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

Phase 1

Completed

Conditions: BH4 Deficiency
Hyperphenylalaninemia

Interventions: Drug: PTC923

Registration Number: NCT03519711

Lead Sponsor: PTC Therapeutics

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1: PTC923 2.5 and 10 mg/kg/day	PTC923	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).
Cohort 2: PTC923 5 and 20 mg/kg/day	PTC923	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).

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	From first dose of study drug (Day 1) up to 30 (±3) days after last dose of study drug (up to 50 days)	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'.

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (4): UT Southwestern
🇺🇸
Dallas, Texas, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
University of Utah Hospital
🇺🇸
Salt Lake City, Utah, United States
Marshfield Clinic
🇺🇸
Marshfield, Wisconsin, United States