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

Tracking Information

• First Submitted Date: October 6, 2021
• First Posted Date: October 29, 2021
• Results First Submitted Date: November 3, 2023
• Results First Posted Date: January 10, 2024
• Last Update Posted Date: January 10, 2024
• Actual Study Start Date: September 30, 2021
• Actual Primary Completion Date: April 3, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 19, 2023)

• 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 [ Time Frame: 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 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: October 18, 2021)

Change From Baseline in Phe Levels at Part 2 Weeks 5 and 6 [ Time Frame: Baseline, Weeks 5 and 6 (average of the 2-week period) ]

Baseline blood Phe level will be the mean of Day -1 and Day 1 (predose) blood Phe levels.

Current Secondary Outcome Measures (submitted: December 19, 2023)

• 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 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 [ Time Frame: 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 [ 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 ]
• 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 ]
• 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 ]
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: October 18, 2021)

• Percentage of Participants With Baseline Phe Levels ≥600 micromoles (μmol)/liter (L) who Achieved Phe Levels <600 μmol/L at the End of the Double-Blind Treatment Period [ Time Frame: Baseline to Week 6 ]
• Change From Baseline in Mean Blood Phe Levels at Each PTC923 Dose Level (Average of the Each 2-Week Period in Part 2) [ Time Frame: Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 ]
  Baseline blood Phe level will be the mean of Day -1 and Day 1 (predose) blood Phe levels.

Current Other Pre-specified Outcome Measures (submitted: December 19, 2023)

• 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 [ Time Frame: 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 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 [ Time Frame: 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 [ Time Frame: 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 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 [ Time Frame: 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.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of PTC923 in Participants With Phenylketonuria
• Official Title: A Phase 3 Study of PTC923 in Subjects With Phenylketonuria
• 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).
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Phenylketonuria

Intervention

• Drug: PTC923
  PTC923 powder for oral use will be suspended in water or apple juice prior to administration.
• Drug: Placebo
  Placebo matching to PTC923

Study Arms

• Experimental: Part 1: PTC923
  Participants will receive PTC923 7.5 milligrams (mg)/kilogram (kg) (participants 0 to <6 months of age), 15 mg/kg (participants 6 to <12 months of age), 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.
  Intervention: Drug: PTC923
• Experimental: Part 2: PTC923
  Participants will receive PTC923 20 mg/kg daily for Weeks 1 and 2, then PTC923 40 mg/kg daily for Weeks 3 and 4, then PTC923 60 mg/kg daily for Weeks 5 and 6.
  Intervention: Drug: PTC923
• Placebo Comparator: Part 2: Placebo
  Participants will receive equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the PTC923 treatment arm.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 3, 2023): 157
• Original Estimated Enrollment (submitted: October 18, 2021): 178
• Actual Study Completion Date: May 3, 2023
• Actual Primary Completion Date: April 3, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Canada, Denmark, France, Georgia, Germany, Italy, Mexico, Netherlands, Portugal, Spain, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05099640
• Other Study ID Numbers: PTC923-MD-003-PKU; 2021-000474-29 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: PTC Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: PTC Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: PTC Therapeutics
• Verification Date: December 2023