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).

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.

Inclusion Criteria:

• Male or female participants 18 years old and above and 12 months old and above for the remaining participants (age reduction pending analysis of safety, PK, and response, in the adult participant(s) by the Data Safety Monitoring Board (DSMB) and Food and Drug Administration [FDA])

• Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic mutations in PTPS or recessive GTP-CH genes, abnormal enzymatic activity of the PTPS or GTP-CH enzymes, or a cerebrospinal fluid (CSF) biochemical profile indicative of PTPS or GTP-CH deficiencies

• 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 second contraceptive method unless they become sexually active.

• Males with female partners of childbearing potential must agree to use barrier contraceptive (that is, 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 milliliters (mL)/minute (min) as estimated using the Cockcroft-Gault equation (≥18 years) or Schwartz-Lyon equation (≥12 months <18 years)

• The participant is clinically stable on therapy for management of their signs and symptoms of PBD as determined by the investigator.

• The participant is willing and able to comply with the protocol.

• No tobacco use (for example; 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 participant's ability to participate in the study or increase the risk of participation for that participant
• 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 milliseconds (msec) in males and ≥480 msec in females (based on the mean of triplicate measurements taken at screening)
• Resting heart rate ≤40 or ≥110 beats/minute (bpm) for ages 12 and older, ≥130 bpm for ages 3 to 12, ≥150 bpm for ages 1 to 2 years, or resting blood pressure <85/40 millimeters of mercury (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 participant, in the opinion of the investigator, is unwilling or unable to adhere to the requirements of the study.

The Safety population included all randomized participants who received any amount of study drug.

From first dose of study drug (Day 1) up to 30 (±3) days after last dose of study drug (up to 50 days)

The Safety population included all randomized participants who received any amount of study drug.