A Study of CNSA-001 in Primary Tetrahydrobiopterin Deficient Patients With Hyperphenylalaninemia

Tetrahydrobiopterin (BH4) is an essential cofactor for phenylalanine hydroxylase, tyrosine
hydroxylase, tryptophan hydroxylase, fatty acid glycerylether oxygenase, and nitric oxide
(NO) synthase. Primary tetrahydrobiopterin deficiency (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 tetrahydrobiopterin (BH4) or by defects in
BH4 recycling (pterin-4a-carbinolamine dehydratase [PCD] or dihydropteridine reductase [DHPR]
deficiency).

Study PBD-001 is a Phase 1/2, multicenter, randomized, open-label, intra-patient dose
titration study designed to evaluate the safety, pharmacokinetics, and preliminary evidence
of efficacy of CNSA-001 in male and female patients with hyperphenylalaninemia due to PBD.
Study PBD-001 will enroll patients with defects in de novo biopterin biosynthesis due to PTPS
or recessive GTP-CH deficiencies. Approximately 6 to 10 patients will be enrolled in this
study at 5 to 6 study centers.

Patients will be screened for participation. Eligible patients who are taking BH4 [Kuvan®
(sapropterin dihydrochloride)] will discontinue the medication following screening and will
remain off this medication during the entire study. Patients will receive treatment with
CNSA-001 for a total of 14 days (i.e., two 7-day treatment periods separated by a 3- to 4-day
washout). Patients will be randomized into one of 2 cohorts, with each cohort assessing 2
dose levels of CNSA-001 via intra-patient titration.

Initially, only adult patient(s) (≥18 years) will be enrolled. After the first adult
patient(s) have completed the study, a 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 to <18 years old, then the eligibility criterion for age at
time of enrollment will be expanded to include adolescents (≥12 years).

Inclusion Criteria:

- Male or Female patients 18 years old and above and 12 years old and above for the
remaining patients (age reduction pending analysis of safety, PK, and response, in the
adult patient(s))

- Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic
mutations in PTPS or recessive GTP-CH

- Informed consent and assent (if necessary) with parental consent

- 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
highly effective methods of contraception (including adolescents 12 to 18 years old)
from Screening through 30 days after the last dose of study drug:

- Hormonal contraception (stable dose for 3 months)

- Intrauterine device/Intrauterine Hormone-releasing System

- 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.

- 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.

- Females with a negative pregnancy test at Screening and on Day 1 prior to dosing

- Creatinine clearance (CrCl) >90 mL/min as estimated using the Cockcroft-Gault equation

- The patient is clinically stable on therapy for management of their signs and symptoms
of PBD as determined by the Investigator

- The patient is willing and able to comply with the protocol

- 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

Exclusion Criteria:

- PBD caused by biallelic pathogenic mutations in PCD, SR, DHPR, or single dominant
mutations in GTP-CH

- Significant chronic medical illness other than PBD, as determined by the Investigator

- Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel
disease, chronic gastritis, peptic ulcer disease, etc.) that could affect the
absorption of study drug

- History of gastric surgery, including Roux-en-Y gastric bypass surgery or an
antrectomy with vagotomy, or gastrectomy

- Inability to tolerate oral medication

- History of allergies or adverse reactions to BH4 or related compounds, or any
excipients in the study drug formulation

- 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

- Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or
hepatitis C virus (HCV)

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) laboratory values
>2 × the upper limit of normal (ULN)

- 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

- Clinically significant cardiac arrhythmia at Screening or prior to the first dose of
study drug

- QTcF (QT with Fridericia's correction) ≥460 msec in males and ≥480 msec in females
(based on the mean of triplicate measurements taken at Screening)

- Resting heart rate ≤40 or ≥110 bpm or resting blood pressure <90/40 mmHg or >150/90
mmHg at Screening or prior to the first administration of study drug

- Current participation in any other investigational drug study or participation within
30 days prior to Screening

- History of alcohol or drug abuse within last 6 months prior to Screening or current
evidence of substance dependence as determined by the Investigator

- Currently taking an antifolate including, but not limited to, methotrexate,
pemetrexed, or trimetrexate

- A female who is nursing or who is pregnant or planning to become pregnant

- The patient, in the opinion of the Investigator, is unwilling or unable to adhere to
the requirements of the study