A Study of PTC923 in Participants With Phenylketonuria

A Phase 3 Study of PTC923 in Subjects With Phenylketonuria

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).

Study Overview

• Status: Completed
• Conditions: Phenylketonuria
• Intervention / Treatment: Drug: PTC923; Drug: Placebo

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
• Enrollment (Actual): 157
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • South Australia
    • Adelaide, South Australia, Australia, SA 5000
      • PARC Clinical Research
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Brazil
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre
  • São Paulo
    • Ribeirão Preto, São Paulo, Brazil, 14051-140
      • Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo
• Canada
  • Alberta
    • Calgary, Alberta, Canada, AB T2M 0L6
      • Metabolics and Genetics in Calgary (MAGIC) Clinic, Ltd.
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children University of Toronto, Adult Clinic: The Fred A Litwin Family Centre in Genetic Medicine University Health Network & Mt. Sinai Hospital
• Denmark
  • Copenhagen, Denmark, DK-2100
    • Copenhagen University Hospital, Rigshospitalet
• France
  • Centre-Val De Loire
    • Tours, Centre-Val De Loire, France, 37000
      • Bretonneau Hospital - CHRU de Tours
    • Tours, Centre-Val De Loire, France, 37044
      • CHRU de Tours- Hôpital Pédiatrique de Clocheville
• Georgia
  • Tbilisi, Georgia, 159
    • Pediatric Surgery Center
• Germany
  • Hamburg, Germany, 20246
    • University Children's Hospital Hamburg Eppendorf (Kinder-UKE) Klinik für Kinder- und Jugendmedizin (Kinder-UKE)
  • Heidelberg, Germany, 69120
    • Universitätsklinikum Heidelberg / Zentrum für Kinder- und Jugendmedizin / Sektion für Neuropädiatrie & Stoffwechselmedizin
  • Münster, Germany, 48149
    • Universitätsklinikum Münster
• Italy
  • Lazio
    • Rome, Lazio, Italy, 00185
      • Policlinico Umberto I
  • Veneto
    • Padua, Veneto, Italy, 35128
      • Division of Inherited Metabolic Diseases, Azienda Ospedaliera-Università Padova
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44670
      • PanAmerican Clinical Research
  • Mexico City
    • Benito Juarez, Mexico City, Mexico, 3310
      • Grupo Medico Camino Sc
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • UMCG Beatrix Children's Hospital
• Portugal
  • Douro Litoral
    • Porto, Douro Litoral, Portugal, 4099-001
      • Centro Hospitalar Universitário Do Porto, Epe
  • Estremadura
    • Lisboa, Estremadura, Portugal, 1649-035
      • CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria,
    • Lisboa, Estremadura, Portugal, 1649-035
      • CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria
• Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Esplugues De Llobregat
    • Barcelona, Esplugues De Llobregat, Spain, 8950
      • Hospital Sant Joan de Deu
• Turkey
  • Adana, Turkey, 1130
    • Cukurova Üniversity Balcali Hospital Health Application and Research Center
  • Ankara
    • Altındağ, Ankara, Turkey, 6230
      • Hacettepe University Medical Faculty
    • Yenimahalle, Ankara, Turkey, 6560
      • Gazi Üniversitesi Tıp Fakültesi
  • Istanbul
    • Fatih, Istanbul, Turkey, 34098
      • İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi
  • Izmir
    • Bornova, Izmir, Turkey, 35100
      • Ege University Faculty of Medicine Children Hospital
• United Kingdom
  • Birmingham, United Kingdom, B4 6DH
    • Birmingham Children's Hospital NHS Foundation Trust
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital
• United States
  • California
    • Stanford, California, United States, 94304
      • Stanford University Center for Academic Medicine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado and the Children's Hospital CO
  • Florida
    • Gainesville, Florida, United States, 32608
      • UF College of Medicine, Department of Pediatrics Division of Genetics and Metabolism
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New York
    • New York, New York, United States, 01009
      • Icahn School of Medicine at Mount Sinai (ISMMS)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center of Texas
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah, Division of Medical Genetics (pediatric and adult clinic)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: PTC923; PTC923 powder for oral use will be suspended in water or apple juice prior to administration.
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.	Drug: PTC923; PTC923 powder for oral use will be suspended in water or apple juice prior to administration.
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.	Drug: Placebo; Placebo matching to PTC923

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Weeks 5 and 6 (average of the 2-week period)
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.	Weeks 5 and 6 (average of the 2-week period)
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.	Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)
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.	Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)
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)	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.	Baseline up to Day 42

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Weeks 5 and 6 (average of the 2-week period)
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.	Baseline, Weeks 5 and 6 (average of the 2-week period)
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.	Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)
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.	Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)

Collaborators and Investigators

• Sponsor: PTC Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2021
• Primary Completion (Actual): April 3, 2023
• Study Completion (Actual): May 3, 2023

Study Registration Dates

• First Submitted: October 6, 2021
• First Submitted That Met QC Criteria: October 18, 2021
• First Posted (Actual): October 29, 2021

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: PTC923-MD-003-PKU; 2021-000474-29 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No