Trial Outcomes & Findings for A Study of PTC923 in Participants With Phenylketonuria (NCT NCT05099640)

Last Updated: 2024-01-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

157 participants

Primary outcome timeframe

Baseline, Weeks 5 and 6 (average of the 2-week period)

Results posted on

2024-01-10

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Part 1: Sepiapterin 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.	Part 2: Sepiapterin 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.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 1: Open-label (14 Days) STARTED	157	0	0
Part 1: Open-label (14 Days) Received at Least 1 Dose of Study Drug	157	0	0
Part 1: Open-label (14 Days) COMPLETED	111	0	0
Part 1: Open-label (14 Days) NOT COMPLETED	46	0	0
Part 2: Randomized Treatment (6 Weeks) STARTED	0	56	54
Part 2: Randomized Treatment (6 Weeks) Received at Least 1 Dose of Study Drug	0	56	54
Part 2: Randomized Treatment (6 Weeks) COMPLETED	0	55	54
Part 2: Randomized Treatment (6 Weeks) NOT COMPLETED	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Sepiapterin 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.	Part 2: Sepiapterin 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.
Part 1: Open-label (14 Days) Non-responsive for sepiapterin	39	0
Part 1: Open-label (14 Days) Participant decision	3	0
Part 1: Open-label (14 Days) Adverse Event	1	0
Part 1: Open-label (14 Days) Withdrawal by Subject	1	0
Part 1: Open-label (14 Days) Other than specified	2	0
Part 2: Randomized Treatment (6 Weeks) Participant decision	0	1

Baseline Characteristics

Baseline blood Phe level data is reported for Part 1 and Part 2 separately in different rows.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1 (Participants Who Participated in Part 1 Only): Sepiapterin n=47 Participants 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.	Part 2: Sepiapterin n=56 Participants 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.	Part 2: Placebo n=54 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Total n=157 Participants Total of all reporting groups
Age, Continuous	18.4 years STANDARD_DEVIATION 15.07 • n=47 Participants	16.5 years STANDARD_DEVIATION 11.12 • n=56 Participants	18.4 years STANDARD_DEVIATION 10.65 • n=54 Participants	17.7 years STANDARD_DEVIATION 12.24 • n=157 Participants
Sex: Female, Male Female	19 Participants n=47 Participants	26 Participants n=56 Participants	27 Participants n=54 Participants	72 Participants n=157 Participants
Sex: Female, Male Male	28 Participants n=47 Participants	30 Participants n=56 Participants	27 Participants n=54 Participants	85 Participants n=157 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=47 Participants	8 Participants n=56 Participants	12 Participants n=54 Participants	25 Participants n=157 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	40 Participants n=47 Participants	47 Participants n=56 Participants	42 Participants n=54 Participants	129 Participants n=157 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=47 Participants	1 Participants n=56 Participants	0 Participants n=54 Participants	3 Participants n=157 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=47 Participants	3 Participants n=56 Participants	2 Participants n=54 Participants	8 Participants n=157 Participants
Race (NIH/OMB) Asian	0 Participants n=47 Participants	0 Participants n=56 Participants	0 Participants n=54 Participants	0 Participants n=157 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=47 Participants	0 Participants n=56 Participants	0 Participants n=54 Participants	0 Participants n=157 Participants
Race (NIH/OMB) Black or African American	0 Participants n=47 Participants	0 Participants n=56 Participants	0 Participants n=54 Participants	0 Participants n=157 Participants
Race (NIH/OMB) White	41 Participants n=47 Participants	52 Participants n=56 Participants	49 Participants n=54 Participants	142 Participants n=157 Participants
Race (NIH/OMB) More than one race	0 Participants n=47 Participants	0 Participants n=56 Participants	0 Participants n=54 Participants	0 Participants n=157 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=47 Participants	1 Participants n=56 Participants	3 Participants n=54 Participants	7 Participants n=157 Participants
Blood Phenylketonuria (Phe) Level Part 1 (Participants who Participated in Part 1 Only) (Non-responders)	651.16 micromoles (μmol)/liter (L) STANDARD_DEVIATION 333.439 • n=47 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 separately in different rows.	—	—	651.16 micromoles (μmol)/liter (L) STANDARD_DEVIATION 333.439 • n=47 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 separately in different rows.
Blood Phenylketonuria (Phe) Level Part 2 (Randomized Responders from Part 1)	—	645.59 micromoles (μmol)/liter (L) STANDARD_DEVIATION 246.085 • n=56 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 separately in different rows.	667.81 micromoles (μmol)/liter (L) STANDARD_DEVIATION 264.574 • n=54 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 separately in different rows.	656.50 micromoles (μmol)/liter (L) STANDARD_DEVIATION 254.397 • n=110 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 separately in different rows.
Blood Phe Level in Classical PKU Participants Part 1 (Participants who Participated in Part 1 Only) (Non-responders with Classical PKU)	1495.8 μmol/L STANDARD_DEVIATION 641.18 • n=17 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 classical PKU participants separately in different rows.	—	—	1495.8 μmol/L STANDARD_DEVIATION 641.18 • n=17 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 classical PKU participants separately in different rows.
Blood Phe Level in Classical PKU Participants Part 2 (Randomized Responders from Part 1 with Classical PKU)	—	737.56 μmol/L STANDARD_DEVIATION 277.279 • n=8 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 classical PKU participants separately in different rows.	812.14 μmol/L STANDARD_DEVIATION 295.239 • n=11 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 classical PKU participants separately in different rows.	780.74 μmol/L STANDARD_DEVIATION 282.411 • n=19 Participants • Baseline blood Phe level data is reported for Part 1 and Part 2 classical PKU participants separately in different rows.

PRIMARY outcome

Timeframe: Baseline, Weeks 5 and 6 (average of the 2-week period)

Population: 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. This outcome measure was pre-specified to collect data only for Part 2.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=49 Participants 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.	Part 2: Placebo n=49 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phenylketonuria (Phe) Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1	-415.75 μmol/L Standard Error 24.066	-19.88 μmol/L Standard Error 24.223	—

PRIMARY outcome

Timeframe: Baseline, Weeks 5 and 6 (average of the 2-week period)

Population: 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. This outcome measure was pre-specified to collect data only for Part 2.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=49 Participants 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.	Part 2: Placebo n=49 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1	-63.40 percent change Standard Error 3.537	0.82 percent change Standard Error 3.561	—

SECONDARY outcome

Timeframe: Weeks 5 and 6 (average of the 2-week period)

Population: 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. This outcome measure was pre-specified to collect data only for Part 2.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=28 Participants 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.	Part 2: Placebo n=30 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Percentage of Participants With Baseline Phe Levels ≥600 μmol/L Who Achieved Phe Levels <600 μmol/L in Participants With Phe Reduction From Baseline ≥30% During Part 1	92.9 percentage of participants Interval 76.5 to 99.12	30.0 percentage of participants Interval 14.73 to 49.4	—

SECONDARY outcome

Timeframe: Weeks 5 and 6 (average of the 2-week period)

Population: 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. This outcome measure was pre-specified to collect data only for Part 2.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=44 Participants 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.	Part 2: Placebo n=43 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Percentage of Participants With Baseline Phe Levels ≥360 μmol/L Who Achieved Phe Levels <360 μmol/L in Participants With Phe Reduction From Baseline ≥30% During Part 1	84.1 percentage of participants Interval 69.93 to 93.36	9.3 percentage of participants Interval 2.59 to 22.14	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)

Population: 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. 'Number analyzed' = participants evaluable at specified timepoint. This outcome measure was pre-specified to collect data only for Part 2.

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.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=49 Participants 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.	Part 2: Placebo n=49 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Weeks 3 and 4	-406.88 μmol/L Standard Deviation 199.259	-30.43 μmol/L Standard Deviation 203.425	—
Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Weeks 1 and 2	-341.18 μmol/L Standard Deviation 226.178	-53.27 μmol/L Standard Deviation 174.461	—
Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Weeks 5 and 6	-410.07 μmol/L Standard Deviation 204.442	-16.19 μmol/L Standard Deviation 198.642	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)

Population: 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. 'Number analyzed' = participants evaluable at specified timepoint. This outcome measure was pre-specified to collect data only for Part 2.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=49 Participants 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.	Part 2: Placebo n=49 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Weeks 1 and 2	-48.55 percent change Standard Deviation 4.265	-6.04 percent change Standard Deviation 4.285	—
Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Weeks 3 and 4	-62.46 percent change Standard Deviation 3.220	-1.43 percent change Standard Deviation 3.257	—
Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Weeks 5 and 6	-63.40 percent change Standard Deviation 3.537	0.82 percent change Standard Deviation 3.561	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 2, 4, 6, 8, and 24 hours postdose at Day 1; 2 and 6 hours postdose at Day 14

Population: 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 outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=17 Participants 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.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 1 (predose)	10.6 nanograms (ng)/milliliter (mL) Standard Deviation 5.34	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 1 (0.5 hr)	22.3 nanograms (ng)/milliliter (mL) Standard Deviation 13.2	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 1 (1 hr)	107 nanograms (ng)/milliliter (mL) Standard Deviation 76.0	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 1 (2 hrs)	236 nanograms (ng)/milliliter (mL) Standard Deviation 124	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 1 (4 hrs)	289 nanograms (ng)/milliliter (mL) Standard Deviation 170	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 1 (6 hrs)	245 nanograms (ng)/milliliter (mL) Standard Deviation 131	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 1 (8 hrs)	205 nanograms (ng)/milliliter (mL) Standard Deviation 130	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 1 (24 hrs)	25.5 nanograms (ng)/milliliter (mL) Standard Deviation 21.1	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 14 (2 hrs)	94.1 nanograms (ng)/milliliter (mL)	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin BH4: Day 14 (6 hrs)	105 nanograms (ng)/milliliter (mL)	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 1 (predose)	0.000 nanograms (ng)/milliliter (mL) Standard Deviation 0.000	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 1 (0.5 hr)	0.939 nanograms (ng)/milliliter (mL) Standard Deviation 0.940	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 1 (1 hr)	2.22 nanograms (ng)/milliliter (mL) Standard Deviation 1.11	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 1 (2 hrs)	2.06 nanograms (ng)/milliliter (mL) Standard Deviation 1.10	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 1 (4 hrs)	1.73 nanograms (ng)/milliliter (mL) Standard Deviation 1.58	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 1 (6 hrs)	1.60 nanograms (ng)/milliliter (mL) Standard Deviation 2.13	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 1 (8 hrs)	0.493 nanograms (ng)/milliliter (mL) Standard Deviation 0.598	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 1 (24 hrs)	0.436 nanograms (ng)/milliliter (mL) Standard Deviation 0.987	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 14 (2 hrs)	3.33 nanograms (ng)/milliliter (mL)	—	—
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Sepiapterin: Day 14 (6 hrs)	2.82 nanograms (ng)/milliliter (mL)	—	—

SECONDARY outcome

Timeframe: Predose and 4 hours postdose at Days 1, 14, 28, and 42

Population: 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 outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=4 Participants 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.	Part 2: Placebo n=4 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin BH4: Day 1 (predose)	6.63 ng/mL Standard Deviation 3.60	8.52 ng/mL Standard Deviation 4.36	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin BH4: Day 1 (4 hrs)	351 ng/mL Standard Deviation 184	12.4 ng/mL Standard Deviation 1.74	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin BH4: Day 14 (predose)	7.04 ng/mL Standard Deviation 3.13	4.27 ng/mL Standard Deviation 4.93	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin BH4: Day 14 (4 hrs)	401 ng/mL Standard Deviation 184	11.3 ng/mL Standard Deviation 8.70	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin BH4: Day 28 (predose)	11.8 ng/mL Standard Deviation 6.29	9.70 ng/mL Standard Deviation 4.18	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin BH4: Day 28 (4 hrs)	406 ng/mL Standard Deviation 57.5	12.2 ng/mL Standard Deviation 4.46	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin BH4: Day 42 (predose)	10.0 ng/mL Standard Deviation 6.43	9.41 ng/mL Standard Deviation 4.58	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin BH4: Day 42 (4 hrs)	442 ng/mL Standard Deviation 197	11.4 ng/mL Standard Deviation 3.91	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Sepiapterin: Day 1 (predose)	0.000 ng/mL Standard Deviation 0.000	0.000 ng/mL Standard Deviation 0.000	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Sepiapterin: Day 1 (4 hrs)	0.620 ng/mL Standard Deviation 1.07	0.000 ng/mL Standard Deviation 0.000	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Sepiapterin: Day 14 (predose)	0.000 ng/mL Standard Deviation 0.000	0.000 ng/mL Standard Deviation 0.000	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Sepiapterin: Day 14 (4 hrs)	1.23 ng/mL Standard Deviation 1.26	0.000 ng/mL Standard Deviation 0.000	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Sepiapterin: Day 28 (predose)	0.000 ng/mL Standard Deviation 0.000	0.000 ng/mL Standard Deviation 0.000	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Sepiapterin: Day 28 (4 hrs)	1.17 ng/mL Standard Deviation 1.09	0.000 ng/mL Standard Deviation 0.000	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Sepiapterin: Day 42 (predose)	0.000 ng/mL Standard Deviation 0.000	0.000 ng/mL Standard Deviation 0.000	—
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Sepiapterin: Day 42 (4 hrs)	1.03 ng/mL Standard Deviation 1.14	0.000 ng/mL Standard Deviation 0.000	—

SECONDARY outcome

Timeframe: 0 to 24 hours postdose at Day 1

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=16 Participants 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.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 1 Open-label Run-in Phase: 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 BH4	2990 hours*ng/mL Standard Deviation 1450	—	—
Part 1 Open-label Run-in Phase: 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 Sepiapterin	19.6 hours*ng/mL Standard Deviation 20.1	—	—

SECONDARY outcome

Timeframe: Baseline up to Day 42

Population: Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.

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.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=157 Participants 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.	Part 2: Placebo n=56 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo n=54 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	68 Participants	33 Participants	18 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Weeks 5 and 6 (average of the 2-week period)

Population: 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. This outcome measure was pre-specified to collect data only for Part 2.

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.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=6 Participants 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.	Part 2: Placebo n=9 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Classical PKU Participants With Phe Reduction From Baseline ≥30% During Part 1	-488.19 μmol/L Standard Error 50.532	4.03 μmol/L Standard Error 46.496	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Weeks 5 and 6 (average of the 2-week period)

Population: 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. This outcome measure was pre-specified to collect data only for Part 2.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=6 Participants 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.	Part 2: Placebo n=9 Participants Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Classical PKU Participants With Phe Reduction From Baseline ≥30% During Part 1	-55.83 percent change Standard Error 9.182	18.90 percent change Standard Error 8.286	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)

Population: 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.

Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 1 Open-label Run-in Phase, 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.

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=103 Participants 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.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 1 Open-label Run-in Phase: Mean Change From Baseline (Part 1) in Blood Phe Level to Weeks 1 and 2 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1	-462.17 μmol/L Standard Deviation 203.620	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)

Outcome measures

Outcome measures
Measure	Part 2: Sepiapterin n=103 Participants 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.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Part 2: Placebo Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Part 1 Open-label Run-in Phase: Percent Change From Baseline (Part 1) in Blood Phe Level to Weeks 1 and 2 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1	-65.25 percent change Standard Deviation 15.764	—	—

Adverse Events

Part 1: Sepiapterin

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Part 2: Sepiapterin

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Part 2: Placebo

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Part 1: Sepiapterin n=157 participants at risk 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.	Part 2: Sepiapterin n=56 participants at risk 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.	Part 2: Placebo n=54 participants at risk Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Nervous system disorders Headache	0.00% 0/157 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	7.1% 4/56 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	1.9% 1/54 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
Gastrointestinal disorders Diarrhoea	5.1% 8/157 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	7.1% 4/56 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	1.9% 1/54 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
Infections and infestations Upper respiratory tract infection	4.5% 7/157 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	5.4% 3/56 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	1.9% 1/54 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
Infections and infestations Gastroenteritis	0.00% 0/157 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	5.4% 3/56 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	5.6% 3/54 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
Infections and infestations Nasopharyngitis	0.00% 0/157 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	0.00% 0/56 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	7.4% 4/54 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
Gastrointestinal disorders Vomiting	0.00% 0/157 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	1.8% 1/56 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	5.6% 3/54 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
Gastrointestinal disorders Nausea	0.00% 0/157 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	0.00% 0/56 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.	5.6% 3/54 • Baseline up to Day 42 Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.

Additional Information

Patient Advocacy

PTC Therapeutics, Inc.

Phone: 1-866-562-4620

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor can review results and/or communications prior to public release and can embargo communications regarding trial results for a period that is up to 180 days from the time submitted to the sponsor for review. The sponsor may consult with the PI to require changes to the communication or extend the embargo.
Publication restrictions are in place

Restriction type: OTHER