A Study of PTC923 in Participants With Phenylketonuria

• ClinicalTrials.gov Identifier: NCT05099640
• Recruitment Status: Completed
• First Posted: October 29, 2021
• Results First Posted: January 10, 2024
• Last Update Posted: January 10, 2024
• Sponsor: PTC Therapeutics
• Information provided by (Responsible Party): PTC Therapeutics

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Phenylketonuria
• Interventions: Drug: PTC923; Drug: Placebo
• Enrollment: 157

Participant Flow

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 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.

Arm/Group Title	Part 1: Sepiapterin	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Period Title: Part 1: Open-label (14 Days)
Started	157	0	0
Received at Least 1 Dose of Study Drug	157	0	0
Completed	111 [1]	0	0
Not Completed	46	0	0
Reason Not Completed
Non-responsive for sepiapterin	39	0	0
Participant decision	3	0	0
Adverse Event	1	0	0
Withdrawal by Subject	1	0	0
Other than specified	2	0	0
[1] 110 participants were eligible to progress to Part 2.
Period Title: Part 2: Randomized Treatment (6 Weeks)
Started	0	56	54
Received at Least 1 Dose of Study Drug	0	56	54
Completed	0	55	54
Not Completed	0	1	0
Reason Not Completed
Participant decision	0	1	0

Baseline Characteristics

Arm/Group Title		Part 1 (Participants Who Participated in Part 1 Only): Sepiapterin	Part 2: Sepiapterin	Part 2: Placebo	Total
Arm/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.	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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.	Total of all reporting groups
Overall Number of Baseline Participants		47	56	54	157
Baseline Analysis Population Description		Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1. Part 2 included participants (≥2 years of age) who experienced a ≥15% reduction in blood Phe levels (responder). Non-responders in Part 1 did not continue to Part 2.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	47 participants	56 participants	54 participants	157 participants
		18.4 (15.07)	16.5 (11.12)	18.4 (10.65)	17.7 (12.24)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	47 participants	56 participants	54 participants	157 participants
	Female	19 40.4%	26 46.4%	27 50.0%	72 45.9%
	Male	28 59.6%	30 53.6%	27 50.0%	85 54.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	47 participants	56 participants	54 participants	157 participants
	Hispanic or Latino	5 10.6%	8 14.3%	12 22.2%	25 15.9%
	Not Hispanic or Latino	40 85.1%	47 83.9%	42 77.8%	129 82.2%
	Unknown or Not Reported	2 4.3%	1 1.8%	0 0.0%	3 1.9%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	47 participants	56 participants	54 participants	157 participants
	American Indian or Alaska Native	3 6.4%	3 5.4%	2 3.7%	8 5.1%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	White	41 87.2%	52 92.9%	49 90.7%	142 90.4%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	3 6.4%	1 1.8%	3 5.6%	7 4.5%
Blood Phenylketonuria (Phe) Level [1]; Mean (Standard Deviation); Unit of measure: Micromoles (μmol)/liter (L)
Part 1 (Participants who Participated in Part 1 Only) (Non-responders)	Number Analyzed	47 participants	0 participants	0 participants	47 participants
		651.16 (333.439)			651.16 (333.439)
Part 2 (Randomized Responders from Part 1)	Number Analyzed	0 participants	56 participants	54 participants	110 participants
			645.59 (246.085)	667.81 (264.574)	656.50 (254.397)
		[1] Measure Analysis Population Description: Baseline blood Phe level data is reported for Part 1 and Part 2 separately in different rows.
Blood Phe Level in Classical PKU Participants [1] [2]; Mean (Standard Deviation); Unit of measure: μmol/L
Part 1 (Participants who Participated in Part 1 Only) (Non-responders with Classical PKU)	Number Analyzed	17 participants	0 participants	0 participants	17 participants
		1495.8 (641.18)			1495.8 (641.18)
Part 2 (Randomized Responders from Part 1 with Classical PKU)	Number Analyzed	0 participants	8 participants	11 participants	19 participants
			737.56 (277.279)	812.14 (295.239)	780.74 (282.411)
		[1] Measure Description: Classical PKU participants: Participants with severe forms of PKU, typically had very high blood Phe levels (>1200 μmol/L).; [2] Measure Analysis Population Description: Baseline blood Phe level data is reported for Part 1 and Part 2 classical PKU participants separately in different rows.

Outcome Measures

1. Primary Outcome

Title	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
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.
Time Frame	Baseline, Weeks 5 and 6 (average of the 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed	49	49
Least Squares Mean (Standard Error); Unit of Measure: μmol/L
	-415.75 (24.066)	-19.88 (24.223)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-395.87
	Confidence Interval	(2-Sided) 95%; -463.07 to -328.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.848
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	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
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.
Time Frame	Baseline, Weeks 5 and 6 (average of the 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed	49	49
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-63.40 (3.537)	0.82 (3.561)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-64.22
	Confidence Interval	(2-Sided) 95%; -74.09 to -54.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.973
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	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
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.
Time Frame	Weeks 5 and 6 (average of the 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed	28	30
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	92.9; (76.50 to 99.12)	30.0; (14.73 to 49.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	30.33
	Confidence Interval	(2-Sided) 95%; 5.30 to 294.24
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	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
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.
Time Frame	Weeks 5 and 6 (average of the 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed	44	43
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	84.1; (69.93 to 93.36)	9.3; (2.59 to 22.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	51.54
	Confidence Interval	(2-Sided) 95%; 12.28 to 245.34
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	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
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.
Time Frame	Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed		49	49
Mean (Standard Deviation); Unit of Measure: μmol/L
Weeks 1 and 2	Number Analyzed	49 participants	49 participants
		-341.18 (226.178)	-53.27 (174.461)
Weeks 3 and 4	Number Analyzed	49 participants	48 participants
		-406.88 (199.259)	-30.43 (203.425)
Weeks 5 and 6	Number Analyzed	49 participants	49 participants
		-410.07 (204.442)	-16.19 (198.642)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	Weeks 1 and 2: Sepiapterin vs. Placebo
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-289.89
	Confidence Interval	(2-Sided) 95%; -356.29 to -223.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.440
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	Weeks 3 and 4: Sepiapterin vs. Placebo
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-375.47
	Confidence Interval	(2-Sided) 95%; -435.88 to -315.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 30.424
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	Weeks 5 and 6: Sepiapterin vs. Placebo
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-395.87
	Confidence Interval	(2-Sided) 95%; -463.07 to -328.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 33.848
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	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
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.
Time Frame	Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed		49	49
Mean (Standard Deviation); Unit of Measure: percent change
Weeks 1 and 2	Number Analyzed	49 participants	49 participants
		-48.55 (4.265)	-6.04 (4.285)
Weeks 3 and 4	Number Analyzed	49 participants	48 participants
		-62.46 (3.220)	-1.43 (3.257)
Weeks 5 and 6	Number Analyzed	49 participants	49 participants
		-63.40 (3.537)	0.82 (3.561)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	Weeks 1 and 2: Sepiapterin vs. Placebo
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-42.52
	Confidence Interval	(2-Sided) 95%; -54.45 to -30.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.008
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	Weeks 3 and 4: Sepiapterin vs. Placebo
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-61.03
	Confidence Interval	(2-Sided) 95%; -70.02 to -52.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.531
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	Weeks 5 and 6: Sepiapterin vs. Placebo
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-64.22
	Confidence Interval	(2-Sided) 95%; -74.09 to -54.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.973
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin
Description	[Not Specified]
Time Frame	Predose, 0.5, 1, 2, 4, 6, 8, and 24 hours postdose at Day 1; 2 and 6 hours postdose at Day 14

Outcome Measure Data

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

Arm/Group Title		Part 1: Sepiapterin
Arm/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.
Overall Number of Participants Analyzed		17
Mean (Standard Deviation); Unit of Measure: nanograms (ng)/milliliter (mL)
BH4: Day 1 (predose)	Number Analyzed	16 participants
		10.6 (5.34)
BH4: Day 1 (0.5 hr)	Number Analyzed	16 participants
		22.3 (13.2)
BH4: Day 1 (1 hr)	Number Analyzed	15 participants
		107 (76.0)
BH4: Day 1 (2 hrs)	Number Analyzed	16 participants
		236 (124)
BH4: Day 1 (4 hrs)	Number Analyzed	16 participants
		289 (170)
BH4: Day 1 (6 hrs)	Number Analyzed	14 participants
		245 (131)
BH4: Day 1 (8 hrs)	Number Analyzed	15 participants
		205 (130)
BH4: Day 1 (24 hrs)	Number Analyzed	16 participants
		25.5 (21.1)
BH4: Day 14 (2 hrs)	Number Analyzed	1 participants
		94.1
BH4: Day 14 (6 hrs)	Number Analyzed	1 participants
		105
Sepiapterin: Day 1 (predose)	Number Analyzed	16 participants
		0.000 (0.000)
Sepiapterin: Day 1 (0.5 hr)	Number Analyzed	16 participants
		0.939 (0.940)
Sepiapterin: Day 1 (1 hr)	Number Analyzed	16 participants
		2.22 (1.11)
Sepiapterin: Day 1 (2 hrs)	Number Analyzed	16 participants
		2.06 (1.10)
Sepiapterin: Day 1 (4 hrs)	Number Analyzed	17 participants
		1.73 (1.58)
Sepiapterin: Day 1 (6 hrs)	Number Analyzed	16 participants
		1.60 (2.13)
Sepiapterin: Day 1 (8 hrs)	Number Analyzed	16 participants
		0.493 (0.598)
Sepiapterin: Day 1 (24 hrs)	Number Analyzed	16 participants
		0.436 (0.987)
Sepiapterin: Day 14 (2 hrs)	Number Analyzed	1 participants
		3.33
Sepiapterin: Day 14 (6 hrs)	Number Analyzed	1 participants
		2.82

8. Secondary Outcome

Title	Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin
Description	[Not Specified]
Time Frame	Predose and 4 hours postdose at Days 1, 14, 28, and 42

Outcome Measure Data

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

Arm/Group Title		Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed		4	4
Mean (Standard Deviation); Unit of Measure: ng/mL
BH4: Day 1 (predose)	Number Analyzed	4 participants	2 participants
		6.63 (3.60)	8.52 (4.36)
BH4: Day 1 (4 hrs)	Number Analyzed	3 participants	4 participants
		351 (184)	12.4 (1.74)
BH4: Day 14 (predose)	Number Analyzed	4 participants	3 participants
		7.04 (3.13)	4.27 (4.93)
BH4: Day 14 (4 hrs)	Number Analyzed	2 participants	4 participants
		401 (184)	11.3 (8.70)
BH4: Day 28 (predose)	Number Analyzed	3 participants	4 participants
		11.8 (6.29)	9.70 (4.18)
BH4: Day 28 (4 hrs)	Number Analyzed	3 participants	4 participants
		406 (57.5)	12.2 (4.46)
BH4: Day 42 (predose)	Number Analyzed	4 participants	4 participants
		10.0 (6.43)	9.41 (4.58)
BH4: Day 42 (4 hrs)	Number Analyzed	2 participants	4 participants
		442 (197)	11.4 (3.91)
Sepiapterin: Day 1 (predose)	Number Analyzed	4 participants	4 participants
		0.000 (0.000)	0.000 (0.000)
Sepiapterin: Day 1 (4 hrs)	Number Analyzed	3 participants	4 participants
		0.620 (1.07)	0.000 (0.000)
Sepiapterin: Day 14 (predose)	Number Analyzed	4 participants	3 participants
		0.000 (0.000)	0.000 (0.000)
Sepiapterin: Day 14 (4 hrs)	Number Analyzed	3 participants	4 participants
		1.23 (1.26)	0.000 (0.000)
Sepiapterin: Day 28 (predose)	Number Analyzed	4 participants	3 participants
		0.000 (0.000)	0.000 (0.000)
Sepiapterin: Day 28 (4 hrs)	Number Analyzed	3 participants	4 participants
		1.17 (1.09)	0.000 (0.000)
Sepiapterin: Day 42 (predose)	Number Analyzed	4 participants	4 participants
		0.000 (0.000)	0.000 (0.000)
Sepiapterin: Day 42 (4 hrs)	Number Analyzed	3 participants	4 participants
		1.03 (1.14)	0.000 (0.000)

9. Secondary Outcome

Title	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
Description	[Not Specified]
Time Frame	0 to 24 hours postdose at Day 1

Outcome Measure Data

Analysis Population 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 outcome measure.

Arm/Group Title	Part 1: Sepiapterin
Arm/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.
Overall Number of Participants Analyzed	16
Mean (Standard Deviation); Unit of Measure: hours*ng/mL
BH4	2990 (1450)
Sepiapterin	19.6 (20.1)

10. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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.
Time Frame	Baseline up to Day 42

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Part 1: Sepiapterin	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed	157	56	54
Measure Type: Count of Participants; Unit of Measure: Participants
	68 43.3%	33 58.9%	18 33.3%

11. Other Pre-specified Outcome

Title	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
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.
Time Frame	Baseline, Weeks 5 and 6 (average of the 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed	6	9
Least Squares Mean (Standard Error); Unit of Measure: μmol/L
	-488.19 (50.532)	4.03 (46.496)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-492.23
	Confidence Interval	(2-Sided) 95%; -614.59 to -369.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 55.588
	Estimation Comments	[Not Specified]

12. Other Pre-specified Outcome

Title	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
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.
Time Frame	Baseline, Weeks 5 and 6 (average of the 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
Overall Number of Participants Analyzed	6	9
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-55.83 (9.182)	18.90 (8.286)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Sepiapterin, Part 2: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-74.73
	Confidence Interval	(2-Sided) 95%; -97.72 to -51.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.436
	Estimation Comments	[Not Specified]

13. Other Pre-specified Outcome

Title	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
Description	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.
Time Frame	Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 1: Sepiapterin
Arm/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.
Overall Number of Participants Analyzed	103
Mean (Standard Deviation); Unit of Measure: μmol/L
	-462.17 (203.620)

14. Other Pre-specified Outcome

Title	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
Description	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.
Time Frame	Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 1: Sepiapterin
Arm/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.
Overall Number of Participants Analyzed	103
Mean (Standard Deviation); Unit of Measure: percent change
	-65.25 (15.764)

Adverse Events

Time Frame	Baseline up to Day 42
Adverse Event Reporting Description	Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
Arm/Group Title	Part 1: Sepiapterin	Part 2: Sepiapterin	Part 2: Placebo
Arm/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.	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.	Participants received equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the sepiapterin treatment arm.
All-Cause Mortality
	Part 1: Sepiapterin	Part 2: Sepiapterin	Part 2: Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/157 (0.00%)	0/56 (0.00%)	0/54 (0.00%)
Serious Adverse Events
	Part 1: Sepiapterin	Part 2: Sepiapterin	Part 2: Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/157 (0.00%)	0/56 (0.00%)	0/54 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Part 1: Sepiapterin	Part 2: Sepiapterin	Part 2: Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	15/157 (9.55%)	14/56 (25.00%)	11/54 (20.37%)
Gastrointestinal disorders
Diarrhoea † 1	8/157 (5.10%)	4/56 (7.14%)	1/54 (1.85%)
Vomiting † 1	0/157 (0.00%)	1/56 (1.79%)	3/54 (5.56%)
Nausea † 1	0/157 (0.00%)	0/56 (0.00%)	3/54 (5.56%)
Infections and infestations
Upper respiratory tract infection † 1	7/157 (4.46%)	3/56 (5.36%)	1/54 (1.85%)
Gastroenteritis † 1	0/157 (0.00%)	3/56 (5.36%)	3/54 (5.56%)
Nasopharyngitis † 1	0/157 (0.00%)	0/56 (0.00%)	4/54 (7.41%)
Nervous system disorders
Headache † 1	0/157 (0.00%)	4/56 (7.14%)	1/54 (1.85%)
1 Term from vocabulary, MedDRA 26.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Patient Advocacy
• Organization: PTC Therapeutics, Inc.
• Phone: 1-866-562-4620
• EMail: medinfo@ptcbio.com

• Responsible Party: PTC Therapeutics
• ClinicalTrials.gov Identifier: NCT05099640
• Other Study ID Numbers: PTC923-MD-003-PKU; 2021-000474-29 ( EudraCT Number )
• First Submitted: October 6, 2021
• First Posted: October 29, 2021
• Results First Submitted: November 3, 2023
• Results First Posted: January 10, 2024
• Last Update Posted: January 10, 2024