Phenylketonuria
Conditions
Brief summary
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).
Detailed description
The study includes 2 parts: Part 1 and 2. Part 1 of the study tests for responsiveness to PTC923, with 14 days of open-label treatment with PTC923. At the end of treatment in Part 1, the mean change in blood Phe levels over the 14-day treatment period for all participants will be assessed against their pretreatment (baseline) blood Phe level. Participants ≥2 years of age who experience a \<15% reduction in blood Phe levels will be classified as non-responsive and participation in the study will be terminated. Participants (≥2 years of age) who experience a ≥15% reduction in blood Phe levels will continue into Part 2. Participants \<2 years of age who experience ≥15% reduction in blood Phe levels will be offered the option to enroll directly into an open-label extension Study PTC923-MD-004-PKU. Participants \<2 years of age who experience a \<15% reduction in blood Phe levels will be classified as nonresponsive, and participation in the study will be terminated. Following the minimum 14-day PTC923 washout period, all eligible participants will be randomized in Part 2 to receive either PTC923 or placebo. After 6 weeks of treatment with either PTC923 or placebo, participants will be offered the option to enter an open-label extension Study PTC923-MD-004-PKU (NCT05166161).
Interventions
DRUGPTC923
PTC923 powder for oral use will be suspended in water or apple juice prior to administration.
DRUGPlacebo
Placebo matching to PTC923
Sponsors
PTC Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Uncontrolled blood Phe level ≥360 μmol/L on current therapy anytime during screening and uncontrolled blood Phe level ≥360 μmol/L on current therapy when taking the average of the 3 most recent Phe levels from the participant's medical history (inclusive of the screening value). * Clinical diagnosis of phenylketonuria with hyperphenylalaninemia (HPA) documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L. * Women of childbearing potential must have a negative pregnancy test at screening and agree to abstinence or the use of at least one highly effective form of contraception for the duration of the study, and for up to 90 days after the last dose of study drug. * Males who are sexually active with women of childbearing potential who have not had a vasectomy must agree to use a barrier method of birth control during the study and for up to 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period. * Willing to continue current diet unchanged while participating in the study.
Exclusion criteria
* Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, and peptic ulcer disease, etc.) that could affect the absorption of study drug. * History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy. * History of allergies or adverse reactions to synthetic tetrahydrobiopterin (BH4) or sepiapterin. * Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to screening. * Any clinically significant laboratory abnormality as determined by the investigator. * A female who is pregnant or breastfeeding, or considering pregnancy. * Serious neuropsychiatric illness (for example, major depression) not currently under medical control, that in the opinion of the investigator or sponsor, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant. * Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate \[GFR\] \<60 milliliters \[mL\]/minute \[min\]) and/or under care of a nephrologist. * Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR \<60 mL/min/1.73 square meter (m\^2). * Requirement for concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate). * Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic mutations in 6-pyruvoyltetrahydropterin synthase, recessive guanosine-5'-triphosphate (GTP) cyclohydrolase I, sepiapterin reductase, quinoid dihydropteridine reductase, or pterin-4-alpha-carbinolamine dehydratase genes. * Major surgery within the prior 90 days of screening. * Concomitant treatment with BH4 supplementation (for example, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ). * Unwillingness to washout from BH4 supplementation (for example, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, Weeks 5 and 6 (average of the 2-week period) | 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. |
| 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 | Baseline, Weeks 5 and 6 (average of the 2-week period) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period) | 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. |
| Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin | Predose, 0.5, 1, 2, 4, 6, 8, and 24 hours postdose at Day 1; 2 and 6 hours postdose at Day 14 | — |
| Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Predose and 4 hours postdose at Days 1, 14, 28, and 42 | — |
| 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 | 0 to 24 hours postdose at Day 1 | — |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Baseline up to Day 42 | 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. |
| 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 | Weeks 5 and 6 (average of the 2-week period) | 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. |
| 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 | Weeks 5 and 6 (average of the 2-week period) | 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. |
| 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 | Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period) | 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. |
| 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 | Baseline, Weeks 5 and 6 (average of the 2-week period) | 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. |
| 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 | Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period) | 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. |
| 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 | Baseline, Weeks 5 and 6 (average of the 2-week period) | 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. |
Countries
Australia, Brazil, Canada, Denmark, France, Georgia, Germany, Italy, Mexico, Netherlands, Portugal, Spain, Turkey (Türkiye), United Kingdom, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 (Participants Who Participated in Part 1 Only): Sepiapterin 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. | 47 |
| 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. | 56 |
| 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. | 54 |
| Total | 157 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1: Open-label (14 Days) | Adverse Event | 1 | 0 | 0 |
| Part 1: Open-label (14 Days) | Non-responsive for sepiapterin | 39 | 0 | 0 |
| Part 1: Open-label (14 Days) | Other than specified | 2 | 0 | 0 |
| Part 1: Open-label (14 Days) | Participant decision | 3 | 0 | 0 |
| Part 1: Open-label (14 Days) | Withdrawal by Subject | 1 | 0 | 0 |
| Part 2: Randomized Treatment (6 Weeks) | Participant decision | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part 1 (Participants Who Participated in Part 1 Only): Sepiapterin | Total | Part 2: Sepiapterin | Part 2: Placebo |
|---|---|---|---|---|
| Age, Continuous | 18.4 years STANDARD_DEVIATION 15.07 | 17.7 years STANDARD_DEVIATION 12.24 | 16.5 years STANDARD_DEVIATION 11.12 | 18.4 years STANDARD_DEVIATION 10.65 |
| 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 | 1495.8 μmol/L STANDARD_DEVIATION 641.18 | — | — |
| Blood Phe Level in Classical PKU Participants Part 2 (Randomized Responders from Part 1 with Classical PKU) | — | 780.74 μmol/L STANDARD_DEVIATION 282.411 | 737.56 μmol/L STANDARD_DEVIATION 277.279 | 812.14 μmol/L STANDARD_DEVIATION 295.239 |
| 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 | 651.16 micromoles (μmol)/liter (L) STANDARD_DEVIATION 333.439 | — | — |
| Blood Phenylketonuria (Phe) Level Part 2 (Randomized Responders from Part 1) | — | 656.50 micromoles (μmol)/liter (L) STANDARD_DEVIATION 254.397 | 645.59 micromoles (μmol)/liter (L) STANDARD_DEVIATION 246.085 | 667.81 micromoles (μmol)/liter (L) STANDARD_DEVIATION 264.574 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 25 Participants | 8 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 129 Participants | 47 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 8 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 7 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 41 Participants | 142 Participants | 52 Participants | 49 Participants |
| Sex: Female, Male Female | 19 Participants | 72 Participants | 26 Participants | 27 Participants |
| Sex: Female, Male Male | 28 Participants | 85 Participants | 30 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 157 | 0 / 56 | 0 / 54 |
| other Total, other adverse events | 15 / 157 | 14 / 56 | 11 / 54 |
| serious Total, serious adverse events | 0 / 157 | 0 / 56 | 0 / 54 |
Outcome results
Primary
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
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 2: Sepiapterin | 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 |
| Part 2: Placebo | 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 | -19.88 μmol/L | Standard Error 24.223 |
p-value: <0.000195% CI: [-463.07, -328.66]Mixed Models Analysis
Primary
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
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 2: Sepiapterin | 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 |
| Part 2: Placebo | 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 | 0.82 percent change | Standard Error 3.561 |
p-value: <0.000195% CI: [-74.09, -54.35]Mixed Models Analysis
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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
Population: Safety analysis set included all participants who received at least 1 dose of study drug, including during Part 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 2: Sepiapterin | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 68 Participants |
| Part 2: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 33 Participants |
| Part 2: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 18 Participants |
Secondary
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
Time frame: 0 to 24 hours postdose at Day 1
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2: Sepiapterin | 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 2: Sepiapterin | 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
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin
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
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 |
| Part 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 |
| Part 2: Sepiapterin | 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 0.94 |
| Part 2: Sepiapterin | 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 2: Sepiapterin | 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 1.1 |
| Part 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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 2: Sepiapterin | 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
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
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)
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2: Sepiapterin | 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 |
| Part 2: Sepiapterin | 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 |
| Part 2: Sepiapterin | 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 |
| Part 2: Placebo | 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 | -53.27 μmol/L | Standard Deviation 174.461 |
| Part 2: Placebo | 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 | -30.43 μmol/L | Standard Deviation 203.425 |
| Part 2: Placebo | 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 | -16.19 μmol/L | Standard Deviation 198.642 |
Comparison: Weeks 1 and 2: Sepiapterin vs. Placebop-value: <0.000195% CI: [-356.29, -223.5]Mixed Models Analysis
Comparison: Weeks 3 and 4: Sepiapterin vs. Placebop-value: <0.000195% CI: [-435.88, -315.06]Mixed Models Analysis
Comparison: Weeks 5 and 6: Sepiapterin vs. Placebop-value: <0.000195% CI: [-463.07, -328.66]Mixed Models Analysis
Secondary
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
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)
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2: Sepiapterin | 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 |
| Part 2: Placebo | 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 | 9.3 percentage of participants |
p-value: <0.000195% CI: [12.28, 245.34]Chi-squared
Secondary
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
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)
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2: Sepiapterin | 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 |
| Part 2: Placebo | 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 | 30.0 percentage of participants |
p-value: <0.000195% CI: [5.3, 294.24]Chi-squared
Secondary
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
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)
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2: Sepiapterin | 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 |
| Part 2: Sepiapterin | 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 3.22 |
| Part 2: Sepiapterin | 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 |
| Part 2: Placebo | 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 | -6.04 percent change | Standard Deviation 4.285 |
| Part 2: Placebo | 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 | -1.43 percent change | Standard Deviation 3.257 |
| Part 2: Placebo | 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 | 0.82 percent change | Standard Deviation 3.561 |
Comparison: Weeks 1 and 2: Sepiapterin vs. Placebop-value: <0.000195% CI: [-54.45, -30.59]Mixed Models Analysis
Comparison: Weeks 3 and 4: Sepiapterin vs. Placebop-value: <0.000195% CI: [-70.02, -52.03]Mixed Models Analysis
Comparison: Weeks 5 and 6: Sepiapterin vs. Placebop-value: <0.000195% CI: [-74.09, -54.35]Mixed Models Analysis
Secondary
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 14 (4 hrs) | 401 ng/mL | Standard Deviation 184 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 1 (predose) | 6.63 ng/mL | Standard Deviation 3.6 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 1 (4 hrs) | 0.620 ng/mL | Standard Deviation 1.07 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 28 (predose) | 11.8 ng/mL | Standard Deviation 6.29 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 14 (predose) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 28 (4 hrs) | 406 ng/mL | Standard Deviation 57.5 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 14 (4 hrs) | 1.23 ng/mL | Standard Deviation 1.26 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 14 (predose) | 7.04 ng/mL | Standard Deviation 3.13 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 28 (predose) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 42 (predose) | 10.0 ng/mL | Standard Deviation 6.43 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 28 (4 hrs) | 1.17 ng/mL | Standard Deviation 1.09 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 1 (4 hrs) | 351 ng/mL | Standard Deviation 184 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 42 (predose) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 42 (4 hrs) | 442 ng/mL | Standard Deviation 197 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 42 (4 hrs) | 1.03 ng/mL | Standard Deviation 1.14 |
| Part 2: Sepiapterin | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 1 (predose) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 42 (4 hrs) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 28 (predose) | 9.70 ng/mL | Standard Deviation 4.18 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 1 (predose) | 8.52 ng/mL | Standard Deviation 4.36 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 1 (4 hrs) | 12.4 ng/mL | Standard Deviation 1.74 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 14 (predose) | 4.27 ng/mL | Standard Deviation 4.93 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 14 (4 hrs) | 11.3 ng/mL | Standard Deviation 8.7 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 28 (4 hrs) | 12.2 ng/mL | Standard Deviation 4.46 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 42 (predose) | 9.41 ng/mL | Standard Deviation 4.58 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | BH4: Day 42 (4 hrs) | 11.4 ng/mL | Standard Deviation 3.91 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 1 (predose) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 1 (4 hrs) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 14 (predose) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 14 (4 hrs) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 28 (predose) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 28 (4 hrs) | 0.000 ng/mL | Standard Deviation 0 |
| Part 2: Placebo | Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin | Sepiapterin: Day 42 (predose) | 0.000 ng/mL | Standard Deviation 0 |
Other Pre-specified
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
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)
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2: Sepiapterin | 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 203.62 |
Other Pre-specified
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
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)
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2: Sepiapterin | 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 |
Other Pre-specified
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
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 2: Sepiapterin | 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 |
| Part 2: Placebo | 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 | 4.03 μmol/L | Standard Error 46.496 |
p-value: <0.000195% CI: [-614.59, -369.87]Mixed Models Analysis
Other Pre-specified
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
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 2: Sepiapterin | 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 |
| Part 2: Placebo | 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 | 18.90 percent change | Standard Error 8.286 |
p-value: <0.000195% CI: [-97.72, -51.74]Mixed Models Analysis