period 
• Collect the 3-day diet record for the treatment period and have dietician review and 
record calculated Phe values consumed for the week 
• Collect/review the abnormal movement seizure journal and provide patients with a new 
abnormal seizure journal. 
• Collect the GENEActive accelerometer and provide a new GENEActive accelerometer 
for the patient to wear continuously (i.e., 24 hours/day) to the End of Study Visit (see 
Section 6.8.4 and Appendix 1) 
• Collect any unused study drug, except for the evening dose needed for Day 7 


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• Check and record study drug compliance for the treatment period 
• Ask patient to stop taking study drug and continue refraining from all BH4 treatments for 
the washout period [3 (±1) days] after taking the evening dose of study drug on Day 7 
• Set up time for patient to return to the clinic for Period 2 after completing the washout 
period 
• Provide a new 3-day diet record to the patient and instruct they bring it back at the 
beginning of Period 2. 
7.3 
Washout Period [3 (±1) Days] 
During the washout period, patient is to refrain from taking all BH4 treatments [i.e., Kuvan® 
(sapropterin dihydrochloride)] and any leftover study drug the patient may have not returned 
to the study site. The washout period should last for 3 (±1) days. Instruct patient to maintain 
a consistent diet (with respect to protein and Phe intake) throughout the washout period. 
Patients should maintain a 3-day diet record during washout period. Patients should also 
document any abnormal seizure movements during the Washout Period in abnormal 
movement seizure journal. 
7.4 
Treatment Period 2 (Day 1 to Day 7) 
7.4.1 
Period 2, Day 1 Procedures 
• The following assessments are to be collected prior to dosing on Day 1: 
- 
Confirm patient continues to meet inclusion/exclusion criteria 
- 
Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) and 
patient weight 
- 
Obtain 12-lead ECG in triplicate. Each read can be taken 1 minute apart 
- 
Conduct a complete physical examination 
- 
Perform CANTAB test battery  
- 
Administer the NIH Toolbox Cognitive Domain test battery (see Section 6.8.5) 
- 
Collect blood sample for clinical chemistry and prolactin 
- 
Collect blood sample for hematology panel 
- 
Collect urine sample for urinalysis 
- 
Obtain urine pregnancy test for all women who are not postmenopausal and for 
adolescents who have started menstruation 
- 
Collect pre-dose blood samples for safety monitoring of Phe to be sent to the site’s 
local laboratory for analysis (see Section 6.8.1). Phe collection should be performed 
pre-fed or at least 3 hours following last meal. 


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- 
Collect pre-dose urine sample for exploratory biomarkers (sepiapterin, BH4, and 
neopterin) to be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3). Urine collection should be the first void of the day, if possible. 
- 
Collect pre-dose blood samples for exploratory biomarker whole blood serotonin to 
be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3) 
- 
Collect pre-dose blood samples (within 30 min of dosing) for pharmacokinetic 
parameters (sepiapterin, BH4, Phe, and Tyr) to be sent to the bioanalytical laboratory  
for analysis (see Section 6.6.2 and Appendix 3).  Pharmacokinetic sampling 
timepoints/duration may be adjusted once the PK data become available from the 
Treatment Period 1. Phe concentrations for preliminary efficacy parameter may be 
obtained from the Phe pharmacokinetic sample. 
• Confirm patient meets safety parameters for dose escalation (see Section 6.12), then 
determine dose for Period 2 based on cohort determined at Day 1 of Period 1: 
- 
Cohort 1: CNSA-001 2.5 mg/kg/day in Period 1 and 10 mg/kg/day in Period 2 
- 
Cohort 2: CNSA-001 5 mg/kg/day in Period 1 and 20 mg/kg/day in Period 2 
• Administer first dose of Period 2 study drug to patient 
• Collect post-dose blood samples for pharmacokinetic parameters (sepiapterin, Phe, BH4, 
and Tyr) to be sent to the bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3) at the following timepoints: +0.5 hr (± 3 min), +1 hr (± 5 min), +2 hr 
(±6 min), +4 hr (± 20 min), +6 hr (± 30 min), and +8 hr (± 60 min) after the first dose of 
study drug. Pharmacokinetic sampling timepoints/duration may be adjusted once the PK 
data become available from the Treatment Period 1.  NOTE: +8-hour sample should be 
prior to the evening dose on Day 1. 
• Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) 2 hours 
after the first dose of Period 2 (prior to the Hour 2 PK sample collection) 
• Administer evening dose of Period 2 study drug to patient (after +8-hour PK sample has 
been collected) 
• Provide the CASC for the parent or caregiver to complete and collect (see Section 6.8.6) 
• Collect/review the 3-day diet record for the washout (dietician to review and record 
calculated Phe values consumed during the washout)  
• Collect/review the abnormal movement seizure journal and provide patients with a new 
abnormal seizure journal. 
• Record all prescription and over-the-counter medications (including herbal medications) 
taken since starting study drug 
• Assess AEs since the last visit 


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7.4.2 
Period 2, Day 2 Procedures 
• The following assessments are to be collected prior to the morning dose on Day 2: 
- 
Collect pre-dose blood samples for pharmacokinetic parameters (sepiapterin, BH4, 
Phe, and Tyr) to be sent to the bioanalytical laboratory for analysis (see Section 6.6.2 
and Appendix 3). Pharmacokinetic sampling timepoints/duration may be adjusted 
once the PK data become available from the Treatment Period 1.  NOTE: Sample 
should be collected 24 (± 2) hr from the time of the first dose of study drug. Phe 
concentrations for preliminary efficacy parameter may be obtained from the Phe 
pharmacokinetic sample. 
- 
Collect pre-dose blood samples for safety monitoring of Phe to be sent to the site’s 
local laboratory for analysis (see Section 6.8.1). Phe collection should be performed 
pre-fed or at least 3 hours following last meal. 
- 
Collect pre-dose urine sample for exploratory biomarkers (sepiapterin, BH4, and 
neopterin) to be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3). Urine collection should be the first void of the day, if possible. 
- 
Collect pre-dose blood samples for exploratory biomarker whole blood serotonin to 
be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3) 
• Administer morning dose of study drug to patient 
• Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) 
• Dispense sufficient study drug for dosing until the Day 7 study visit and instruct patient 
on how to administer study drug (see Section 5.2) 
• Dispense dosing diary and instruct patient on how to complete it 
• Provide a new 3-day diet record to the patient and instruct they bring it back at Day 7 
• Collect/review the abnormal movement seizure journal and provide patients with a new 
abnormal seizure journal. 
• Record all prescription and over-the-counter medications (including herbal medications) 
taken since the last visit 
• Assess/record AEs since last visit 
• Set up time for patient to have blood and urine samples for preliminary efficacy and 
exploratory biomarkers on Day 4 (± 1 day) 
• Instruct patient to take their morning dose of study drug prior to the Day 4 (±1 day) 
laboratory visit, and to not eat another meal for at least 3 hours prior to the visit  
• Set up time for patients to return to the clinic on Day 7 and ask them to bring all diaries 
and study drug supplies with them to the visit 


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• Instruct patient to take their morning dose of study drug prior to the Day 7 visit 
7.4.3 
Period 2, Day 4 (±1 Day) Procedures 
• Collect post-dose blood sample for pharmacokinetic parameters (Phe and Tyr) to be sent 
to the bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3). Phe 
concentrations for preliminary efficacy parameter may be obtained from the Phe 
pharmacokinetic sample. 
• Collect post-dose blood samples for safety monitoring of Phe to be sent to the site’s local 
laboratory for analysis (see Section 6.8.1). Phe collection should be performed pre-fed or 
at least 3 hours following last meal. 
• Collect pre-dose urine sample for exploratory biomarkers (sepiapterin, BH4, and 
neopterin) to be sent to bioanalytical laboratory for analysis (see Section 6.6.2 and 
Appendix 3). Urine collection should be the first void of the day, if possible. 
• Collect post-dose blood samples for exploratory biomarker whole blood serotonin to be 
sent to bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3) 
• Record all prescription and over-the-counter medications (including herbal medications) 
taken since the last visit 
• Assess/record AEs since last visit 
• Collect/review the abnormal movement seizure journal and provide patients with a new 
abnormal seizure journal. 
• Instruct patient to continue taking study drug twice daily until Day 7 visit 
• Remind patient to take the morning dose of study drug prior to the Day 7 visit and to 
bring their dosing diary and diet record to the Day 7 visit 
7.4.4 
Period 2, Day 7 Procedures 
• Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) 
• Obtain 12-lead ECG in triplicate. Each read can be taken 1 minute apart 
• Conduct a complete physical examination 
• Collect blood sample for clinical chemistry and prolactin 
• Collect blood sample for hematology panel 
• Collect urine sample for urinalysis 
• Perform CANTAB test battery 
• Administer the NIH Toolbox Cognitive Domain test battery (see Section 6.8.5) 


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• Provide the CASC for the parent or caregiver to complete and collect (see Section 6.8.6) 
• Collect post-dose blood sample for Phe concentrations for preliminary efficacy. Phe 
collection should be performed pre-fed or at least 3 hours following last meal. 
• Collect post-dose blood samples for safety monitoring of Phe to be sent to the site’s local 
laboratory for analysis (see Section 6.8.1). Phe collection should be performed pre-fed or 
at least 3 hours following last meal. 
• Collect post-dose urine sample for exploratory biomarkers (sepiapterin, BH4, and 
neopterin) to be sent to local laboratory or bioanalytical laboratory for analysis (see 
Section 6.6.2 and Appendix 3).  
• Collect post-dose blood samples for exploratory biomarker whole blood serotonin to be 
sent to bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3) 
• Record all prescription and over-the-counter medications (including herbal medications) 
taken since the last visit 
• Assess/record AEs since last visit 
• Collect the dosing diaries for the treatment period 
• Collect the 3-day diet record for the treatment period and have dietician review and 
record the calculated Phe values consumed for the week 
• Collect/review the abnormal movement seizure journal and provide patients with a new 
abnormal seizure journal. 
• Collect any unused study drug, except for the evening dose needed for Day 7 
• Check and record study drug compliance for the treatment period 
• Set up time for patient to return to the clinic for the EOS visit 
7.5 
Early Termination Procedures 
If a patient is required to withdraw early from the study (see Section 6.13), the patient should 
return to the study site within 24 hours of withdrawal and complete all of the procedures 
outlined for the EOS visit (Section 7.6). 
7.6 
End of Study Visit 
Patients are to complete the EOS visit within 48 hours of the last dose of study drug. During 
the EOS visit, the following assessments will be completed: 
• Collect blood sample for pharmacokinetic parameters (Phe and Tyr) to be sent to the 
bioanalytical laboratory for analysis (see Section 6.6.2 and Appendix 3). 


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• Collect blood sample for safety monitoring of Phe to be sent to the site’s local laboratory 
for analysis (see Section 6.8.1). Phe collection should be performed pre-fed or at least 
3 hours following last meal. 
• Obtain vital signs (blood pressure, pulse, respiratory rate, and oral temperature) 
• Conduct complete physical examination (not needed if performed at Day 7 of Treatment 
Period 2) 
• Obtain blood sample for clinical chemistry and prolactin (not needed if performed at Day 
7 of Treatment Period 2) 
• Obtain blood sample for hematology panel (not needed if performed at Day 7 of 
Treatment Period 2) 
• Obtain urine sample for urinalysis (not needed if performed at Day 7 of Treatment 
Period 2) 
• Obtain urine pregnancy test for all women who are not postmenopausal and for 
adolescents who have started menstruation 
• Record/review all prescription and over-the-counter medications (including herbal 
medications) taken during the study (since signing the informed consent) 
• Assess/record/review all AEs that occurred during the study (since signing the informed 
consent) 
• Collect all dosing diaries for all study periods (if not already collected) 
• Collect all 3-day diet records for all study periods (if not already collected) 
• Collect/review the abnormal movement seizure journal. 
• Collect the GENEActive accelerometer  
• Collect all unused study drug 
• Check/record study drug compliance for the entire study 
• Instruct patient on restarting BH4 therapy if taken prior to entering the study 
7.7 
Phone Follow-up Visits 
7.7.1 
Phone Follow-up 7 to 10 Days After Last Dose 
• Call the patient to see if patient experienced any AEs during the 7 days after the last dose 
of study drug 
• Record AEs in the eCRF, if applicable 


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7.7.2 
Phone Follow-up 30 (± 3) Days after Last Dose 
• Call the patient to see if patient experienced any SAEs during the 30 days after the last 
dose of study drug 
• Record SAEs in the eCRF, if applicable 
 


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8 
QUALITY CONTROL AND ASSURANCE 
Regular monitoring and an independent audit, if conducted, must be performed according to 
International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP). See also 
Section 10.6. 
Quality control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirements (e.g., Good 
Laboratory Practices (GLP), Good Manufacturing Practices (GMP). 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by Censa 
Pharmaceuticals, and inspection by local and regulatory authorities. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
Descriptive statistics, including the numbers and percentages for categorical variables, and 
the numbers, means, standard deviations, medians, minimums, and maximums for 
continuous variables will be provided. Exploratory analyses may also be performed. Listings 
of individual patient data will be produced. Additional details can be found in the statistical 
analysis plan (SAP). 
9.2 
Determination of Sample Size 
The primary objective of this study is to evaluate the safety of 4 doses of CNSA-001. The 
sample size for this study is not based on statistical considerations, and a sample size of 
6-10 patients (with 2 doses administered per patient) is considered adequate for this orphan 
population. Also, the treatment induced changes in Phe level is not powered for this study 
and caution is needed in the interpretation of efficacy results. 
9.3 
Analysis Populations 
Three study populations will be analyzed: 
• The Safety population: all patients who were randomized and received any amount of 
study drug. All safety summaries will be conducted in this population. 
• The Efficacy population: all patients who were randomized, received any amount of 
study drug, and had available pre-dose Phe Concentrations at Day 1 and at least one post-
Day 1 visit within a period. All efficacy analyses will be conducted in this population. 
• PK Population: all patients who received at least one dose of study drug and had at least 
1 quantifiable post-dose blood sample collected for analysis of sepiapterin, BH4, Phe, or 
Tyr concentrations. 
9.4 
Demographics and Baseline Characteristics 
Enrollment, protocol deviations, demographics (age, sex, race/ethnicity), medical history, 
and ECG parameters will be summarized using descriptive statistics. Discontinuations from 
study drug and the study will be summarized for all patients as well as by cohort and the last 
dose of study drug received. 
9.5 
Statistical Analysis of Efficacy Variables 
Efficacy will be assessed in the Efficacy population. Phe concentrations at each visit and 
changes from baseline (Day 1, pre-dose) to each post-Day 1 assessment will be summarized 
using summary statistics within each dose cohort and period. 
Other Secondary measures will include the following descriptive statistics (at each visit) as 
well as summary statistics changes from Day 1 to each post-Day 1 visit (as applicable) for: 


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• Percent of patients with Phe concentrations in acceptable treatment range of 130 to 
360 µmol/L at Day 7 
• Percent of patients with Phe concentrations <130 µmol/L at Day 7 
Exploratory measures include: 
• Urine sepiapterin, neopterin, and BH4 
• Serum prolactin 
• Whole blood serotonin 
• Computerized testing (CANTAB) at Screening, Day 1 (pre-dose), and Day 7 of each 
treatment period will also be summarized 
• Movement and sleep assessment via the GENEActiv accelerometer 
• NIH Toolbox Cognitive Domain test battery 
• Parent or caregiver assessment of sleep (CASC) 
9.6 
Safety Analysis 
Safety will be assessed in the Safety population. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA®). The number and percentage of patients 
with TEAEs (events that begin after first dose of study drug) will be tabulated by dose 
cohort, period, system organ class, and MedDRA preferred term. The dose cohort for each 
AE is identified based on the last dose of study drug taken at or before the start of the AE. 
Severity of AEs and SAEs will be summarized similarly. AEs leading to premature 
discontinuation from the study drug and serious TEAEs will be presented in a table or a 
listing. Clinical laboratory test results and vital signs, as well as corresponding changes from 
baseline, will be summarized at each visit, within each cohort and period. 
9.7 
Statistical Analysis of Pharmacokinetic Variables 
All analysis of PK variables will be assessed in the PK population. 
The blood concentrations of sepiapterin, BH4, Phe, and Tyr will be summarized and listed. 
The following non-compartmental PK parameters for sepiapterin, BH4, Phe, and Tyr will be 
estimated and summarized along with graphical presentation of the concentration data vs. 
time: 
Parameter 
Definition 
AUC0-inf 
Area under the curve from time 0 to infinity using trapezoidal method 
(linear-up/log-down method) and extrapolation to infinite time 
AUC0-last 
Area under the curve from time 0 to the time of the last quantifiable 
concentration using trapezoidal method (linear-up/log-down method) 
Cmax 
Maximum observed concentration 


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Parameter 
Definition 
Tmax 
Time to Cmax 
t1/2 
Half-life 
Ke 
Elimination rate constant 
 


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10 
ADMINISTRATIVE CONSIDERATIONS 
10.1 
Investigators and Study Administrative Structure 
Table 2 summarizes the administrative structure for this study. 
Table 2 
Administrative Structure for PBD-001 Study 
Lead Principal Investigator 
Clinical Research Organization 
InClin, Inc 
2000 Alameda De Las Pulgas, Ste 242 
San Mateo, CA 94403 
Phone: 
 
Bioanalytical Laboratory 
Medical Neurogenetics Laboratories 
5424 Glenridge Dr 
Atlanta, GA 30342 
Phone: 
 
 
10.2 
Institutional Review Board or Independent Ethics Committee Approval 
The Investigator will submit this protocol, any protocol modifications, and the patient 
consent form to be utilized in this study, to the appropriate IRB/IEC for review and approval. 
This committee must operate in accordance with ICH GCPs. Documentation of approval of 
the protocol and the informed consent document must be forwarded to Censa 
Pharmaceuticals (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 patients 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 patients. 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 Censa Pharmaceuticals (or 
designee). The Investigator will provide notice to the IRB/IEC of completion of participation 
in the study. 
10.3 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol; GCPs, including ICH 
Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines; 


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applicable regional regulatory requirements (e.g., ICH E6, 41(2) AMG); and in accordance 
with the ethical principles of the Declaration of Helsinki. 
To this end, minors (study participants ages ≥ 12 months ≤ 18 years of age) have been 
included into this study and their needs (i.e., potential for direct benefit from treatment, no 
alternative means to obtain the data in a different population with dissimilar genetic mutation 
or disease, and burden to participate has been minimized or is at most, temporary) have been 
considered and determined justified in accordance with the requirements outlined in the 
Declaration of Helsinki.  
10.4 
Patient Information and Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate 
in the study and continues throughout the individual’s study participation. Discussion in 
understandable terms of the purposes, procedures, risks and possible benefits of participation, 
and rights of study patients will be conducted with patients, and, as appropriate, their legally 
authorized representatives (LARs; henceforth in the discussion of informed consent, study 
patient means “patient and/or LAR”) and their family members. The study patients should 
have the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate. Study patients will be asked to carefully review a ICF approved by 
Censa Pharmaceuticals and the IRB/IEC. After any needed discussion and consideration of 
study participation and before undergoing any procedures specifically for the study, the 
participant will sign the ICF. The ICF will be retained in the study patient’s study records, 
and a copy of the ICF will be given to the study patient. 
Individuals may decline to participate in the study and withdraw consent at any time or for 
any reason throughout the course of the study without AEs on the quality of their medical 
care. 
10.5 
Confidentiality 
The Investigator must assure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties. This extends to testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Only 
an identification code (i.e., not names) should be recorded on any form or document 
submitted to Censa Pharmaceuticals, the Contract Research Organization (CRO), or the 
IRB/IEC. The Investigator must keep logs on screened and enrolled patients. In addition, the 
Investigator must have a list where the identity of all treated patients can be found. 
The Investigator agrees that all information received from Censa Pharmaceuticals, including, 
but not limited to, the IB, this protocol, CRFs, and any other information related to the 
protocol-specified treatment of the study, remain the sole and exclusive property of Censa 
Pharmaceuticals during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of 
the study or as required by law) without prior written consent from Censa Pharmaceuticals. 
The Investigator further agrees to take all reasonable precautions to prevent the disclosure by 


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any employee or agent of the study center to any third party or otherwise into the public 
domain. 
The study monitor, other authorized representatives of Censa Pharmaceuticals, and 
representatives of the IRB/IEC may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to, medical records (office, clinic, 
and hospital) and pharmacy records for the participants in this study. The clinical study site’s 
research staff will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local IRB/IEC and Institutional 
regulations. 
10.6 
Study Monitoring 
A clinical monitor authorized to represent Censa Pharmaceuticals will conduct site visits to 
inspect study data, patients’ medical records, and eCRFs in accordance with ICH guidelines 
GCPs, and applicable regulations and guidelines. The clinical monitor will also monitor 
ongoing drug accountability and adherence to protocol procedures. Details of clinical site 
monitoring are specified in a Clinical Monitoring Plan (CMP). 
Independent audits may be conducted to ensure that monitoring practices are performed 
consistently across all participating sites and that monitors are following the CMP. 
The Investigator will allow representatives of the Censa Pharmaceuticals and regulatory 
authorities to inspect facilities and records relevant to this study. 
10.7 
Case Report Forms and Study Records 
The eCRFs will be supplied by Censa Pharmaceuticals or designee for the recording of all 
information and study data as specified by this protocol. Original eCRF data should be 
handled in accordance with instructions from Censa Pharmaceuticals or designee. All eCRFs 
must be completed by the clinical study site’s research staff authorized to do so by the 
Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
Data reported in the eCRF derived from source documents should be consistent with the 
source documents. Source documents are defined as records of documentation related to 
original observations and activities of a clinical investigation. Source documents may 
include, but are not limited to, study progress notes, study- or patient-specific email 
correspondence, computer printouts, laboratory data, and recorded data from automated 
instruments. All source documents produced in this study will be maintained by the 
Investigator and made available for inspections by Censa Pharmaceuticals or designee and by 
regulatory authorities. The original ICF for each participating patient shall be filed with 
records kept by the Investigator, and copies shall be given to the patient. 


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Once all data queries and issues have been resolved for each patient the Investigator will 
electronically sign each patient’s eCRF. This signature will indicate that the data have been 
thoroughly inspected and will thereby certify the contents of the eCRF. 
Clinical data will be entered into a 21 CFR Part 11-compliant electronic data capture system. 
The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical 
data will be entered by the clinical study site’s research staff directly from the source 
documents. 
10.8 
Data Monitoring Committee 
The safety of study patients will be monitored by a DSMB. The function and membership of 
the DSMB will be described in the DSMB Charter but at minimum will consist of a 
physician familiar with PBD, a statistician, and the Medical Monitor. 
10.9 
Protocol Violations/Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol requirements. The 
noncompliance may be either on the part of the participant, the Investigator, or the study site 
staff. Because of deviations, corrective actions are to be developed by the site and 
implemented promptly. This is consistent with the following sections in ICH E6: 
• 4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, Section 5.1.1 
• 5.20 Noncompliance, Sections 5.20.1, and 5.20.2. 
10.10 
Access to Source Documentation 
The Investigator agrees by his/her participation that the results of this study may be used for 
submission for national or international registration. If required, national or international 
authorities will be provided with the name of the Investigator and his or her address, full 
disclosure of his or her qualifications, any potential conflicts of interests, payments, and 
extent of involvement. 
During site visits, the clinical monitor will review original patient records, drug 
accountability records, and additional documents as needed. During the course of the study, 
Censa Pharmaceutical’s or designee’s Quality Assurance personnel may conduct an on-site 
audit visit. The Investigator will provide direct access to and allow verification and copying 
of all trial related documents (e.g., source data) for trial related monitoring, audits, IRB/IEC 
reviews, and regulatory inspections. 
10.11 
Data Generation and Analysis 
Some or all of the obligations of implementing or conducting this study may be transferred 
from Censa Pharmaceuticals to the CRO. 


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A case report, comprised of individual eCRFs, will be completed for every patient who signs 
an ICF (or for whom an ICF is signed by a LAR) and is enrolled into the study. 
All original source documentation (laboratory results, treatment records, audit query 
responses, etc.) will be retained by the Investigator or institution unless specified otherwise 
by the protocol. The results as they become available will be entered on the appropriate 
eCRFs. Legible reproductions of the original laboratory reports for selected tests or variables 
will be submitted to Censa Pharmaceuticals or CRO as requested. 
eCRFs will be reviewed by a clinical monitor who will evaluate the completeness and 
accuracy of the data. Queries will be generated for omissions, corrections, and clarifications. 
Data may also be reviewed in-house by a clinical auditor and data management or other 
personnel. 
Data analyses will be performed after database lock, when all queries have been resolved. 
10.12 
Retention of Data 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents should be retained for a longer period, however, if required by local regulations. 
No records will be destroyed without the written consent of Censa Pharmaceuticals, if 
applicable. It is the responsibility of Censa Pharmaceuticals to inform the Investigator when 
these documents no longer need to be retained. 
10.13 
Financial Disclosure 
Each Investigator must submit to Censa Pharmaceuticals (or designee) financial disclosure 
information according to national law and/or local regulations. 
10.14 
Publication and Disclosure Policy 
The data generated in this clinical study are the exclusive property of Censa Pharmaceuticals 
and are confidential. Authorship on any publication of the results from this study will be 
based on contributions to study design, patient enrollment, data analysis, interpretation of 
results, and drafting and editing of any publication in accordance with published authorship 
ethical guidelines for publication of research studies. Independent analysis and/or publication 
of these data by the Investigator(s) or any member of their staff is not permitted without the 
prior, written consent of Censa Pharmaceuticals. 
10.15 
Clinical Trial Insurance 
Censa Pharmaceuticals will ensure that clinical trial insurance sufficient to meet local and 
national requirements for the conduct of clinical research in patients is obtained prior to the 
conduct of this study and remains in effect for the duration of this study. 


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11 
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62. 
Danks DM, Cotton RG, Schlesinger P. Letter: Tetrahydrobiopterin treatment of variant form 
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De Souza VC, Rabilloud M, Cochat P, Selistre L, Hadj-Aissa A, et al. (2012) Schwartz 
Formula: Is One k-Coefficient Adequate for All Children? PLoS ONE 7(12): e53439. 
doi:10.1371/journal.pone.0053439. 
Dhondt JL, Farriaux JP, Boudha A, Largilliere C, Ringel J, Roger MM, et al. Neonatal 
hyperphenylalaninemia presumably caused by guanosine triphosphate cyclohydrolase 
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Dudesek A, Roschinger W, Muntau AC, Seidel J, Leupold D, Thony B, et al. Molecular 
analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-
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Fleming S, Thompson M, Stevens R, Heneghan C, Pluddemann A, Maconochie I, 
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Gerson RC, Slotkin J, Manly JJ, Blitz DL, Beaumont JL, Schnipke D, Wallner-Allen K, 
Golinkoff RM, Gleason JB, Hirsh-Pasek K, Adams MJ, Weintraub S. IV. NIH Toolbox 
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Giudici TA, Blaskovics M, Lim B, Gambetta R, Curtius HC. Blau N. Excretion of 7-
substituted pterins by a hyperphenylalaninemic variant (primapterinuria). Administration of 
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Hardelid P, Cortina-Borja M, Munro A, Jones H, Cleary M, Champion MP, et al. The birth 
prevalence of PKU in populations of European, South Asian and sub-Saharan African 
ancestry living in South East England. Ann Hum Genet. 2008;72(Pt 1):65-71. 
Hase Y, Shintaku H, Turuhara T, Oura T, Kobashi M, Iwai K. A case of tetrahydrobiopterin 
deficiency due to a defective synthesis of dihydrobiopterin. J Inherit Metab Dis. 
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Ichiyama A, Nakamura S, Nishizuka Y, Hayaishi O. Enzymic studies on the biosynthesis of 
serotonin in mammalian brain. J Biol Chem. 1970;245(7):1699-709. 
Jaggi L, Zurfluh MR, Schuler A, Ponzone A, Porta F, Fiori L, et al. Outcome and long-term 
follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab. 
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Kaufman S. A new cofactor required for the enzymatic conversion of phenylalanine to 
tyrosine. J Biol Chem. 1958;230(2):931-9. 
Kaufman S, Holtzman NA, Milstien S, Butler LJ, Krumholz A. Phenylketonuria due to a 
deficiency of dihydropteridine reductase. N Engl J Med. 1975;293(16):785-90. 


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Kitagawa T, Yamato T, Shininchiro A, Kinyoshi N et al. Clinical Results of Using 
Apropterin Hydrochloride (R-Tetrahydrobiopterin) for Atypical Hyperphenylalanemia. Jap J 
Pediatr Med. 1990; 22:1737-1750. 
Kwon NS, Nathan CF, Stuehr DJ. Reduced biopterin as a cofactor in the generation of 
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Mayer B, Werner ER. In search of a function for tetrahydrobiopterin in the biosynthesis of 
nitric oxide. Naunyn Schmiedebergs Arch Pharmacol. 1995;351(5):453-63. 
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Norepinephrine Biosynthesis. J Biol Chem. 1964;239:2910-7. 
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NIH. Phenylketonuria (PKU): screening and management. NIH Consens Statement 17[3], 1-
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Ponzone A, Ferraris S, Baglieri S, Spada M. Treatment of tetrahydrobiopterin deficiencies. 
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Wasserstein M, Burton B, Cederbaum S, Munser J, Scott R, Harding C, et al. Interim results 
of a Phase II, multicenter, open-label study of sapropterin dihydrochloride in subjects with 
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BG, Nowinski CJ, Gershon RC. I. NIH Toolbox cognition battery (CB): Introduction and 
pediatric data. Monographs of the Society for Research in Child Development 2013;78(4):1-
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Toolbox cognition battery (CB): measuring executive function and attention. Monographs of 
the Society for Research in Child Development 2013;78(4):16-33. 
https://doi.org/10.1111/mono.12032 
 
 
 
 


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Appendix 1 
Schedule of Events 
Evaluation 
Screen 
Period 
BH4 
Washout 
Treatment Period 
End of 
Study  
(≤ 48 hrs 
after last 
dose) 
Phone  
Follow-up 
Period 1 
Washout 
Period 2 
Day-14 
to  
Day -4 
Day -3  
to  
Day -1 
Day 1 Day 2 Day 4 
(±1) 
Day 7 
3 (±1) 
days 
Day 1 Day 2 
Day 4 
(±1) 
Day 7 
7 - 10 
days 
after last 
dose 
30 (±3) 
days 
after last 
dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm inclusion/exclusion 
criteria eligibility 
X 
 
Xa 
 
 
 
 
Xa 
 
 
 
 
 
 
Confirm mutation analysis 
for PBD genes b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, height, and 
weight d 
X 
 
Xa 
X 
 
X 
 
Xa 
X 
 
X 
X 
 
 
ECGs e 
X 
 
Xa 
 
 
X 
 
Xa 
 
 
X 
 
 
 
Physical examination f 
X 
 
Xa 
 
 
X 
 
Xa 
 
 
X 
Xg 
 
 
Clinical laboratory tests and 
serum prolactin h 
X 
 
Xa 
 
 
X 
 
Xa 
 
 
X 
Xg 
 
 
Serum/urine pregnancy test i 
X 
 
Xa 
 
 
 
 
Xa 
 
 
 
X 
 
 
Prior/Concomitant meds j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Phe concentrations l 
X 
X 
Xa 
Xa 
X 
X 
 
Xa 
Xa 
X 
X 
X 
 
 
Consistent diet/ 3-day diet 
record m 
 
X 
X 
 
X 
X 
X 
 
X 
Xg 
 
 
Seizure journal 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Discontinue BH4 n 
 
X 
 
 
 
 
PK: Sepiapterin, BH4, and 
Phe/Tyr o 
 
 
Xa 
Xa 
X 
X 
 
Xa 
Xa 
X 
X 
X 
 
 
Biomarkers in urine p 
X 
 
Xa 
Xa 
X 
X 
 
Xa 
Xa 
X 
X 
 
 
 
Whole blood serotonin 
X 
 
Xa 
Xa 
X 
X 
 
Xa 
Xa 
X 
X 
 
 
 
CANTAB testing q 
X 
 
Xa 
 
 
X 
 
Xa 
 
 
X 
 
 
 
Don GENEActive 
Accelerometeru 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NIH ToolBox Test Battery 
 
Xa,v 
Xa,v 
 
 
X 
 
X 
 
 
X 
 
 
 
Administer the CASC 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
Administer study drug r 
 
 
 
 
 
 
 
 


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Evaluation 
Screen 
Period 
BH4 
Washout 
Treatment Period 
End of 
Study  
(≤ 48 hrs 
after last 
dose) 
Phone  
Follow-up 
Period 1 
Washout 
Period 2 
Day-14 
to  
Day -4 
Day -3  
to  
Day -1 
Day 1 Day 2 Day 4 
(±1) 
Day 7 
3 (±1) 
days 
Day 1 Day 2 
Day 4 
(±1) 
Day 7 
7 - 10 
days 
after last 
dose 
30 (±3) 
days 
after last 
dose 
Dispense study drug s 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Dispense Dosing Diary t 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Collect Study Drug, Dosing 
Diary, Assess Compliance 
 
 
 
 
 
X 
 
 
 
 
X 
X  
 
 
Resume BH4 therapy 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
a. 
To be completed prior to initial dosing. 
b. 
Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic mutations in PTPS or recessive GTP-CH genes, abnormal enzyme activity of the PTPS 
or GTP-CH enzymes, or a CSF biochemical profile indicative of PTPS or GTP-CH deficiencies. No genetic testing or retesting is required. 
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; and neurological. Also, includes documentation of 3 most recent historical Phe concentrations. 
d. 
Includes blood pressure, pulse, respiratory rate, and oral temperature. Patients will have a 5-minute rest in a supine position before vital signs are assessed. Weight will only 
be collected at Screening and on Day 1 of each treatment period. Height will only be collected at Screening. Vital signs will be collected both pre-dose and 2-hours post-dose 
(before 2-hour blood collection for PK) on Day 1 of each treatment period; for all other timepoints they will be taken at any time during the visit. 
e. 
12-lead ECGs to be performed at Screening, and on Day 1 (pre-dose) and Day 7 of each treatment period. ECGs will be performed in triplicate, with each read taken 1 
minute apart. 
f. 
The examination will assess general appearance, as well as dermatologic, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neurological 
parameters. 
g. 
Can be performed either on Day 7 visit of Treatment Period 2 or at the EOS Visit. Does not need to be conducted at both. 
h. 
Includes clinical chemistry panel (albumin, AP, ALT, AST, BUN, calcium, CO2, chloride, creatinine, GGT, glucose, LDH, phosphorus, potassium, sodium, total bilirubin, 
direct bilirubin, total cholesterol, total protein, uric acid), and serum prolactin; hematology panel (hematocrit, hemoglobin, platelet count, RBC, WBC, and WBC 
differential); and urinalysis (appearance, bilirubin, color, glucose, ketones, microscopic examination of sediment, occult blood, pH, protein, specific gravity, and 
urobilinogen). 
i. 
Serum and urine pregnancy test required for all women who are not postmenopausal and for adolescents who have started menstruation; serum testing to occur during the 
Screening Period and urine testing to occur prior to dosing on Day 1 of Periods 1 and 2 and EOS. A positive urine test must be confirmed with a serum test. 
j. 
Record all Rx and OTC medications starting from 30 days prior to Screening through last study visit. 
k. 
Adverse events are to be collected from the time of informed consent until 7 days after the last dose of study drug (30 days after last dose for SAEs). 
l. 
Blood Phe concentrations collected during Screening (prior to BH4 Washout) and during BH4 Washout Period on Days -3 and -1 will be analyzed by the site’s local 
laboratory. To minimize burden on patients, Phe collection on Days -3 and -1 during the Washout Period may be obtained via filter paper with overnight shipping to the 
site’s designated laboratory. All other blood Phe concentrations will be used for safety monitoring and analyzed by the site’s local laboratory and are collected on Day 1 and 
Day 2 (pre-dose), and on Day 4 (±1 day) and Day 7 (after the AM dose) during Period 1 and Period 2 of Study Treatment, and EOS visit. Unscheduled Phe collection may 
occur if at any time a patient is hypophenylalaninemic (i.e., <30 µmol/L). Phe collection should be performed with pre-fed or at least 3 hours following last meal and at 
approximately the same time of day at each visit. 
m. Patients are to maintain a consistent diet (with respect to protein and Phe intake) during the study. The 3-day diet records will be collected during BH4 Washout and during 
each treatment period. 


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n. 
BH4 treatment [i.e., Kuvan® (sapropterin dihydrochloride)] will be discontinued starting with the BH4 Washout period. Patients will remain off BH4 treatment until the 
EOS visit. 
o. 
Blood samples for CNSA-001 (sepiapterin), BH4, Phe, and Tyr will be collected and analyzed by the bioanalytical laboratory at the following timepoints during Period 1 and 
Period 2: Day 1 (pre-dose, within 30 min of dosing), +0.5 hr (±3 min), +1 hr (±5 min), +2 hr (±6 min), +4 hr (±20 min), +6 hr (±30 min), and +8 hr (±60 min, prior to Day 1 
evening dose), and +24 hours (± 2 hr, prior to Day 2 AM dose) after the first dose of study drug; +72 hr (Day 4, ±1 day; Phe/Tyr only); on Day 7 (Phe/Tyr only); and EOS 
(Phe/Tyr only) (see Table 2). Phe concentrations for preliminary efficacy will be obtained from the same sample collected for Phe/Tyr concentrations on Day 1 and Day 2 
(pre-dose), Day 4 (±1 day) and Day 7 (after the AM dose), and EOS. 
p. 
Exploratory biomarkers in urine include sepiapterin, BH4, and neopterin. These samples will be collected at Screening, pre-dose on Day 1 and Day 2, and post-dose on Day 
4 (±1 day) and Day 7. Urine samples should be the first void of the day. Samples will be sent to the bioanalytical laboratory (see Table 3). 
q. 
CANTAB testing will include RTI, SSP, SWM, and RVP tests. These will be administered at the Screening visit and on Day 1 (pre-dose) and Day 7 of each treatment 
period. 
r. 
Study drug will be administered twice daily (with breakfast and with supper) on Days 1 to 7 of each treatment period. Doses on Day 1 and Day 2 (AM only) will be 
administered by research staff, while all remaining doses will be self-administered. 
s. 
Study drug will be dispensed at each Day 2 Study visit and will include enough study drug for dosing until the Day 7 study visit. CNSA-001 treatment will be discontinued if 
criteria related to safety or lack of efficacy are met (see Section 6.13.1).  
t. 
Patient will receive a dosing diary and instructions for recording all doses of study drug taken and times they were taken; if a patient vomits after taking a dose of study drug, 
this should also be recorded in the diary and the patient should wait until the next scheduled time point to administer a dose. 
u. 
Patients will be asked to wear a GENEActiv accelerometer device continuously for up to two 14-day periods.  The initial device will be placed on the patient’s wrist, ankle 
or other suitable location and secured with the appropriate band no earlier than Day -7 during Screening.  The initial device will be removed on Day 7 of Treatment Period 1 
and replaced with a second device to be worn until the End of Study visit.  All devices will be collected at the End of Study visit. 
v. 
Patients ages 3-17 will be administered the NIH Toolbox Cognitive Domain test battery on either Day -1 or Day 1 predose for Treatment Period 1 at the clinical site’s option.  
Only one assessment will be performed and will be used as the baseline assessment for Treatment Period 1. 
Abbreviations:  AE = adverse event; AM = morning; AP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CO2 = carbon dioxide; HEENT=hear, eyes, ears, nose, throat; ECG = electrocardiogram; EOS = end of study; GGT = gamma glutamyl transferase; LDH = lactate 
dehydrogenase; Phe = phenylalanine; PK = pharmacokinetic; RBC = red blood cell; RVP = Rapid Visual Information Processing; SAE = serious adverse event; RTI = Reaction 
Time; SSP = Spatial Span; SWM = Spatial Working Memory; WBC = white blood cell.


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Appendix 2 
Cockcroft-Gault Formula (Adults, ≥ 18) and Schwartz-Lyon Formula 
(Children < 18 Years) for Creatinine Clearance 
 
D.W. Cockcroft, M.H. Gault. Prediction of creatinine clearance from serum creatinine. Nephron, 16 (1976),  
pp. 31-41 
 
 
SCHWARTZ-LYON FORMULA:       
CrCl (ml/min/1.73m2) = k * height (cm) /PCr (plasma creatinine expressed in µmol/L) 
k = 36.5 for males >13 years old 
k = 32.5 for all others 
 
De Souza VC, Rabilloud M, Cochat P, Selistre L, Hadj-Aissa A, et al. (2012) Schwartz Formula: Is One k-Coefficient 
Adequate for All Children? PLoS ONE 7(12): e53439. doi:10.1371/journal.pone.0053439.  
COCKCROFT-GAULT FORMULA: 


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Appendix 3 
Pharmacokinetic, Efficacy and Exploratory Biomarker Samples 
Table 3 
PK, Preliminary Efficacy Biomarker, and Exploratory Biomarker Sampling Times for Plasma/Whole Blood 
and Urine Samples 
Analyte 
Tube 
Screen 
Day 1 
Day 2 
Day 4 
(±1) 
Day 7 
EOS 
Pre 
0.5  
hr 
1 
hr 
2 
hr 
4 
hr 
6 
hr 
8 
hr 
24 
hr 
72 
hr 
186 
hr 
 
Plasma or Whole Blood Samples Collection 
SEP /BH4a 
A/B 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Phe / Tyr 
C/D 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5HT (WB) 
I/J 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
Urine Sample Collectionb 
SEP 
E/F 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
BH4 
E/F 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
Neop 
E/F 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
Creatinine 
G/H 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
Abbreviations: 5HT = serotonin, BH4 = tetrahydrobiopterin; EOS = End of Study; Neop = neopterin; Phe = phenylalanine; SEP = sepiapterin, Tyr = tyrosine, WB= whole blood 
a 
Pharmacokinetic sampling timepoints/duration may be adjusted once the PK data become available from the Treatment Period 1. 
b 
Urine samples will not be collected from toddlers unless they are toilet trained and a sample can be obtained. 
 
 
 


PTC923
Administrative Addendum
28 February 2022
1
The chemical name and structure of sepiapterin, or PTC923 (formerly known as CNSA-001), has 
been presented in various ways in the published literature. One such chemical name and structure
was included in the Protocols included in PBD-001 CSR Section 16.1.1. However, the preferred 
representation of the active agent is as follows:
Chemical name: (S)-2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one
Chemical structure: 

SAP_001.pdf: 
DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra-patient Dose 
Escalation Study to Evaluate the Safety, Pharmacokinetics and Preliminary 
Efficacy of CNSA-001 (Sepiapterin) in Primary Tetrahydrobiopterin Deficient 
Patients with Hyperphenylalaninemia 
Protocol: PBD-001 
Version 2.0: 09 Nov 2020 
STATISTICAL ANALYSIS PLAN 
Censa Pharmaceuticals, Inc. was acquired by and is a subsidiary of PTC 
Therapeutics, Inc. and its name officially changed to PTC Therapeutics 
MP, Inc. Any reference to Censa Pharmaceuticals, Inc, Censa, PTC 
Therapeutics MP, Inc. equate to the same organization. 
NCT #NCT03519711


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PTC Therapeutics, Inc. 
SAP for Protocol PBD-001 
CNSA-001 (Sepiapterin) 
 
 
STATISTICAL ANALYSIS PLAN APPROVAL 
Protocol: PBD-001 
Version 1.0 
 
 
 
 
 
 
 
09-Nov-2020 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
09-Nov-2020 
 
Date 
PTC Therapeutics, Inc. 


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PTC Therapeutics, Inc. 
SAP for Protocol PBD-001 
CNSA-001 (Sepiapterin) 
 
 
SAP Amendments before database lock 
 
Version Issue Date 
Section 
Revision / Addition 
Rationale 
2 
09-Nov-2020 
7.4 Medical 
History 
Changed MedDRA from 
Version 21.1 to Version 
23.1 
Coding will be done 
using Version 23.1 
2 
09-Nov-2020 
7.5 Prior and 
Concomitant 
Medications 
Change WHODrug from 
Version March 2018 to 
September 2020 
Coding will be done 
using Version 
September 2020 
2 
09-Nov-2020 
7.8.1 Adverse 
Events 
Changed MedDRA from 
Version 21.1 to Version 
23.1 
Coding will be done 
using Version 23.1 


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PTC Therapeutics, Inc. 
SAP for Protocol PBD-001 
CNSA-001 (Sepiapterin) 
 
 
Table of Contents 
LIST OF ABBREVIATIONS ....................................................................................................... 6 
1.0 
INTRODUCTION.............................................................................................................. 8 
2.0 
STUDY DESIGN ................................................................................................................ 8 
3.0 
STUDY OBJECTIVES .................................................................................................... 10 
4.0 
ANALYSIS POPULATIONS ......................................................................................... 11 
4.1 
Safety Population ................................................................................................... 11 
4.2 
Efficacy Population ................................................................................................ 11 
4.3 
PK Population ........................................................................................................ 11 
5.0 
DEFINITIONS OF OUTCOME MEASURES ............................................................. 12 
5.1 
Efficacy Outcomes ................................................................................................. 12 
5.2 
Safety Outcomes .................................................................................................... 12 
6.0 
STATISTICAL METHODS AND GENERAL CONSIDERATIONS ....................... 13 
6.1 
Sample Size ............................................................................................................ 13 
6.2 
Randomization ....................................................................................................... 13 
6.3 
Interim Analysis / DSMB ...................................................................................... 13 
6.4 
Standard Calculations ............................................................................................ 13 
6.5 
Comments on the Statistical Analyses ................................................................... 14 
6.6 
Decimal Places ....................................................................................................... 15 
6.7 
Conventions for Missing and Partial Dates ........................................................... 15 
6.8 
Handling of Missing Data ...................................................................................... 15 
7.0 
STATISTICAL ANALYSES .......................................................................................... 16 
7.1 
Patient Disposition ................................................................................................. 16 
7.2 
Protocol Deviations ................................................................................................ 16 
7.3 
Demographics and Baseline Characteristics .......................................................... 17 
7.4 
Medical History...................................................................................................... 17 
7.5 
Prior and Concomitant Medications ...................................................................... 17 
7.6 
Extent of Exposure ................................................................................................. 18 
7.7 
Efficacy Analyses .................................................................................................. 18 
7.7.1 
Efficacy Outcomes ................................................................................ 18 
7.7.2 
Exploratory Outcomes ........................................................................... 18 
7.8 
Safety Analyses ...................................................................................................... 19 
7.8.1 
Adverse Events (AEs) ........................................................................... 19 


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PTC Therapeutics, Inc. 
SAP for Protocol PBD-001 
CNSA-001 (Sepiapterin) 
7.8.2 
Clinical Laboratory Evaluations ............................................................ 21 
7.8.3 
ECG Parameters .................................................................................... 21 
7.8.4 
Vital Signs ............................................................................................. 21 
7.8.5 
Physical Examinations .......................................................................... 22 
7.9 
Pharmacokinetic Assessments ............................................................................... 22 
Appendix A: Schedule of Assessments and Procedures .................................................... 24 
Appendix B: Group Labels Used in Table, Figure and Listing Deliverables .................... 27 


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SAP for Protocol PBD-001 
CONFIDENTIAL 
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LIST OF ABBREVIATIONS 
 
5-HTP 
5-Hydroxytryptophan 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration-time curve from time zero to time ‘t’ 
where t is a defined time point after administration 
BH4 
Tetrahydrobiopterin 
BLQ 
Below the limit of quantitation 
BMI 
Body mass index 
bpm 
Beats per minute 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CASC 
Child and Adolescent Sleep Checklist 
Cmax 
Maximum plasma drug concentration 
CSF 
Cerebrospinal fluid 
CSR 
Clinical study report 
DBP 
Diastolic blood pressure 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case report form 
ECG 
Electrocardiogram 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GGT 
Gamma glutamyl transferase 
GM 
Geometric mean 
GCV% 
Geometric coefficient of variation % 
GTP-CH 
Guanosine triphosphate cyclohydrolase I 
HR 
Heart rate 
MedDRA 
Medical dictionary for regulatory activities 
NIH 
National Institutes of Health 
PBD 
Primary tetrahydrobiopterin deficiency 
Phe 
Phenylalanine 
PD 
Pharmacodynamic 


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SAP for Protocol PBD-001 
CONFIDENTIAL 
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PK 
Pharmacokinetic 
PT 
Preferred Term 
PTPS 
Pyruvoyl-tetrahydropterin synthase 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval calculated using Fridericia’s formula 
RR 
Respiratory rate 
RTI 
Reaction Time (CANTAB) 
RVP 
Rapid Visual Information Processing (CANTAB) 
SAE 
Serious AE 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOC 
System Organ Class 
SSP 
Spatial Span (CANTAB) 
SWM 
Spatial Working Memory (CANTAB) 
TEAE 
Treatment-emergent AE 
Tlast 
Time of last observed quantifiable concentration 
Tmax 
Time to maximum observed plasma concentration 
Tyr 
Tyrosine 
US 
United States 
WHO 
World health organization 


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1.0 
INTRODUCTION 
 
This Statistical Analysis Plan (SAP) provides the framework for the summarization and analysis 
of the clinical data from the study, “A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra- 
patient Dose Escalation Study to Evaluate the Safety, Pharmacokinetics and Preliminary Efficacy 
of CNSA-001 (Sepiapterin) in Primary Tetrahydrobiopterin Deficient Patients with 
Hyperphenylalaninemia”. Major changes made to the SAP after it has been signed but prior to 
database lock will be documented in an amendment. Any major changes made to the planned 
analysis will be described in the clinical study report (CSR). 
2.0 
STUDY DESIGN 
 
This is a Phase 1/2, multicenter, randomized, open-label, intra-patient dose escalation study 
designed to evaluate the safety, pharmacokinetics, and preliminary efficacy of CNSA-001 
(sepiapterin) in male and female patients with primary tetrahydrobiopterin deficient (PBD). 
 
This study will enroll patients with confirmed defects in de novo biopterin biosynthesis due to 6- 
pyruvoyl-tetrahydropterin synthase (PTPS) or recessive guanosine triphosphate cyclohydrolase I 
(GTP-CH) genes, abnormal enzyme activity of the PTPS or GTP-CH enzymes, or a 
cerebrospinal fluid (CSF) biochemical profile indicative of PTPS or GTP-CH deficiencies. 
 
Six (6) to 10 patients will be enrolled in this study at 5 to 6 study centers. 
 
The study design is summarized in the study schema that follows and the schedule of 
assessments and procedures is provided in Appendix A. 
Screening Period (Day -14 to Day -4): An informed consent or assent (if applicable) form must 
be signed before any study-related procedures are performed. After consenting to the study, PBD 
patients will undergo Screening procedures which include medical/surgical history, 
demographics, vital signs, 12-lead electrocardiogram (ECG), physical examination, and clinical 
laboratory tests (chemistry, hematology, urinalysis). Blood phenylalanine (Phe) levels will be 
measured at Screening and compared to the 3 most recent historical Phe concentrations. Patients 
who are eligible based on Screening tests will proceed to the tetrahydrobiopterin (BH4) Washout 
Period. 
BH4 Washout Period (Day -3 to Day -1): Eligible patients who are taking BH4 [Kuvan® 
(sapropterin dihydrochloride)] will discontinue the medication during the BH4 Washout Period 
and will remain off this medication during the entire study. Patients will be instructed to maintain 
a consistent diet (with respect to protein and Phe intake) and 3-day diet records will be collected 
during BH4 Washout Period and throughout the study. On Days -3, and -1 during the BH4 
Washout Period, blood will be collected for determination of Phe concentrations. 


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Treatment Period 1 and Period 2: Patients will receive treatment with CNSA-001 twice daily for 
a total of 14 days (that is, two 7-day treatment periods separated by a 3 (±1) day washout). 
Patients will be randomized into one of 2 cohorts, with each cohort assessing 2 dose levels of 
CNSA-001 via intra-patient dose escalation. 
• Cohort 1, patients will receive 2.5 mg/kg/day for 7 days in Period 1, undergo a 3 (±1) 
day washout period, then escalate to 10 mg/kg/day for 7 days in Period 2 (14 days total 
treatment) 
• Cohort 2, patients will receive 5 mg/kg/day for 7 days in Period 1, undergo a 3 (±1) day 
washout period, then escalate to 20 mg/kg/day for 7 days in Period 2 (14 days total 
treatment). 
 
Patients will be eligible for dose escalation during Period 2 if they meet the criteria for intra- 
patient dose escalation (refer to Section 6.12 of protocol). 
Data Safety Monitoring Board (DSMB) and possible inclusion of patients between 12 months 
and 17 years of age inclusive: Initially, only adult patient(s) (≥18 years) will be enrolled. The 
first adult patient will be enrolled into Cohort 1 and then a second adult patient will be enrolled 
into Cohort 2 of the study, with subsequent patients being randomized into either cohort. After 
the first adult patient(s) have completed the study, the DSMB will review safety and 


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pharmacokinetic/ pharmacodynamic (PK/PD) data, including preliminary efficacy, for the adult 
patient(s). If the data display no safety issues and provide for the prospect of clinical benefit in 
patients ≥ 12 months to < 18 years old, then the eligibility criterion for age at time of enrollment 
will be expanded to include children (≥12 months). The safety, and PK/PD data on the dosed 
adult patient(s) will be submitted for review to the United States (US) Food and Drug 
Administration (FDA) for review prior to enrolling patients ≥12 months to < 18 years old. 
 
Acceptable Concomitant Medications: During the study, patients will continue their other current 
medications for PBD (including L-dopa/carbidopa, 5-Hydroxytryptophan (5-HTP), melatonin, 
Monoamine oxidase inhibitors, and dopamine receptor agonists as prescribed) except for BH4 
supplementation (if they were taking BH4), and will be monitored clinically as per standard of 
care for PBD to optimize treatment. 
 
Safety and tolerability will primarily be assessed by adverse events (AEs), vital signs, clinical 
laboratory tests including chemistry, hematology, and urinalysis, physical examinations, and 12- 
lead ECGs. Preliminary efficacy will be assessed by the reduction in plasma Phe levels. Other 
secondary measures will include whole blood serotonin, serum prolactin and BH4, and urine 
sepiapterin, BH4 and neopterin. 
Blood samples will be collected to characterize the pharmacokinetics of sepiapterin and its effect 
on serum BH4, Phe, and tyrosine (Tyr) levels. 
 
Discontinuation of Study Drug: Patients will receive treatment with CNSA-001 for a total of 14 
days (that is, two 7-day treatment periods separated by a 3 (±1) day washout), unless they meet 
criteria for discontinuing CNSA-001 treatment. Permanent discontinuation of CNSA-001 
treatment may be triggered by safety reasons or lack of efficacy. Patients who discontinue 
CNSA-001 treatment early will complete the End of Study (EOS) assessments. After completion 
of the EOS assessments, patients should immediately revert to pre-study standard of care for 
their PBD, including BH4 if they were taking it previously. 
Phone follow-up visits to assess for AEs and serious AEs (SAEs) will occur 7 to 10 days, and 30 
(±3) days after the last dose of study drug. 
3.0 
STUDY OBJECTIVES 
 
Primary: 
• To assess the safety and tolerability of 4 dose levels of CNSA-001 in PBD patients with 
PTPS or recessive GTP-CH deficiency. 
 
Secondary: 


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• To assess the PK profile of CNSA-001 and its effect BH4, Phe, and Tyr in PBD patients 
with PTPS or recessive GTP-CH deficiency. 
• To evaluate the preliminary efficacy of CNSA-001 in reducing blood Phe levels in PBD 
patients with PTPS or recessive GTP-CH deficiency after 7 days of treatment. 
 
Exploratory: 
• To assess the change from baseline in other exploratory biomarkers of this disease such 
as serum prolactin, whole blood serotonin, urine sepiapterin, BH4, and neopterin levels. 
• To assess the change from baseline in Cambridge Neuropsychological Test Automated 
Battery (CANTAB) tests, including the Reaction Time (RTI), the Spatial Span (SSP), the 
Spatial Working Memory (SWM) and Rapid Visual Information Processing (RVP). 
• To assess changes in movement and sleep for euphenylalaninemic and 
hyperphenylalaninemic states as assessed by an accelerometer device (GeneActiv, 
Activinsights Ltd.). 
• To evaluate changes from baseline in cognitive assessments via the National Institutes of 
Health (NIH) Cognition Toolbox. 
• To evaluate changes from baseline in the Child and Adolescent Sleep Checklist (CASC). 
 
4.0 
ANALYSIS POPULATIONS 
 
4.1 
Safety Population 
 
The Safety population will consist of all randomized patients who receive any amount of study 
drug. All safety analyses will be performed on this population. Any patients who receive the 
wrong dosing of study drug for their entire course of treatment will be analyzed in the dosing 
group based on the drug dosing received. 
4.2 
Efficacy Population 
 
The Efficacy population will consist of all patients who were randomized, received any amount 
of study drug, and had available pre-dose Phe concentrations at Day 1 and at least one post-Day 
1 visit within a given period. All efficacy analyses will be performed on this population. 
4.3 
PK Population 
 
The PK population will consist of all patients who received at least one dose of study drug and 
had at least 1 quantifiable post-dose blood sample collected for analysis of sepiapterin, BH4, 
Phe, or Tyr concentrations. All PK analyses will be performed on this population. 


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5.0 
DEFINITIONS OF OUTCOME MEASURES 
 
Efficacy will be assessed in the Efficacy population. Efficacy measurements considered, are as 
follows: 
5.1 
Efficacy Outcomes 
 
Outcome 
Measure-ment 
type 
Day 7 change in plasma Phe levels with respect to baseline 
Continuous 
Number and percent of patients with Day 7 Phe concentrations in acceptable 
treatment range of 130 to 360 µmol/L 
Number and 
Percent 
Number and percent of patients with Day 7 Phe concentrations <130 µmol/L 
Number and 
Percent 
Biomarker measurements at each visit, from baseline onwards as per the 
schedule of assessments (Appendix A): 
• Biomarkers in urine sepiapterin, neopterin, and BH4 
• Serum prolactin 
• Whole blood serotonin 
Continuous 
CANTAB at Screening, Day 1 (pre-dose) and Day 7 of each treatment period 
Continuous 
Movement and sleep assessment via the GENEActiv accelerometer 
Continuous 
NIH Toolbox Cognitive Domain test battery 
Continuous 
Parent or caregiver assessment of sleep (CASC) 
Categorical 
 
5.2 
Safety Outcomes 
 
Safety will be assessed by analysis of the occurrence of treatment emergent AEs (TEAEs), as 
well as by adverse changes in laboratory evaluations (hematology, serum chemistry panel, 
urinalysis, and urine microscopic), ECG parameters, vital signs, and physical examinations. 
Laboratory abnormalities will not be considered AEs unless the abnormality is part of a clinical 
signs or syndrome. However, a clinically significant laboratory abnormality (e.g. detected on 
hematology, serum chemistry panel, urinalysis, and urine microscopic evaluations) that is 
independent from the underlying medical condition and that requires medical or surgical 
intervention, or leads to study drug interruption or discontinuation, will be considered an AE. 


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6.0 
STATISTICAL METHODS AND GENERAL CONSIDERATIONS 
 
6.1 
Sample Size 
 
The primary objective of this study is to evaluate the safety of 4 doses of CNSA-001. The sample 
size for this study is not based on statistical considerations, and a sample size of 6 to 10 patients 
(with 2 doses administered per patient) is considered adequate for this orphan population. Also, 
the treatment induced changes in Phe level is not powered for this study and caution is needed in 
the interpretation of efficacy results. 
6.2 
Randomization 
 
This is an open-label randomized parallel arm, intra-patient dose escalation study. Initially, only 
adult patient(s) (≥18 years) will be enrolled. The first adult patient will be enrolled into Cohort 1 
and then a second adult patient will be enrolled into Cohort 2 of the study, with subsequent 
patients being randomized into either cohort. After the first adult patient(s) have completed the 
study, the DSMB will review safety and PK/PD data, including preliminary efficacy, for the 
adult patient(s). If the data display no safety issues and provide for the prospect of clinical 
benefit in patients ≥12 months to <18 years old, then the eligibility criterion for age at time of 
enrollment will be expanded to include children (≥12 months). 
6.3 
Interim Analysis / DSMB 
 
An interim analysis to assess efficacy is not planned. However, a DSMB will review safety and 
PK/PD data. A detailed DSMB charter will outline the responsibilities, membership, format and 
frequency of the meetings, methods of providing data to and from the DSMB, statistical issues, 
and communication pathways. At a minimum, the DSMB will consist of a physician familiar 
with PBD, a statistician, and the Medical Monitor. 
6.4 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
 
• Baseline: A baseline value, unless specified otherwise, is the last non-missing value recorded 
prior to the first dose of study drug for a given dosing period. If an assessment has both a 
date and time that exactly match the date and time of first dose of study drug, the assessment 
will be counted as baseline. Note each dosing period within a cohort will have its own 
baseline. 
• Change from Baseline: Change from baseline will be calculated for each patient at the 
specified time point as the value at the specified time point minus the baseline value. 


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• Study day: For a given date (date), study day is calculated as days since the date of first dose 
of study drug within the dosing cohort (firstdose). For example, if the washout between 
treatment periods is 3 days long, then period 2 day 1 will become study day 11: 
Study day = date – firstdose + 1, where date ≥ firstdose 
Study day = date – firstdose, where date < firstdose 
• Days: Durations, expressed in days, between one date (date1) and another later date (date2) 
are calculated using the following formula: duration in days = (date2 – date1 + 1). 
• Weeks: Durations, expressed in weeks, between one date (date1) and another later date 
(date2) are calculated using the following formula: duration in weeks = (date2 – date1 + 1) / 
7. 
• Months: Durations, expressed in months, between one date (date1) and another later date 
(date2) are calculated using the following formula: duration in months = (date2 – date1 + 1) / 
30.4375. 
• Years: Durations, expressed in years, between one date (date1) and another later date (date2) 
are calculated using the following formula: duration in years = (date2 – date1 + 1) / 365.25. 
• Body Mass Index (BMI): BMI (kg/m2) = weight (kg) / [(height (cm)/100)2] 
• Age at time of consent is collected. 
6.5 
Comments on the Statistical Analyses 
 
• All relevant data captured on the electronic Case Report Forms (eCRFs), including specific 
descriptions of ‘other’ and comments fields will be included on the listings. All listings will 
be sorted by patient number in ascending order within dose cohort and period. 
• All summary tables will be presented by dose cohort and dose / period. Disposition, 
discontinuations, demographic and other baseline characteristics, medical history, AEs, and 
prior and concomitant medication summaries will also include an overall summary column. 
Summary tables presenting results by study visit will include all scheduled study visits using 
informative visit labels. 
• Continuous variables will be summarized using number (n), mean, standard deviation (SD), 
median, minimum, and maximum. Except for the time to maximum observed plasma 
concentration (Tmax), summaries of PK parameters will also include the geometric mean 
(GM) and geometric coefficient of variation percentage (GCV%). 
• Categorical variables will be summarized by presenting the frequency and percent. 
Percentages will be based on the patient population unless otherwise specified. For each 
variable, all categories will be shown. Zero frequencies within a category will be presented 
without percent. 


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SAP for Protocol PBD-001 
CONFIDENTIAL 
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• If a laboratory result is reported relative to a lower/upper range of detection for an assay (e.g. 
“<10”) the numeric portion of the result (e.g. 10) will be used for statistical analyses and the 
full result, including any symbols, will be provided in the patient listings. 
• Version 9.4 (or higher) of SAS statistical software package will be used to provide all 
summaries, listings, figures and statistical analyses. R version 4.0.2 using PKNCA package 
version 0.9.4 will be used to calculate the PK parameters. 
6.6 
Decimal Places 
 
• For PK data, individual concentrations and PK parameters will be reported to 3 significant 
figures. For summary statistics, n will be reported as a whole number; mean, SD, median, 
min, max, geometric mean, CV% and GM CV% will be reported to 3 significant figures. 
Time will also be presented to 3 significant figures. 
• For safety summaries, means and medians will be displayed to one more decimal place than 
the original data, SD will be displayed to two more decimal places, and the minimum and 
maximum will be displayed to the same number of decimal places. Percentages will be 
reported with exactly one decimal place, with the exception of 100% which will be reported 
without a decimal place. 
• Derived data where it is known in advance the result will be an integer for example number 
of days will be presented with zero decimal places. 
6.7 
Conventions for Missing and Partial Dates 
 
It is not expected that there will be any missing dates, however in the rare case that an Adverse 
Event (AE) start date or time is missing and it is unclear whether the AE is treatment emergent or 
not then a conservative approach will be taken and it will be assumed that the AE occurred after 
first dosing. 
 
All dates presented in the individual subject listings will be as recorded on the eCRF. 
 
6.8 
Handling of Missing Data 
 
Missing data are handled as follows: 
 
• Missing values for individual data points will remain as missing. Missing values will not be 
imputed for data and only observed values will be used in safety and efficacy data analyses 
and presentations. If there is missing data for PK assessments from the central lab at a 
specific timepoint, the local lab result for that timepoint will be used for analysis. 


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• Where individual data points are missing, categorical data will be summarized based on 
reduced denominators (that is, only patients with available data will be included in the 
denominators). 
 
• Handling of below the limit of quantitation (BLQ) plasma concentration values is defined 
under Section 7.9 Pharmacokinetic Assessments. 
 
7.0 
STATISTICAL ANALYSES 
 
7.1 
Patient Disposition 
 
Patient disposition information will be summarized for all patients as follows: 
 
• The number of patients completing the study drug, the reason for discontinuation of study 
drug, the number of patients completing the study, and the reason for discontinuation of 
study will be summarized by dose cohort and overall. 
• The number of randomized patients and number of patients in each analysis population 
by dose level, cohort and overall. 
 
A listing of all patients who prematurely discontinued from study drug or prematurely withdrew 
from the study will be presented, and the primary reason for discontinuation of study drug or 
withdrawal from the study will be provided. And a listing of patients excluded from the analysis 
populations and the reason for their exclusion will be provided. 
7.2 
Protocol Deviations 
In accordance with ICH E3, Sponsor-defined eligibility violations and important post- 
randomization protocol deviations will be identified and listed separately by patient. 
 
Deviation type/code as provided by Sponsor: 
• Eligibility criteria related 
• Study procedure not done 
• Study procedure not per protocol 
• Withdrawal criteria 
• Missed study visit 
• Visit out of study window 
• Patient not withdrawn as per protocol 
• Prohibited medication/therapy 
• Informed consent 
• Laboratory samples 
• Safety reporting 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
PTC Therapeutics, Inc. 
CNSA-001 (Sepiapterin) 
SAP for Protocol PBD-001 
CONFIDENTIAL 
Page 17 of 27 
 
 
 
 
• Study drug administration 
• Study drug storage and handling 
• Other 
 
A listing of protocol deviations will be provided. 
 
7.3 
Demographics and Baseline Characteristics 
 
Demographic data and baseline characteristics will be presented for the Safety, Efficacy and PK 
populations. A table will present the patient demographics (that is, gender, age, ethnicity and 
race) and baseline characteristics of height (cm), weight (kg) and BMI (kg/m2), collected before 
the start of study drug. Additionally, the baseline Phe values will be summarized under baseline 
characteristics. 
 
A demographic listing, which includes the date the informed consent was signed, will be 
provided. 
7.4 
Medical History 
 
Medical history collected at screening will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) classification, version 23.1. Medical history will be summarized by system 
organ class (SOC) and preferred term (PT). Patients who report 2 or more medical history items 
that are coded to the same SOC and/or PT will be counted only once by the unique coded term in 
the summary. The summary will be provided for the Safety population. 
 
A listing will be provided by patient for the Safety population. 
 
7.5 
Prior and Concomitant Medications 
Verbatim terms on eCRFs will be mapped to Anatomical Therapeutic Chemical (ATC) class and 
Generic Drug Names using the World Health Organization (WHO) (WHODrug Enhanced 
September 2020) dictionary. 
 
Prior medications are those medications that discontinued before the start of study drug. 
Concomitant medications are those medications taken at the start of study drug or initiated after 
the initial dose of study drug, or medications that were initiated prior to the start of study drug 
and continue to be taken after study drug is administered. 
 
Prior medications and concomitant medications will be summarized by ATC level 1 term, ATC 
level 3 term and Preferred Term (generic name) with frequency and percentage of patients in 
each dosing arm using each prior medication and each concomitant medication. At each level of 
patient summarization, a patient is counted once if he/she reported one or more medications at 


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PTC Therapeutics, Inc. 
CNSA-001 (Sepiapterin) 
SAP for Protocol PBD-001 
CONFIDENTIAL 
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that level. Each summary will be ordered by descending patient count in the overall column by 
each level of ATC class and generic drug name within each level of ATC class. The summary of 
prior and concomitant medications will be provided for the Safety population. 
 
Prior and concomitant medications will also be listed separately. Those medications that are 
initiated after the last dose of study drug will be flagged in the concomitant medication listing. 
7.6 
Extent of Exposure 
 
Extent of exposure to study drug will be examined by assessing days dosed. 
 
Days dosed will be defined as the number of days during which the patient received any amount 
of study drug to be administered orally (powder of suspension) and will be summarized for days 
dosed by period and then overall. 
7.7 
Efficacy Analyses 
 
All efficacy analyses will be performed on the Efficacy population. 
 
7.7.1 
Efficacy Outcomes 
 
• Change in Phe levels with respect to baseline 
 
Phe concentrations at each visit and changes from baseline (Day 1, pre-dose) to each 
post-Day 1 assessment will be summarized using summary statistics within each dose 
cohort and period. The primary efficacy outcome is the reduction in plasma Phe levels 
defined as the change of plasma Phe concentrations at Day 7 from baseline (Day 1, pre- 
dose) within the same treatment period. 95% confidence intervals will be calculated for 
the change in baseline to Day 7 Phe values for each period within a cohort. 
• Number and percent of patients with Phe concentrations in acceptable treatment range of 
130 to 360 µmol/L at Day 7 
• Number and percent of patients with Phe concentrations <130 µmol/L at Day 7 
7.7.2 
Exploratory Outcomes 
Exploratory biomarker, prolactin and serotonin outcomes will be summarized by visit along with 
changes from baseline within each cohort and period. A listing will be provided by patient for 
the Safety population. 
 
• Urine sepiapterin, neopterin, and BH4 
• Serum prolactin 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
PTC Therapeutics, Inc. 
CNSA-001 (Sepiapterin) 
SAP for Protocol PBD-001 
CONFIDENTIAL 
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• Whole blood serotonin 
 
Cognitive impairment as measured using the CANTAB will be summarized at Screening, Day 1 
(pre-dose) and Day 7 of each treatment period. The CANTAB test components of RTI, SSP, 
SWM and RVP will be represented graphically through time by cohort to assess chronological 
and treatment effects if any. Each component of the CANTAB will be summarized at each visit 
and also changes from baseline, if possible. A listing will be provided by patient for the Safety 
population. 
 
Changes in physical activity and sleep patterns of behavior will be recorded using wrist-worn 
GENEActiv accelerometer. A listing will be provided by patient for the Safety population. 
 
NIH Toolbox Cognition Domain will be used to evaluate the changes in cognitive assessment 
from baseline. The Toolbox was specifically designed to measure neuropsychological and 
behavioral functions over time and to measure key constructs across developmental stages. This 
facilitates the potential evaluation of treatment effectiveness of CNSA-001, as well. This study 
will use an age-based battery of assessments from the Cognitive Domain of the NIH Toolbox. 
All tests will be administered via an iPad on either Day-1 or Day 1 predose (that is, at baseline) 
and on Day 7 of each treatment period. A listing will be provided by patient for the Safety 
population. 
 
Child and Adolescent Sleep Checklist: A questionnaire will be provided to identify sleep 
problems in children, ages 3-18 years. Parents or caregivers are asked to recall the child’s sleep 
during the last 7 days when providing responses to questions. Responses to the questions about 
sleep habits are scored from 0 (never or don’t know) to 3 (always), yielding an overall score of 0-
72. Scores above 18 indicate sleep problems. In addition, there are four categories of scores: 
Bedtime problems (Q1-Q6; 6 questions), sleep breathing and unstable sleep (Q7-Q12; 6 
questions), parasomnia and sleep movement (Q13-Q18; 6 questions), and daytime problems 
(Q19-Q24; 6 questions). A listing will be provided by patient for the Safety population. 
 
7.8 
Safety Analyses 
 
All safety analyses will be performed on the Safety population. 
 
7.8.1 
Adverse Events (AEs) 
 
Adverse events will be coded to SOC and PT using MedDRA version 23.1. The coding process 
will be described in the Data Management Plan. 
Summaries will be provided for AEs, with the number and percentage of patients reporting each 
type of event presented. If a patient reports the same PT more than once, it is counted only once 
within that category. A similar comment applies to the SOC; namely if a patient has AEs of two 
or more PTs under the same SOC, then that patient only counts once for that SOC. Further, for a 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
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CNSA-001 (Sepiapterin) 
SAP for Protocol PBD-001 
CONFIDENTIAL 
Page 20 of 27 
 
 
 
 
given summary, the PT will only be counted once at its worst severity and strongest relationship 
to treatment. 
Pre-treatment AEs are defined as AEs that have an onset prior to the time of the first dose and 
after the informed consent date. 
AEs will be regarded as TEAEs if they start on or after first dose of study drug administration 
and no more than 7 days after the last dose of study drug (30 days after last dose of study drug 
for SAEs). The following rules will be used to assign a TEAE to a treatment group: 
• A TEAE will be assigned to the treatment received immediately before onset. 
• Any TEAE reported within the washout period between doses will be attributed to the 
previous treatment. 
• If the severity of a TEAE increases in a later period, the TEAE at the increased severity 
will be assigned to the treatment received immediately before the increase in severity. 
 
The following summaries for TEAEs will be provided: 
 
o An overall summary table of TEAEs summarizing the number and percent of 
patients, in the following categories: any TEAE, severe TEAE, TEAE related to 
study drug, serious TEAE, TEAE’s leading to premature discontinuation of study 
drug and TEAEs leading to discontinuation of study. 
 
o Incidence of TEAEs by MedDRA SOC and PT. 
o Incidence of TEAEs by MedDRA SOC and PT, and worst severity. 
o Incidence of TEAEs by MedDRA SOC and PT, and strongest relationship to 
study drug. 
 
o Listing of All SAEs 
o Listing of All AEs for patients who prematurely discontinued study drug or 
prematurely withdrew from the study due to an AE. 
 
o Listing of All AEs for patients who died. 
o Incidence of serious TEAEs (SAEs) by MedDRA SOC and PT. 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
PTC Therapeutics, Inc. 
CNSA-001 (Sepiapterin) 
SAP for Protocol PBD-001 
CONFIDENTIAL 
Page 21 of 27 
 
 
 
 
In addition to the by-treatment summaries described above, a data listing will be provided for all 
AEs (including a TEAE flag). 
7.8.2 
Clinical Laboratory Evaluations 
 
Descriptive statistics for chemistry, hematology and urinalysis parameter values and the change 
from baseline at will be summarized for the Safety population. Change from baseline will be 
calculated for each patient at each post-baseline visit. 
 
Additionally, shift in liver parameters from baseline to the highest post-baseline result 
(worsening) will be presented for alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase (ALP), Bilirubin and gamma glutamyl transferase (GGT); these will 
be based on the provided laboratory reference ranges for high and low. 
 
A listing of hematology, chemistry and urinalysis laboratory measurements will be provided. 
 
7.8.3 
ECG Parameters 
 
Descriptive statistics for ECG parameters (that is, Heart Rate [HR], RR interval, PR interval, 
QRS duration, QT interval, corrected QT interval [QTc] and QTc calculated using Fridericia’s 
formula [QTcF]) at baseline and the Day 7 visit and the change from baseline will be presented. 
Given that triplicate readings of ECGs will be collected, where each reading is taken 1 minute 
apart, means will be calculated on these multiple ECG measurements (by time point), and the 
table summaries will be based on these means. 
 
For QTcF, a distribution of the increase from baseline to Day 7 on the categories <0 msec, ≥1 to 
<30 msec, ≥30 to <60 msec, ≥60 to <90 msec, and >=90 msec will be presented; as well as a 
distribution on the categories ≤ 450 msec, > 450 to ≤ 480 msec, >480 to ≤ 500 msec, and >500 
msec. If needed, QTcFs will be calculated using the following formula: QT/(RR)1/3. 
Listings of electrocardiogram data will be provided, including the normal, abnormal and 
clinically significant status of each measurements. 
7.8.4 
Vital Signs 
 
Systolic and diastolic blood pressures (SBP and DBP), HR, respiratory rate (RR) and body 
temperature, will be summarized using descriptive statistics at each time point at which they 
were measured. Temperature will be collected in °C (Celsius) or °F (Fahrenheit) in eCRF, all 
values will be converted to °C for analysis using the formula °C = (°F – 32) * 5/9. 
 
Descriptive statistics of the change from baseline to each post-baseline time point will also be 
provided. 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
PTC Therapeutics, Inc. 
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SAP for Protocol PBD-001 
CONFIDENTIAL 
Page 22 of 27 
 
 
 
 
A summary of abnormal values based on absolute and relative criteria, identified by the criteria 
provided in the table below, will be provided for patients with both baseline and post-baseline 
values. The summary table will have two sets of summary statistics for each parameter; one row 
of summaries for the absolute criterion and then another row based on the more restrictive 
summaries of absolute and relative criterion (both must be met). In the table that follows 
absolute criteria are provided in the 3rd column and relative criterion is contained in the last 
column. 
All vital sign parameters will also be provided in listings. 
 
Criteria for Treatment Emergent Clinically Significant Vital Signs 
 
Vital Sign Parameter 
Flag (*) 
Criterion Value 
Change from Baseline 
Systolic Blood 
Pressure (mmHg) 
High (CH) 
≥ 180 
Increase of ≥ 20 mmHg 
Low (CL) 
≤ 90 
Decrease of ≥ 20 mmHg 
Diastolic Blood 
Pressure (mmHg) 
High (CH) 
≥ 105 
Increase of ≥ 15 mmHg 
Low (CL) 
≤ 50 
Decrease of ≥ 15 mmHg 
Heart Rate (bpm) 
High (CH) 
≥ 120 
Increase of ≥ 15 bpm 
Low (CL) 
≤ 50 
Decrease of ≥ 15 bpm 
(*) CH = clinically high; CL = clinically low. 
 
7.8.5 
Physical Examinations 
 
The percentage of patients with an abnormal body system examination at baseline and each post- 
baseline visit will be summarized by body system for patients on the Safety population. Physical 
examination results will also be presented in listings. 
7.9 
Pharmacokinetic Assessments 
 
Sampling for PK analysis (with evaluation of sepiapterin and its effect on BH4, Phe and Tyr 
levels) will occur at the following time points for each dose level: on Day 1 at pre-dose (within 
30 min of dosing), +0.5 hr (± 3 min), +1 hr (± 5 min), +2 hr (±6 min), +4 hr (± 20 min), +6 hr (± 
30 min), +8 hr (±60 min, prior to Day 1 evening dose), and +24 hours (±2 hr, prior to Day 2 
morning dose) after the first dose of study drug. 
For these analyses, the patients will be analyzed using the PK population (as per the treatment 
received). The concentration of CNSA-001 (sepiapterin), BH4, Phe, and Tyr in plasma samples 
will be analyzed by MNG Laboratories using a validated LC/MS/MS method. The following 
non-compartmental PK parameters will be estimated and listed along with graphical presentation 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
PTC Therapeutics, Inc. 
CNSA-001 (Sepiapterin) 
SAP for Protocol PBD-001 
CONFIDENTIAL 
Page 23 of 27 
 
 
 
 
of the concentration data (note: additional PK parameters may be calculated as needed to 
adequately characterize the PK of sepiapterin and associated analytes): 
 
Parameter 
Definition 
AUC0-last 
Area under the curve from time 0 to the time of the last quantifiable 
concentration trapezoidal method (linear-up/log-down method) 
Tlast 
Time of last observed quantifiable concentration 
Cmax 
Maximum observed concentration 
Tmax 
Time to Cmax 
 
Data Considerations: Plasma concentration values that are below the lower limit of quantitation 
(BLQ) will be presented as “BLQ” in the concentration data listing. For noncompartmental 
analysis BLQ values are handled as follows: 
• BLQ values prior to the first quantifiable concentration will be treated as 0. 
• BLQ values appearing between two quantifiable concentrations will be treated as 
missing. 
• BLQ values in the terminal elimination phase are treated as missing. Once two BLQ 
values are observed in the terminal phase, the profile is deemed to have terminated and 
all subsequent quantifiable values are treated as missing. 
 
PK Graphs: 
For each of the following analytes: sepiapterin, BH4, Phe, and Tyr, figures will be derived and 
will include, individual patient PK profiles, mean PK profiles and as needed box plots or scatter 
plots comparing derived PK. 
 
PK concentrations time graphs: 
For sepiapterin, BH4, Phe, and Tyr analytes, the following linear and semi-log graphs will be 
presented: 
• Individual (patient) PK profiles by dose level 
• “Spaghetti plots” displaying all individual profiles together, and 
• Mean/Median plots comparing PK profiles across all dose levels 
 
Nominal blood sampling times will be used to calculate the median and mean concentrations at 
each time point. 
 
PK Listings: Detailed patient listings of plasma PK results will be provided. 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
PTC Therapeutics, Inc. 
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SAP for Protocol PBD-001 
CONFIDENTIAL 
Page 24 of 27 
 
 
 
Appendix A: Schedule of Assessments and Procedures 
 
Evaluation 
Screen 
Period 
BH4 
Washout 
Treatment Period 
End of 
Study 
(≤ 48 hrs 
after last 
dose) 
Phone 
Follow-up 
Period 1 
Washout 
Period 2 
Day-14 
to 
Day -4 
Day -3 
to 
Day -1 
Day 1 Day 2 Day 4 
(±1) 
Day 7 
3 (±1) 
days 
Day 1 Day 2 
Day 4 
(±1) 
Day 7 
7 - 10 
days after 
last dose 
30 (±3) 
days after 
last dose 
Informed consent 
X 
Confirm inclusion/exclusion 
criteria eligibility 
X 
Xa 
Xa 
Confirm mutation analysis for 
PBD genes b 
X 
Demographics 
X 
Medical history c 
X 
Vital signs, height and weight d 
X 
Xa 
X 
X 
Xa 
X 
X 
X 
ECGs e 
X 
Xa 
X 
Xa 
X 
Physical examination f 
X 
Xa 
X 
Xa 
X 
Xs 
Clinical laboratory tests and, 
serum prolactin h 
X 
Xa 
X 
Xa 
X 
Xs 
Serum/urine pregnancy test i 
X 
Xa 
Xa 
X 
Prior/Concomitant meds j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Phe concentrations l 
X 
X 
Xa 
Xa 
X 
X 
Xa 
Xa 
X 
X 
X 
Consistent diet/ 3-day diet 
record m 
X 
X 
 
X 
X 
X 
 
X 
Xs 
Seizure journal 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discontinue BH4 n 
X 
 
PK: Sepiapterin, BH4, and 
Phe/Tyr o 
Xa 
Xa 
X 
X 
Xa 
Xa 
X 
X 
X 
Biomarkers in urine p 
X 
Xa 
Xa 
X 
X 
Xa 
Xa 
X 
X 
Whole blood serotonin 
X 
Xa 
Xa 
X 
X 
Xa 
Xa 
X 
X 
CANTAB testing q 
X 
X 
Xa 
X 
Xa 
X 
Don GENEActive 
Accelerometer u 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NIH ToolBox Test Battery 
Xa,v 
Xa,v 
X 
X 
X 
Administer the CASC 
X 
X 
X 
X 
Administer study drug r 
 
 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
PTC Therapeutics, Inc. 
CNSA-001 (Sepiapterin) 
SAP for Protocol PBD-001 
CONFIDENTIAL 
Page 25 of 27 
 
 
 
Dispense study drug s 
X 
X 
Dispense Dosing Diary t 
X 
X 
Collect Study Drug, Dosing 
Diary, Assess Compliance 
X 
X 
X 
Resume BH4 therapy 
X 
X 
X 
a. 
To be completed prior to initial dosing. 
b. 
Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic mutations in PTPS or recessive GTP-CH genes, abnormal enzyme activity of the PTPS or GTP- 
CH enzymes, or a CSF biochemical profile indicative of PTPS or GTP-CH deficiencies. No genetic testing or retesting is required. 
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; and neurological. Also, includes documentation of 3 most recent historical Phe concentrations. 
d. 
Includes blood pressure, pulse, respiratory rate, and oral temperature. Patients will have a 5-minute rest in a supine position before vital signs are assessed. Weight will only be 
collected at Screening and on Day 1 of each treatment period. Height will only be collected at Screening. Vital signs will be collected both pre-dose and 2-hours post-dose (before 2- 
hour blood collection for PK) on Day 1 of each treatment period; for all other timepoints they will be taken at any time during the visit. 
e. 
12-lead ECGs to be performed at Screening, and on Day 1 (pre-dose) and Day 7 of each treatment period. ECGs will be performed in triplicate, with each read taken 1 minute apart. 
f. 
The examination will assess general appearance, as well as dermatologic, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neurological 
parameters. 
g. 
Can be performed either on Day 7 visit of Treatment Period 2 or at the EOS Visit. Does not need to be conducted at both. 
h. 
Includes clinical chemistry panel (albumin, AP, ALT, AST, BUN, calcium, CO2, chloride, creatinine, GGT, glucose, LDH, phosphorus, potassium, sodium, total bilirubin, direct 
bilirubin, total cholesterol, total protein, uric acid), and serum prolactin; hematology panel (hematocrit, hemoglobin, platelet count, RBC, WBC, and WBC differential); and urinalysis 
(appearance, bilirubin, color, glucose, ketones, microscopic examination of sediment, occult blood, pH, protein, specific gravity, and urobilinogen). 
i. 
Serum and urine pregnancy test required for all women who are not postmenopausal and for adolescents who have started menstruation; serum testing to occur during the Screening 
Period and urine testing to occur prior to dosing on Day 1 of Periods 1 and 2 and EOS. A positive urine test must be confirmed with a serum test. 
j. 
Record all Rx and OTC medications starting from 30 days prior to Screening through last study visit. 
k. 
Adverse events are to be collected from the time of informed consent until 7 days after the last dose of study drug (30 days after last dose for SAEs). 
l. 
Blood Phe concentrations collected during Screening (prior to BH4 Washout) and during BH4 Washout Period on Days -3 and -1 will be analyzed by the site’s local laboratory. To 
minimize burden on patients, Phe collection on Days -3 and -1 during the Washout Period may be obtained via filter paper with overnight shipping to the site’s designated laboratory. 
All other blood Phe concentrations will be used for safety monitoring and analyzed by the site’s local laboratory and are collected on Day 1 and Day 2 (pre-dose), and on Day 4 (±1 
day) and Day 7 (after the AM dose) during Period 1 and Period 2 of Study Treatment, and EOS visit. Unscheduled Phe collection may occur if at any time a patient is 
hypophenylalaninemic (i.e., <30 μmol/L). Phe collection should be performed with pre-fed or at least 3 hours following last meal and at approximately the same time of day at each 
visit. 
m. Patients are to maintain a consistent diet (with respect to protein and Phe intake) during the study. The 3-day diet records will be collected during BH4 Washout and during each 
treatment period. 


DocuSign Envelope ID: 753DEEC6-9084-4E22-885F-BA7CDD3B9A8C 
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CONFIDENTIAL 
Page 26 of 27 
 
 
 
n. 
BH4 treatment [i.e., Kuvan® (sapropterin dihydrochloride)] will be discontinued starting with the BH4 Washout period. Patients will remain off BH4 treatment until the EOS visit. 
o. 
Blood samples for CNSA-001 (sepiapterin), BH4, Phe, and Tyr will be collected and analyzed by the bioanalytical laboratory at the following timepoints during Period 1 and Period 
2: Day 1 (pre-dose, within 30 min of dosing), +0.5 hr (±3 min), +1 hr (±5 min), +2 hr (±6 min), +4 hr (±20 min), +6 hr (±30 min), and +8 hr (±60 min, prior to Day 1 evening dose), 
and +24 hours (± 2 hr, prior to Day 2 AM dose) after the first dose of study drug; +72 hr (Day 4, ±1 day; Phe/Tyr only); on Day 7 (Phe/Tyr only); and EOS (Phe/Tyr only) (see Table 
2). Phe concentrations for preliminary efficacy will be obtained from the same sample collected for Phe/Tyr concentrations on Day 1 and Day 2 (pre-dose), Day 4 (±1 day) and Day 7 
(after the AM dose), and EOS. 
p. 
Exploratory biomarkers in urine include sepiapterin, BH4, and neopterin. These samples will be collected at Screening, pre-dose on Day 1 and Day 2, and post-dose on Day 4 (±1 
day) and Day 7. Urine samples should be the first void of the day. Samples will be sent to the bioanalytical laboratory (see Table 3). 
q. 
CANTAB testing will include RTI, SSP, SWM, and RVP tests. These will be administered at the Screening visit and on Day 1 (pre-dose) and Day 7 of each treatment period. 
r. 
Study drug will be administered twice daily (with breakfast and with supper) on Days 1 to 7 of each treatment period. Doses on Day 1 and Day 2 (AM only) will be administered by 
research staff, while all remaining doses will be self-administered. 
s. 
Study drug will be dispensed at each Day 2 Study visit and will include enough study drug for dosing until the Day 7 study visit. CNSA-001 treatment will be discontinued if criteria 
related to safety or lack of efficacy are met (see Section 6.13.1). 
t. 
Patient will receive a dosing diary and instructions for recording all doses of study drug taken and times they were taken; if a patient vomits after taking a dose of study drug, this 
should also be recorded in the diary and the patient should wait until the next scheduled time point to administer a dose. 
u. 
Patients will be asked to wear a GENEActiv accelerometer device continuously for up to two 14-day periods. The initial device will be placed on the patient’s wrist, ankle or other 
suitable location and secured with the appropriate band no earlier than Day -7 during Screening. The initial device will be removed on Day 7 of Treatment Period 1 and replaced with 
a second device to be worn until the End of Study visit. All devices will be collected at the End of Study visit. 
v. 
Patients ages 3-17 will be administered the NIH Toolbox Cognitive Domain test battery on either Day -1 or Day 1 predose for Treatment Period 1 at the clinical site’s option. Only 
one assessment will be performed and will be used as the baseline assessment for Treatment Period 1. 
Abbreviations: AE = adverse event; AM = morning; AP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase; BUN = blood urea nitrogen; CO2 = 
carbon dioxide; HEENT=hear, eyes, ears, nose, throat; ECG = electrocardiogram; EOS = end of study; GGT = gamma glutamyl transferase; LDH = lactate dehydrogenase; Phe = 
phenylalanine; PK = pharmacokinetic; RBC = red blood cell; RVP = Rapid Visual Information Processing; SAE = serious adverse event; RTI = Reaction Time; SSP = Spatial Span; SWM 
= Spatial Working Memory; WBC = white blood cell. 


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PTC Therapeutics, Inc. 
SAP for Protocol PBD-001 
CNSA-001 (Sepiapterin) 
 
Appendix B: Group Labels Used in Table, Figure and Listing Deliverables. 
 
 
Cohort 1 
Cohort 2 
Group labels 
used for TFLs: 
CNSA-001 
2.5 mg/kg 
CNSA-001 
10 mg/kg 
CNSA-001 
5 mg/kg 
CNSA-001 
20 mg/kg 
Matching 
Protocol group 
definitions: 
2.5 mg/kg/day for 7 
days for Cohort 1 in 
Period 1 
escalate to 10 mg/kg/day 
for 7 days for Cohort 1 in 
Period 2 
5 mg/kg/day for 7 days 
for Cohort 2 in Period 1 
escalate to 20 mg/kg/day 
for 7 days for Cohort 2 in 
Period 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 27 of 27 


PTC923
Administrative Addendum
28 February 2022
1
The chemical name and structure of sepiapterin, or PTC923 (formerly known as CNSA-001), has 
been presented in various ways in the published literature. One such chemical name and structure
was included in the Protocols included in PBD-001 CSR Section 16.1.1. However, the preferred 
representation of the active agent is as follows:
Chemical name: (S)-2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one
Chemical structure: