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    Clinical Trial Results:
    A Phase 3 Study of PTC923 in Subjects With Phenylketonuria

    Summary
    EudraCT number
    		 2021-000474-29
    Trial protocol
    		 DE   ES   PT   DK   NL   IT  
    Global end of trial date
    03 May 2023

    Results information
    Results version number
    		 v1
    This version publication date
    19 Nov 2023
    First version publication date
    19 Nov 2023
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PTC923-MD-003-PKU
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05099640
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PTC Therapeutics, Inc.
    Sponsor organisation address
    100 Corporate Court, South Plainfield, United States, NJ 07080
    Public contact
    Medical Information, PTC Therapeutics, Inc., +011 44 1-866-562-4620, medinfo@ptcbio.com
    Scientific contact
    Medical Information, PTC Therapeutics International Limited, +353 19068700, medinfo@ptcbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this trial is to evaluate the efficacy of PTC923 in reducing blood phenylalanine (Phe) levels in participants with phenylketonuria as measured by mean change in blood Phe levels from baseline to Weeks 5 and 6 (that is, the average of each respective treatment dose 2-week period of double-blind treatment).
    Protection of trial subjects
    This trial was designed and monitored in accordance with Sponsor procedures, which comply with the ethical principles of Good Clinical Practices (GCP) as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Georgia: 16
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Turkey: 21
    Country: Number of subjects enrolled
    Australia: 15
    Worldwide total number of subjects
    157
    EEA total number of subjects
    34
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    55
    Adolescents (12-17 years)
    43
    Adults (18-64 years)
    56
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted in 2 parts: Part 1: Open-label and Part 2: Placebo-controlled Randomized Treatment. In Part 1, 157 participants received sepiapterin. In Part 2, 56 participants received sepiapterin and 54 participants received placebo.

    Pre-assignment
    Screening details
    		 Participants (≥2 years of age) who experienced a ≥15% reduction in blood Phe levels (responder) continued into Part 2. Non-responders did not continue to Part 2. Out of 111 participants who completed Part 1, 110 participants were eligible to progress to Part 2.

    Period 1
    Period 1 title
    Part 1: Open-label (14 Days)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part 1: Sepiapterin
    Arm description
    		 Participants received sepiapterin 30 milligrams (mg)/kilogram (kg) (participants 12 months to <2 years of age) or 60 mg/kg (participants ≥2 years of age) orally once daily for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sepiapterin
    Investigational medicinal product code
    PTC923
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    Sepiapterin was administered per schedule specified in the arm description.

    Number of subjects in period 1
    		Part 1: Sepiapterin
    Started
    157
    Received at least 1 dose of study drug
    157
    Completed
    111
    Not completed
    46
         Consent withdrawn by subject
    1
         Participant decision
    3
         Adverse event, non-fatal
    1
         Non-responsive for sepiapterin
    39
         Other than specified
    2
    Period 2
    Period 2 title
    Part 2: Randomized Treatment (6 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 2: Sepiapterin
    Arm description
    		 Participants received sepiapterin 20 mg/kg daily for Weeks 1 and 2, then sepiapterin 40 mg/kg daily for Weeks 3 and 4, then sepiapterin 60 mg/kg daily for Weeks 5 and 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sepiapterin
    Investigational medicinal product code
    PTC923
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    Sepiapterin was administered per schedule specified in the arm description.

    Arm title
    		 Part 2: Placebo
    Arm description
    		 Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to sepiapterin was administered per schedule specified in the arm description.

    Number of subjects in period 2 [1]
    		Part 2: Sepiapterin Part 2: Placebo
    Started
    56
    54
    Received at least 1 dose of study drug
    56
    54
    Completed
    55
    54
    Not completed
    1
    0
         Participant decision
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: In Part 2, 56 participants were randomized to receive sepiapterin and 54 participants were randomized to receive placebo.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Sepiapterin
    Reporting group description
    		 Participants received sepiapterin 30 milligrams (mg)/kilogram (kg) (participants 12 months to <2 years of age) or 60 mg/kg (participants ≥2 years of age) orally once daily for 14 days.

    Reporting group values
    		 Part 1: Sepiapterin Total
    Number of subjects
    		 157 157
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 17.7 ( 12.24 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 72 72
        Male
    		 85 85
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 25 25
        Not Hispanic or Latino
    		 129 129
        Unknown or Not Reported
    		 3 3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 8 8
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 142 142
        More than one race
    		 0 0
        Unknown or Not Reported
    		 7 7
    Blood Phe Level in Classical PKU Participants
    Classical PKU participants: Participants with severe forms of PKU, typically very high blood Phe levels (>1200 μmol/L). Here, 'N' = 17 for Part 1 (Participants who Participated in Part 1 Only): Sepiapterin; 8 for Part 2: Sepiapterin; and 11 for Part 2: Placebo.
    Units: μmol/L
        arithmetic mean (standard deviation)
    		 ( ) -
    Blood Phenylketonuria (Phe) Level
    Units: micromoles (μmol)/liter (L)
        arithmetic mean (standard deviation)
    		 ( ) -
    Subject analysis sets

    Subject analysis set title
    Part 1 (Participants Participated in Part 1 Only): Sepiapterin
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received sepiapterin 30 mg/kg (participants 12 months to <2 years of age) or 60 mg/kg (participants ≥2 years of age) orally once daily for 14 days.

    Subject analysis set title
    Part 2: Sepiapterin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received sepiapterin 20 mg/kg daily for Weeks 1 and 2, then sepiapterin 40 mg/kg daily for Weeks 3 and 4, then sepiapterin 60 mg/kg daily for Weeks 5 and 6.

    Subject analysis set title
    Part 2: Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.

    Subject analysis sets values
    		 Part 1 (Participants Participated in Part 1 Only): Sepiapterin Part 2: Sepiapterin Part 2: Placebo
    Number of subjects
    47
    56
    54
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    18.4 ( 15.07 )
    16.5 ( 11.12 )
    18.4 ( 10.65 )
    Sex: Female, Male
    Units: participants
        Female
    19
    26
    27
        Male
    28
    30
    27
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    5
    8
    12
        Not Hispanic or Latino
    40
    47
    42
        Unknown or Not Reported
    2
    1
    0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    3
    3
    2
        Asian
    0
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
        Black or African American
    0
    0
    0
        White
    41
    52
    49
        More than one race
    0
    0
    0
        Unknown or Not Reported
    3
    1
    3
    Blood Phe Level in Classical PKU Participants
    Classical PKU participants: Participants with severe forms of PKU, typically very high blood Phe levels (>1200 μmol/L). Here, 'N' = 17 for Part 1 (Participants who Participated in Part 1 Only): Sepiapterin; 8 for Part 2: Sepiapterin; and 11 for Part 2: Placebo.
    Units: μmol/L
        arithmetic mean (standard deviation)
    1495.8 ( 641.18 )
    737.56 ( 277.279 )
    812.14 ( 295.239 )
    Blood Phenylketonuria (Phe) Level
    Units: micromoles (μmol)/liter (L)
        arithmetic mean (standard deviation)
    651.16 ( 333.439 )
    645.59 ( 246.085 )
    667.81 ( 264.574 )

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Sepiapterin
    Reporting group description
    		 Participants received sepiapterin 30 milligrams (mg)/kilogram (kg) (participants 12 months to <2 years of age) or 60 mg/kg (participants ≥2 years of age) orally once daily for 14 days.
    Reporting group title
    Part 2: Sepiapterin
    Reporting group description
    		 Participants received sepiapterin 20 mg/kg daily for Weeks 1 and 2, then sepiapterin 40 mg/kg daily for Weeks 3 and 4, then sepiapterin 60 mg/kg daily for Weeks 5 and 6.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    		 Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.

    Subject analysis set title
    Part 1 (Participants Participated in Part 1 Only): Sepiapterin
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received sepiapterin 30 mg/kg (participants 12 months to <2 years of age) or 60 mg/kg (participants ≥2 years of age) orally once daily for 14 days.

    Subject analysis set title
    Part 2: Sepiapterin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received sepiapterin 20 mg/kg daily for Weeks 1 and 2, then sepiapterin 40 mg/kg daily for Weeks 3 and 4, then sepiapterin 60 mg/kg daily for Weeks 5 and 6.

    Subject analysis set title
    Part 2: Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.

    Primary: Mean Change From Baseline in Blood Phenylketonuria (Phe) Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in the Part 2 Double-blind Phase

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    End point title
    		 Mean Change From Baseline in Blood Phenylketonuria (Phe) Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in the Part 2 Double-blind Phase
    End point description
    Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. Least square (LS) mean and standard error (SE) were calculated using mixed model repeated measures (MMRM) method. Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of double-blind study drug in Part 2. Non-responders in Part 1 did not continue to Part 2 and were not included in the analysis. Here, 'Overall number of participants analyzed' = participants of FAS with Phe reduction from Baseline ≥30% during Part 1, who continued in Part 2.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 5 and 6 (average of the 2-week period)
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    49
    49
    Units: μmol/L
        least squares mean (standard error)
    -415.75 ( 24.066 )
    -19.88 ( 24.223 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -395.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -463.07
         upper limit
    		 -328.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    33.848

    Primary: Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in the Part 2 Double-blind Phase

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    End point title
    		 Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in the Part 2 Double-blind Phase
    End point description
    Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. LS mean and SE were calculated using MMRM method. FAS included all participants who were randomized and received at least 1 dose of double-blind study drug in Part 2. Non-responders in Part 1 did not continue to Part 2 and were not included in the analysis. Here, 'Overall number of participants analyzed' = participants of FAS with Phe reduction from Baseline ≥30% during Part 1, who continued in Part 2.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 5 and 6 (average of the 2-week period)
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    49
    49
    Units: percent change
        least squares mean (standard error)
    -63.40 ( 3.537 )
    0.82 ( 3.561 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -64.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -74.09
         upper limit
    		 -54.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.973

    Secondary: Percentage of Participants With Baseline Phe Levels ≥600 μmol/L who Achieved Phe Levels <600 μmol/L in the Part 2 Double-blind Phase

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    End point title
    		 Percentage of Participants With Baseline Phe Levels ≥600 μmol/L who Achieved Phe Levels <600 μmol/L in the Part 2 Double-blind Phase
    End point description
    Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. FAS included all participants who were randomized and received at least 1 dose of double-blind study drug in Part 2. Non-responders in Part 1 did not continue to Part 2 and were not included in the analysis. Here, 'Overall number of participants analyzed' = participants of FAS with Phe reduction from baseline ≥30% during Part 1 and had Part 2 baseline Phe levels ≥600 μmol/L.
    End point type
    Secondary
    End point timeframe
    Weeks 5 and 6 (average of the 2-week period)
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    28
    30
    Units: percentage of participants
        number (confidence interval 95%)
    92.9 (76.50 to 99.12)
    30.0 (14.73 to 49.40)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    30.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.3
         upper limit
    		 294.24

    Secondary: Percentage of Participants With Baseline Phe Levels ≥360 μmol/L who Achieved Phe Levels <360 μmol/L in the Part 2 Double-blind Phase

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    End point title
    		 Percentage of Participants With Baseline Phe Levels ≥360 μmol/L who Achieved Phe Levels <360 μmol/L in the Part 2 Double-blind Phase
    End point description
    Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. FAS included all participants who were randomized and received at least 1 dose of double-blind study drug in Part 2. Non-responders in Part 1 did not continue to Part 2 and were not included in the analysis. Here, 'Overall number of participants analyzed' = participants of FAS with Phe reduction from baseline ≥30% during Part 1 and Part 2 baseline Phe levels ≥360 μmol/L.
    End point type
    Secondary
    End point timeframe
    Weeks 5 and 6 (average of the 2-week period)
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    44
    43
    Units: percentage of participants
        number (confidence interval 95%)
    84.1 (69.93 to 93.36)
    9.3 (2.59 to 22.14)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    51.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.28
         upper limit
    		 245.34

    Secondary: Mean Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in the Part 2 Double-blind Phase

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    End point title
    		 Mean Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in the Part 2 Double-blind Phase
    End point description
    Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean levels at Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 were calculated as the average of blood Phe levels collected during the Week 1-2, Week 3-4, and Week 5-6 analysis visit windows, respectively. FAS included all participants who were randomized and received at least 1 dose of double-blind study drug in Part 2. Non-responders in Part 1 did not continue to Part 2 and were not included in the analysis. Here, 'Overall number of participants analyzed' = participants of FAS with Phe reduction from Baseline ≥30% during Part 1 and continued in Part 2. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    49
    49
    Units: μmol/L
    arithmetic mean (standard deviation)
        Weeks 1 and 2 (n = 49, 49)
    -341.18 ( 226.178 )
    -53.27 ( 174.461 )
        Weeks 3 and 4 (n = 49, 48)
    -406.88 ( 199.259 )
    -30.43 ( 203.425 )
        Weeks 5 and 6 (n = 49, 49)
    -410.07 ( 204.442 )
    -16.19 ( 198.642 )
    Statistical analysis title
    		 Statistical Analysis 1 (Weeks 1 and 2)
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -289.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -356.29
         upper limit
    		 -223.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    33.44
    Statistical analysis title
    		 Statistical Analysis 3 (Weeks 5 and 6)
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -395.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -463.07
         upper limit
    		 -328.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    33.848
    Statistical analysis title
    		 Statistical Analysis 2 (Weeks 3 and 4)
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -375.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -435.88
         upper limit
    		 -315.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    30.424

    Secondary: Percent Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in the Part 2 Double-blind Phase

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    End point title
    		 Percent Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in the Part 2 Double-blind Phase
    End point description
    Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean levels at Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 were calculated as the average of blood Phe levels collected during the Week 1-2, Week 3-4, and Week 5-6 analysis visit windows, respectively. FAS included all participants who were randomized and received at least 1 dose of double-blind study drug in Part 2. Non-responders in Part 1 did not continue to Part 2 and were not included in the analysis. Here, 'Overall number of participants analyzed' = participants of FAS with Phe reduction from Baseline ≥30% during Part 1 and continued in Part 2. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    49
    49
    Units: percent change
    least squares mean (standard error)
        Weeks 1 and 2 (n=49,49)
    -48.55 ( 4.265 )
    -6.04 ( 4.285 )
        Weeks 3 and 4 (n=49,48)
    -62.46 ( 3.220 )
    -1.43 ( 3.257 )
        Weeks 5 and 6 (n=49,49)
    -63.40 ( 3.537 )
    0.82 ( 3.561 )
    Statistical analysis title
    		 Statistical Analysis 1 (Weeks 1 and 2)
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -42.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.45
         upper limit
    		 -30.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.008
    Statistical analysis title
    		 Statistical Analysis 3 (Weeks 5 and 6)
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -64.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -74.09
         upper limit
    		 -54.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.973
    Statistical analysis title
    		 Statistical Analysis 2 (Weeks 3 and 4)
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -61.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -70.02
         upper limit
    		 -52.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.531

    Secondary: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin in Part 1 Open-label Run-in Phase

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    End point title
    		 Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin in Part 1 Open-label Run-in Phase
    End point description
    Pharmacokinetic (PK) Analysis Set included all participants who had at least 1 measurable plasma concentration of sepiapterin or BH4. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. 'n' = participants evaluable at specified timepoint. '99999' signifies standard deviation (SD) data could not be calculated due to single participants.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, and 24 hours postdose at Day 1; 2 and 6 hours postdose at Day 14
    End point values
    		 Part 1: Sepiapterin
    Number of subjects analysed
    17
    Units: nanograms (ng)/milliliter (mL)
    arithmetic mean (standard deviation)
        BH4: Day 1 (predose) (n = 16)
    10.6 ( 5.34 )
        BH4: Day 1 (0.5 hr) (n = 16)
    22.3 ( 13.2 )
        BH4: Day 1 (1 hr) (n = 15)
    107 ( 76.0 )
        BH4: Day 1 (2 hrs) (n = 16)
    236 ( 124 )
        BH4: Day 1 (4 hrs) (n = 16)
    289 ( 170 )
        BH4: Day 1 (6 hrs) (n = 14)
    245 ( 131 )
        BH4: Day 1 (8 hrs) (n = 15)
    205 ( 130 )
        BH4: Day 1 (24 hrs) (n = 16)
    25.5 ( 21.1 )
        BH4: Day 14 (2 hrs) (n = 1)
    94.1 ( 99999 )
        BH4: Day 14 (6 hrs) (n = 1)
    105 ( 99999 )
        Sepiapterin: Day 1 (predose) (n = 16)
    0.000 ( 0.000 )
        Sepiapterin: Day 1 (0.5 hr) (n = 16)
    0.939 ( 0.940 )
        Sepiapterin: Day 1 (1 hr) (n = 16)
    2.22 ( 1.11 )
        Sepiapterin: Day 1 (2 hrs) (n = 16)
    2.06 ( 1.10 )
        Sepiapterin: Day 1 (4 hrs) (n = 17)
    1.73 ( 1.58 )
        Sepiapterin: Day 1 (6 hrs) (n = 16)
    1.60 ( 2.13 )
        Sepiapterin: Day 1 (8 hrs) (n = 16)
    0.493 ( 0.598 )
        Sepiapterin: Day 1 (24 hrs) (n = 16)
    0.436 ( 0.987 )
        Sepiapterin: Day 14 (2 hrs) (n = 1)
    3.33 ( 99999 )
        Sepiapterin: Day 14 (6 hrs) (n = 1)
    2.82 ( 99999 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of BH4 and Sepiapterin in Part 2 Double-blind Phase

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    End point title
    		 Plasma Concentration of BH4 and Sepiapterin in Part 2 Double-blind Phase
    End point description
    PK Analysis Set included all participants who had at least 1 measurable plasma concentration of sepiapterin or BH4. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Predose and 4 hours postdose at Days 1, 14, 28, and 42
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    4
    4
    Units: ng/mL
    arithmetic mean (standard deviation)
        BH4: Day 1 (predose) (n= 4,2)
    6.63 ( 3.60 )
    8.52 ( 4.36 )
        BH4: Day 1 (4 hrs) (n= 3,4)
    351 ( 184 )
    12.4 ( 1.74 )
        BH4: Day 14 (predose) (n= 4,3)
    7.04 ( 3.13 )
    4.27 ( 4.93 )
        BH4: Day 14 (4 hrs) (n= 2,4)
    401 ( 184 )
    11.3 ( 8.70 )
        BH4: Day 28 (predose) (n= 3,4)
    11.8 ( 6.29 )
    9.70 ( 4.18 )
        BH4: Day 28 (4 hrs) (n= 3,4)
    406 ( 57.5 )
    12.2 ( 4.46 )
        BH4: Day 42 (predose) (n= 4,4)
    10.0 ( 6.43 )
    9.41 ( 4.58 )
        BH4: Day 42 (4 hrs) (n= 2,4)
    442 ( 197 )
    11.4 ( 3.91 )
        Sepiapterin: Day 1 (predose) (n= 4,4)
    0.000 ( 0.000 )
    0.000 ( 0.000 )
        Sepiapterin: Day 1 (4 hrs) (n= 3,4)
    0.620 ( 1.07 )
    0.000 ( 0.000 )
        Sepiapterin: Day 14 (predose) (n= 4,3)
    0.000 ( 0.000 )
    0.000 ( 0.000 )
        Sepiapterin: Day 14 (4 hrs) (n= 3,4)
    1.23 ( 1.26 )
    0.000 ( 0.000 )
        Sepiapterin: Day 28 (predose) (n= 4,3)
    0.000 ( 0.000 )
    0.000 ( 0.000 )
        Sepiapterin: Day 28 (4 hrs) (n= 3,4)
    1.17 ( 1.09 )
    0.000 ( 0.000 )
        Sepiapterin: Day 42 (predose) (n= 4,4)
    0.000 ( 0.000 )
    0.000 ( 0.000 )
        Sepiapterin: Day 42 (4 hrs) (n= 3,4)
    1.03 ( 1.14 )
    0.000 ( 0.000 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) of Sepiapterin and BH4 Following the First Dose of Sepiapterin at 60 mg/kg in Part 1 Open-label Run-in Phase

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    End point title
    		 Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) of Sepiapterin and BH4 Following the First Dose of Sepiapterin at 60 mg/kg in Part 1 Open-label Run-in Phase
    End point description
    PK Analysis Set included all participants who had at least 1 measurable plasma concentration of sepiapterin or BH4. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    0 to 24 hours postdose at Day 1
    End point values
    		 Part 1: Sepiapterin
    Number of subjects analysed
    16
    Units: hours*ng/mL
    arithmetic mean (standard deviation)
        BH4
    2990 ( 1450 )
        Sepiapterin
    19.6 ( 20.1 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAEs were considered: - Part 1 TEAEs, which included all AEs occurring after first dose in Part 1 but before first dose in Part 2; - Part 2 TEAEs, which included all AEs after first randomized dose in Part 2. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the ‘Reported Adverse Events’ Section. Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 42
    End point values
    		 Part 1: Sepiapterin Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    157
    56
    54
    Units: participants
    68
    33
    18
    No statistical analyses for this end point

    Other pre-specified: Mean Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in the Part 2 Double-blind Phase for Classical PKU Participants

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    End point title
    		 Mean Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in the Part 2 Double-blind Phase for Classical PKU Participants
    End point description
    Classical PKU participants: Participants with severe forms of PKU, typically very high blood Phe levels (>1200 μmol/L). Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. LS mean and SE were calculated using MMRM method. FAS included all participants who were randomized and received at least 1 dose of double-blind study drug in Part 2. Non-responders in Part 1 did not continue to Part 2 and were not included in the analysis. Here, 'Overall number of participants analyzed' = Classical PKU participants of FAS with Phe reduction from Baseline ≥30% during Part 1 and continued in Part 2.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Weeks 5 and 6 (average of the 2-week period)
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    6
    9
    Units: μmol/L
        least squares mean (standard error)
    -488.19 ( 50.532 )
    4.03 ( 46.496 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -492.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -614.59
         upper limit
    		 -369.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    55.588

    Other pre-specified: Mean Change From Baseline (Part 1) in Blood Phe Level to Weeks 1 and 2 (Averaged Over a 2-week Period) in the Part 1 Open-label Run-in Phase

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    End point title
    		 Mean Change From Baseline (Part 1) in Blood Phe Level to Weeks 1 and 2 (Averaged Over a 2-week Period) in the Part 1 Open-label Run-in Phase
    End point description
    Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 1, and mean level at Weeks 1 and 2 was calculated as the average of blood Phe levels collected during the Week 1-2 analysis visit window. LS mean and SE were calculated using MMRM method. FAS included all participants who were enrolled and received at least 1 dose of open-label study drug in Part 1. Here "Overall number of participants analyzed" = participants of FAS with Phe reduction from Baseline ≥30% during Part 1.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)
    End point values
    		 Part 1: Sepiapterin
    Number of subjects analysed
    103
    Units: μmol/L
        arithmetic mean (standard deviation)
    -462.17 ( 203.620 )
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in the Part 2 Double-blind Phase for Classical PKU Participants

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    End point title
    		 Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in the Part 2 Double-blind Phase for Classical PKU Participants
    End point description
    Classical PKU participants: Participants with severe forms of PKU, typically very high blood Phe levels (>1200 μmol/L). Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. LS mean and SE were calculated using MMRM method. FAS included all participants who were randomized and received at least 1 dose of double-blind study drug in Part 2. Non-responders in Part 1 did not continue to Part 2 and were not included in the analysis. Here, 'Overall number of participants analyzed' = Classical PKU participants of FAS with Phe reduction from Baseline ≥30% during Part 1 and continued in Part 2.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Weeks 5 and 6 (average of the 2-week period)
    End point values
    		 Part 2: Sepiapterin Part 2: Placebo
    Number of subjects analysed
    6
    9
    Units: percent change
        least squares mean (standard error)
    -55.83 ( 9.182 )
    18.90 ( 8.286 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 2: Sepiapterin v Part 2: Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -74.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -97.72
         upper limit
    		 -51.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.436

    Other pre-specified: Percent Change From Baseline (Part 1) in Blood Phe Level to Weeks 1 and 2 (Averaged Over a 2-week Period) in the Part 1 Open-label Run-in Phase

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    End point title
    		 Percent Change From Baseline (Part 1) in Blood Phe Level to Weeks 1 and 2 (Averaged Over a 2-week Period) in the Part 1 Open-label Run-in Phase
    End point description
    Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 1, and mean level at Weeks 1 and 2 was calculated as the average of blood Phe levels collected during the Week 1-2 analysis visit window. LS mean and SE were calculated using MMRM method. FAS included all participants who were enrolled and received at least 1 dose of open-label study drug in Part 1. Here "Overall number of participants analyzed" = participants of FAS with Phe reduction from Baseline ≥30% during Part 1.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)
    End point values
    		 Part 1: Sepiapterin
    Number of subjects analysed
    103
    Units: percent change
        arithmetic mean (standard deviation)
    -65.25 ( 15.764 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 42
    Adverse event reporting additional description
    Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Part 1: Sepiapterin
    Reporting group description
    		 Participants received sepiapterin 30 mg/kg (participants 12 months to <2 years of age) or 60 mg/kg (participants ≥2 years of age) orally once daily for 14 days.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    		 Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.

    Reporting group title
    Part 2: Sepiapterin
    Reporting group description
    		 Participants received sepiapterin 20 mg/kg daily for Weeks 1 and 2, then sepiapterin 40 mg/kg daily for Weeks 3 and 4, then sepiapterin 60 mg/kg daily for Weeks 5 and 6.

    Serious adverse events
    		 Part 1: Sepiapterin Part 2: Placebo Part 2: Sepiapterin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Sepiapterin Part 2: Placebo Part 2: Sepiapterin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 157 (9.55%)
    11 / 54 (20.37%)
    14 / 56 (25.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 54 (1.85%)
    4 / 56 (7.14%)
         occurrences all number
    0
    1
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 157 (5.10%)
    1 / 54 (1.85%)
    4 / 56 (7.14%)
         occurrences all number
    8
    1
    4
    Vomiting
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 54 (5.56%)
    1 / 56 (1.79%)
         occurrences all number
    0
    3
    1
    Nausea
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 54 (5.56%)
    0 / 56 (0.00%)
         occurrences all number
    0
    3
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 157 (4.46%)
    1 / 54 (1.85%)
    3 / 56 (5.36%)
         occurrences all number
    7
    1
    3
    Gastroenteritis
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 54 (5.56%)
    3 / 56 (5.36%)
         occurrences all number
    0
    3
    4
    Nasopharyngitis
         subjects affected / exposed
    0 / 157 (0.00%)
    4 / 54 (7.41%)
    0 / 56 (0.00%)
         occurrences all number
    0
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2021
    It included following changes: • The dosing schedule was updated throughout to detail age dependent dosing. • Screening visit was updated to up to 45 days. • Window for the early termination visit (ETV) was extended to 21 days of last dose. • Specified throughout that participants from birth can be included in this study. • Statement was removed throughout that all participants will receive PTC923 60 mg/kg in Part 1 of the study. • Statement was added throughout to include specific details on participants <2 years of age with ≥30% response to PTC923 and enrollment into Study PTC923-MD-004-PKU. • Statement was added throughout to state participants who experience <15% reduction (≥2 years of age) or <30% reduction (<2 years of age) will be classified as nonresponsive and will be contacted to schedule an ETV (on or between Day 28 to Day 35). • Specified throughout that the Days -1 and 1 samples for Parts 1 and 2 should be taken predose. • Specified that specific information pertaining to previous use of sepiapterin and pegvaliase-pqpz should be collected. • Specified that blood Phe levels should be measured on Days 1, 20, and 30 during the pegvaliase-pqpz washout. • Additional details added regarding collection of blood Phe and Tyr samples and timepoints for participants participating in the PK substudy. • Inclusion Criteria were updated to align with current (2020) Clinical Trials Facilitation Group (CTFG) guidance. • Inclusion Criterion was updated to clarify that the surgery was not permitted within 90 days of screening . • Exclusion Criteria were added to exclude participants with renal impairment/disease. • Total blood volume for Part 1 and Part 2 was updated. • Statement added regarding unblinding and continuing study participation. • Age-based dosing specifications were updated and added. • Specified that the sepiapterin washout should be a minimum of 14 days. Day 15 was removed. • Specified that the additional sample taken at the ETV should be a DBS.
    06 Dec 2021
    • Protocol was updated to state that Phe responsiveness is defined as mean Phe reduction is ≥15% for participants <2 years. • A risk/benefit assessment section was added. • Inclusion Criterion was updated to specify “uncontrolled” blood Phe levels while on current therapy. • Inclusion Criterion was updated to specify that effective contraception/abstinence must be utilized for up to 90 days after the last dose of study drug. • Total blood volume was updated. • Details of the excipients were added. • A section was added to detail assessment of laboratory abnormalities. • PK sampling timepoints were updated. • SAE reporting timeframe was updated.
    13 Jan 2022
    • A definition for End of Study was added. • Exclusion criterion was expanded to include specific pathogenic mutations.
    24 Jun 2022
    • Tables were updated to detail additional blood sampling timepoints for Part 2. • Clarification was added to ensure full alignments with CTFG throughout the protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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