A Study of PTC923 (CNSA-001) in Primary Tetrahydrobiopterin (BH4) Deficient Participants With Hyperphenylalaninemia

Study Overview
=================
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.

Official 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

Conditions
-----------------
BH4 Deficiency, Hyperphenylalaninemia

Intervention / Treatment
-----------------
* Drug: PTC923


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 12 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: PTC923 2.5 and 10 mg/kg/day<br>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). | Drug: PTC923<br>* PTC923 will be administered per dose and schedule specified in arm description.<br>* Other names: CNSA-001, Sepiapterin;|
| Experimental: Cohort 2: PTC923 5 and 20 mg/kg/day<br>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). | Drug: PTC923<br>* PTC923 will be administered per dose and schedule specified in arm description.<br>* Other names: CNSA-001, Sepiapterin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. TEAEs were defined as AEs that commenced or worsened after the first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | From first dose of study drug (Day 1) up to 30 (±3) days after last dose of study drug (up to 50 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4) |  | Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose) | 
| Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) |  | Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose) | 
| Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4 |  | Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose) | 
| AUC0-last of Phe and Tyr |  | Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose) | 
| Time to Reach Cmax (Tmax) of PTC923 and BH4 |  | Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose) | 
| Tmax of Phe and Tyr |  | Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose) | 
| Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 |  | Baseline (Day 1, pre-dose); Day 7 | 
| Number of Participants With Phe Concentrations in Acceptable Treatment Range of 130 to 360 μmol/L at Day 7 |  | Day 7 | 
| Number of Participants With Normal Blood Phe Concentrations <130 μmol/L at Day 7 |  | Day 7 |