BH4 Deficiency, Hyperphenylalaninemia
Conditions
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.
Interventions
DRUGPTC923
PTC923 will be administered per dose and schedule specified in arm description.
Sponsors
PTC Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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) |
| 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) |
| 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 |
| 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: PTC923 2.5 and 10 mg/kg/Day Participants received PTC923 suspension 2.5 mg/kg/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, underwent a 3 (±1) day washout period, then escalated 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). | 4 |
| Cohort 2: PTC923 5 and 20 mg/kg/Day Participants received PTC923 suspension 5 mg/kg/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, underwent a 3 (±1) day washout period, then escalated 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). | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Cohort 1: PTC923 2.5 and 10 mg/kg/Day | Total | Cohort 2: PTC923 5 and 20 mg/kg/Day |
|---|---|---|---|
| Age, Continuous | 11.75 years STANDARD_DEVIATION 5.123 | 11.65 years STANDARD_DEVIATION 6.659 | 11.55 years STANDARD_DEVIATION 8.786 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 2 / 4 | 2 / 4 | 4 / 4 | 3 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 |
Outcome results
Primary
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'.
Time frame: From first dose of study drug (Day 1) up to 30 (±3) days after last dose of study drug (up to 50 days)
Population: The Safety population included all randomized participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 2 Participants |
| Cohort 1: PTC923 10 mg/kg/Day | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 2 Participants |
| Cohort 2: PTC923 5 mg/kg/Day | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 4 Participants |
| Cohort 2: PTC923 20 mg/kg/Day | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
Secondary
Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of study drug and had at least 1 quantifiable post-dose blood sample collected for analysis of PTC923, BH4, Phe, or Tyr concentrations. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4 | BH4 | 72.826 hours*ng/mL | Standard Deviation 62.8038 |
| Cohort 1: PTC923 10 mg/kg/Day | Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4 | PTC923 | 2.532 hours*ng/mL | Standard Deviation 2.237 |
| Cohort 1: PTC923 10 mg/kg/Day | Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4 | BH4 | 457.330 hours*ng/mL | Standard Deviation 204.2517 |
| Cohort 2: PTC923 5 mg/kg/Day | Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4 | BH4 | 221.358 hours*ng/mL | Standard Deviation 82.6201 |
| Cohort 2: PTC923 20 mg/kg/Day | Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4 | PTC923 | 5.605 hours*ng/mL | Standard Deviation 1.0517 |
| Cohort 2: PTC923 20 mg/kg/Day | Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4 | BH4 | 1158.337 hours*ng/mL | Standard Deviation 227.0332 |
Secondary
AUC0-last of Phe and Tyr
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of study drug and had at least 1 quantifiable post-dose blood sample collected for analysis of PTC923, BH4, Phe, or Tyr concentrations. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | AUC0-last of Phe and Tyr | Phe | 3636.030 hours*µmol/L | Standard Deviation 4275.9593 |
| Cohort 1: PTC923 2.5 mg/kg/Day | AUC0-last of Phe and Tyr | Tyr | 883.337 hours*µmol/L | Standard Deviation 65.2122 |
| Cohort 1: PTC923 10 mg/kg/Day | AUC0-last of Phe and Tyr | Tyr | 836.526 hours*µmol/L | Standard Deviation 143.4899 |
| Cohort 1: PTC923 10 mg/kg/Day | AUC0-last of Phe and Tyr | Phe | 1877.091 hours*µmol/L | Standard Deviation 1633.8636 |
| Cohort 2: PTC923 5 mg/kg/Day | AUC0-last of Phe and Tyr | Phe | 3655.897 hours*µmol/L | Standard Deviation 1239.8499 |
| Cohort 2: PTC923 5 mg/kg/Day | AUC0-last of Phe and Tyr | Tyr | 1037.085 hours*µmol/L | Standard Deviation 346.7325 |
| Cohort 2: PTC923 20 mg/kg/Day | AUC0-last of Phe and Tyr | Phe | 2086.787 hours*µmol/L | Standard Deviation 871.7262 |
| Cohort 2: PTC923 20 mg/kg/Day | AUC0-last of Phe and Tyr | Tyr | 1023.856 hours*µmol/L | Standard Deviation 368.7586 |
Secondary
Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7
Time frame: Baseline (Day 1, pre-dose); Day 7
Population: The Efficacy population included all randomized participants who received any amount of study drug, and had available pre-dose Phe concentrations at Day 1 and at least 1 post-Day 1 visit within a given period. Here, 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 | Baseline | 884.20 μmol/L | Standard Deviation 975.507 |
| Cohort 1: PTC923 2.5 mg/kg/Day | Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 | Change at Day 7 | -812.25 μmol/L | Standard Deviation 967.423 |
| Cohort 1: PTC923 10 mg/kg/Day | Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 | Change at Day 7 | -622.02 μmol/L | Standard Deviation 840.853 |
| Cohort 1: PTC923 10 mg/kg/Day | Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 | Baseline | 675.68 μmol/L | Standard Deviation 842.579 |
| Cohort 2: PTC923 5 mg/kg/Day | Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 | Baseline | 1516.98 μmol/L | Standard Deviation 442.673 |
| Cohort 2: PTC923 5 mg/kg/Day | Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 | Change at Day 7 | -1428.19 μmol/L | Standard Deviation 531.327 |
| Cohort 2: PTC923 20 mg/kg/Day | Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 | Baseline | 971.48 μmol/L | Standard Deviation 455.598 |
| Cohort 2: PTC923 20 mg/kg/Day | Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7 | Change at Day 7 | -913.63 μmol/L | Standard Deviation 448.282 |
Secondary
Cmax of Phenylalanine (Phe) and Tyrosine (Tyr)
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of study drug and had at least 1 quantifiable post-dose blood sample collected for analysis of PTC923, BH4, Phe, or Tyr concentrations. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) | Phe | 939.35 micromoles (µmol)/liter (L) | Standard Deviation 1059.225 |
| Cohort 1: PTC923 2.5 mg/kg/Day | Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) | Tyr | 157.15 micromoles (µmol)/liter (L) | Standard Deviation 31.229 |
| Cohort 1: PTC923 10 mg/kg/Day | Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) | Tyr | 152.98 micromoles (µmol)/liter (L) | Standard Deviation 22.314 |
| Cohort 1: PTC923 10 mg/kg/Day | Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) | Phe | 725.98 micromoles (µmol)/liter (L) | Standard Deviation 883.411 |
| Cohort 2: PTC923 5 mg/kg/Day | Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) | Phe | 1420.30 micromoles (µmol)/liter (L) | Standard Deviation 487.712 |
| Cohort 2: PTC923 5 mg/kg/Day | Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) | Tyr | 173.40 micromoles (µmol)/liter (L) | Standard Deviation 42.981 |
| Cohort 2: PTC923 20 mg/kg/Day | Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) | Phe | 991.63 micromoles (µmol)/liter (L) | Standard Deviation 555.802 |
| Cohort 2: PTC923 20 mg/kg/Day | Cmax of Phenylalanine (Phe) and Tyrosine (Tyr) | Tyr | 178.13 micromoles (µmol)/liter (L) | Standard Deviation 48.925 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4)
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of study drug and had at least 1 quantifiable post-dose blood sample collected for analysis of PTC923, BH4, Phe, or Tyr concentrations. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4) | BH4 | 19.455 nanograms (ng)/milliliter (mL) | Standard Deviation 19.3731 |
| Cohort 1: PTC923 10 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4) | PTC923 | 1.110 nanograms (ng)/milliliter (mL) | Standard Deviation 0.4031 |
| Cohort 1: PTC923 10 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4) | BH4 | 109.375 nanograms (ng)/milliliter (mL) | Standard Deviation 58.944 |
| Cohort 2: PTC923 5 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4) | PTC923 | 0.533 nanograms (ng)/milliliter (mL) | Standard Deviation 0.5033 |
| Cohort 2: PTC923 5 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4) | BH4 | 48.200 nanograms (ng)/milliliter (mL) | Standard Deviation 20.157 |
| Cohort 2: PTC923 20 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4) | PTC923 | 2.120 nanograms (ng)/milliliter (mL) | Standard Deviation 0.5292 |
| Cohort 2: PTC923 20 mg/kg/Day | Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4) | BH4 | 275.030 nanograms (ng)/milliliter (mL) | Standard Deviation 42.7941 |
Secondary
Number of Participants With Normal Blood Phe Concentrations <130 μmol/L at Day 7
Time frame: Day 7
Population: The Efficacy population included all randomized participants who received any amount of study drug, and had available pre-dose Phe concentrations at Day 1 and at least 1 post-Day 1 visit within a given period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Number of Participants With Normal Blood Phe Concentrations <130 μmol/L at Day 7 | 4 Participants |
| Cohort 1: PTC923 10 mg/kg/Day | Number of Participants With Normal Blood Phe Concentrations <130 μmol/L at Day 7 | 4 Participants |
| Cohort 2: PTC923 5 mg/kg/Day | Number of Participants With Normal Blood Phe Concentrations <130 μmol/L at Day 7 | 3 Participants |
| Cohort 2: PTC923 20 mg/kg/Day | Number of Participants With Normal Blood Phe Concentrations <130 μmol/L at Day 7 | 4 Participants |
Secondary
Number of Participants With Phe Concentrations in Acceptable Treatment Range of 130 to 360 μmol/L at Day 7
Time frame: Day 7
Population: The Efficacy population included all randomized participants who received any amount of study drug, and had available pre-dose Phe concentrations at Day 1 and at least 1 post-Day 1 visit within a given period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Number of Participants With Phe Concentrations in Acceptable Treatment Range of 130 to 360 μmol/L at Day 7 | 0 Participants |
| Cohort 1: PTC923 10 mg/kg/Day | Number of Participants With Phe Concentrations in Acceptable Treatment Range of 130 to 360 μmol/L at Day 7 | 0 Participants |
| Cohort 2: PTC923 5 mg/kg/Day | Number of Participants With Phe Concentrations in Acceptable Treatment Range of 130 to 360 μmol/L at Day 7 | 0 Participants |
| Cohort 2: PTC923 20 mg/kg/Day | Number of Participants With Phe Concentrations in Acceptable Treatment Range of 130 to 360 μmol/L at Day 7 | 0 Participants |
Secondary
Time to Reach Cmax (Tmax) of PTC923 and BH4
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of study drug and had at least 1 quantifiable post-dose blood sample collected for analysis of PTC923, BH4, Phe, or Tyr concentrations. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Time to Reach Cmax (Tmax) of PTC923 and BH4 | BH4 | 4.017 hours |
| Cohort 1: PTC923 10 mg/kg/Day | Time to Reach Cmax (Tmax) of PTC923 and BH4 | PTC923 | 1.000 hours |
| Cohort 1: PTC923 10 mg/kg/Day | Time to Reach Cmax (Tmax) of PTC923 and BH4 | BH4 | 3.050 hours |
| Cohort 2: PTC923 5 mg/kg/Day | Time to Reach Cmax (Tmax) of PTC923 and BH4 | PTC923 | 1.000 hours |
| Cohort 2: PTC923 5 mg/kg/Day | Time to Reach Cmax (Tmax) of PTC923 and BH4 | BH4 | 4.000 hours |
| Cohort 2: PTC923 20 mg/kg/Day | Time to Reach Cmax (Tmax) of PTC923 and BH4 | PTC923 | 1.000 hours |
| Cohort 2: PTC923 20 mg/kg/Day | Time to Reach Cmax (Tmax) of PTC923 and BH4 | BH4 | 4.017 hours |
Secondary
Tmax of Phe and Tyr
Time frame: 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)
Population: The PK population included all participants who received at least 1 dose of study drug and had at least 1 quantifiable post-dose blood sample collected for analysis of PTC923, BH4, Phe, or Tyr concentrations. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: PTC923 2.5 mg/kg/Day | Tmax of Phe and Tyr | Phe | 0.250 hours |
| Cohort 1: PTC923 2.5 mg/kg/Day | Tmax of Phe and Tyr | Tyr | 4.992 hours |
| Cohort 1: PTC923 10 mg/kg/Day | Tmax of Phe and Tyr | Tyr | 4.025 hours |
| Cohort 1: PTC923 10 mg/kg/Day | Tmax of Phe and Tyr | Phe | 0.517 hours |
| Cohort 2: PTC923 5 mg/kg/Day | Tmax of Phe and Tyr | Phe | 0.000 hours |
| Cohort 2: PTC923 5 mg/kg/Day | Tmax of Phe and Tyr | Tyr | 4.000 hours |
| Cohort 2: PTC923 20 mg/kg/Day | Tmax of Phe and Tyr | Phe | 0.000 hours |
| Cohort 2: PTC923 20 mg/kg/Day | Tmax of Phe and Tyr | Tyr | 2.000 hours |