A Long-Term Safety Study of PTC923 in Participants With Phenylketonuria

A Phase 3 Open-Label Study of PTC923 (Sepiapterin) in Phenylketonuria

The main purpose of this study is to evaluate the long-term safety of PTC923 in participants with phenylketonuria, and to evaluate the changes from baseline in dietary phenylalanine (Phe)/protein consumption.

Study Overview

• Status: Active, not recruiting
• Conditions: Phenylketonuria
• Intervention / Treatment: Drug: PTC923

Detailed Description

Eligible participants are:

Feeder participants: those who have completed a Phase 3 PTC Therapeutics (PTC) sponsored feeder study.

Non-feeder controlled participants: those who have not completed a feeder study and have blood Phe levels <360 μmol/L at study entry.

Non-feeder uncontrolled participants: those who have not completed a feeder study and have blood Phe levels ≥360 μmol/L at study entry.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane
    • South Brisbane, Brisbane, Australia
      • The Queensland Children's Hospital
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • South Australia
    • Adelaide, South Australia, Australia, SA 5000
      • PARC Clinical Research
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's 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, T2E 7Z4
      • Metabolics and Genetics in Calgary (MAGIC) Clinic, Ltd.
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital Hamilton Health Sciences
    • 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
• Czechia
  • Prague, Czechia, 100 34
    • Fakultní nemocnice Královské Vinohrady Klinika dětí a dorostu Ambulance pro léčbu PKU a HPA
• Denmark
  • Copenhagen, Denmark, DK-2100
    • Copenhagen University Hospital, Rigshospitalet
• France
  • Paris, France, 75015
    • Hôpital Necker-Enfants Malades - Centre de Référence des Maladies Héréditaires du Métabolisme
• Georgia
  • Tbilisi, Georgia, 0159
    • Medical Genetics and Laboratory Diagnostics 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
    • Universitatsklinikum Munster
• Italy
  • Rome, Italy, 00185
    • Department of Human Neuroscience, Child and Adolescent Neuropsychiatry, Policlinico Umberto I
  • Veneto
    • Padua, Veneto, Italy, 35129
      • Azienda Ospedaliera-Universita Padova
• Japan
  • Multiple Locations, Japan
    • PTC Clinical Site 1
  • Multiple Locations, Japan
    • PTC Clinical Site 2
  • Multiple Locations, Japan
    • PTC Clinical Site 3
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44670
      • PanAmerican Clinical Research
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • UMCG Beatrix Children's Hospital
• Poland
  • Szczecin, Poland, 71-252
    • Pomorski Uniwersytet Medyczny w Szczecinie Centrum Wsparcia Badań Klinicznych
• Portugal
  • Porto, Portugal, 4099-001
    • Centro Hospitalar Universitario do Porto, EPE
  • Estremadura
    • Lisbon, Estremadura, Portugal, 1649-035
      • CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria,
    • Lisbon, Estremadura, Portugal, 1649-035
      • CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Univerzitetni klinicni center Ljubljana
• Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Seville, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Esplugues de Llobregat
    • Barcelona, Esplugues de Llobregat, Spain, 08950
      • Hospital Sant Joan de Déu
• Turkey (Türkiye)
  • Adana, Turkey (Türkiye), 01330
    • Çukurova Üniversitesi Tıp Fakültesi Balcalı Hastanesi
  • Ankara
    • Altındağ, Ankara, Turkey (Türkiye), 06230
      • Hacettepe University Medical Faculty
    • Yenimahalle, Ankara, Turkey (Türkiye), 06500
      • Gazi Üniversitesi Tıp Fakültesi
  • Istanbul
    • Fatih, Istanbul, Turkey (Türkiye), 34098
      • İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi
  • İzmir
    • Bornova, İzmir, Turkey (Türkiye), 35100
      • Ege University Faculty of Medicine Children Hospital
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital NHS Foundation Trust
  • Birmingham, United Kingdom
    • University Hospitals Birmingham NHS Foundation Trust
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Gainesville, Florida, United States, 32610
      • UF College of Medicine, Department of Pediatrics Division of Genetics and Metabolism
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine Department of Medical and Molecular Genetics
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New York
    • New York, New York, United States, 10009
      • Icahn School of Medicine at Mount Sinai (ISMMS)
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Clinical diagnosis of PKU 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 the 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 (unless specifically instructed to change diet during the study by the investigator).

Exclusion Criteria:

• Inability to tolerate oral medication.
• 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 PTC, 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] min as estimated most recently during qualifying participation in a feeder study) and/or under care of a nephrologist.
• Any other condition that in the opinion of the investigator or PTC, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant.
• Requirement for concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate).
• Concomitant treatment with tetrahydrobiopterin (BH4) supplementation (for example, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ).

Additional criteria for non-feeder participants who did not participate in a feeder study:

• 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 BH4 or sepiapterin.
• Any clinically significant laboratory abnormality as determined by the investigator.
• Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR <60 milliliters (mL)/minute/1.73 square meter (m^2).

Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic mutations in 6-pyruvoyltetrahydropterin synthase, recessive GTP cyclohydrolase I, sepiapterin reductase, quinoid dihydropteridine reductase, or pterin-4-alphacarbinolamine dehydratase genes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: PTC923; Participants will receive PTC923 7.5 mg/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 a minimum of 12 months or until participant experiences lack of efficacy, adverse events (AEs) that lead to discontinuation, withdraws from treatment, or PTC923 is authorized and commercially available in the specific country.

Drug: PTC923; PTC923 powder for oral use will be suspended in water or apple juice prior to administration.; Other Names: Sepiapterin; Sephience

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Dietary Phe/Protein Consumption at Week 26, Measured During Phe Tolerance Assessment Period	Phe tolerance is defined as the total amount of dietary Phe (milligrams [mg]/kilogram [kg] per day) ingested while maintaining blood Phe levels within the range of 40 to 360 micromoles (μmol)/liter (L) (defined as ≥40 to <360 μmol/L).	Baseline, Week 26
Number of Treatment-Emergent Adverse Events (TEAEs)	A TEAE is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or disease in a study participant who is administered study drug in this study	Baseline up to end of study (up to 4 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in QOL Using the European Quality of Life - 5 Dimensions (EQ-5D) at Months 8, 14, 20, 26, 32, and 38	QOL will be assessed using the EQ-5D (EQ-5D-Y Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 15 years]; EQ-5D-5L ([≥16 years]).	Baseline, Months 8, 14, 20, 26, 32, and 38
Change From Baseline in Quality of Life (QOL) Using Phenylketonuria-Quality of Life (PKU-QOL) Questionnaire at Months 8, 14, 20, 26, 32, and 38	QOL using PKU-QOL questionnaire will be assessed in the subset of participants who are able to complete the PKU-QOL (that is, participants whose primary language is English [British or American], Turkish, Dutch, German, Spanish, Italian, Portuguese, or French) (ages 6 to 8 years Parent PKU-QOL; ages 9 to 11 years Child PKU-QOL; ages 12 to 17 years Adolescent PKU-QOL; ages ≥18 years Adult PKU-QOL).	Baseline, Months 8, 14, 20, 26, 32, and 38
Palatability of PTC923	For participants <5 years of age, palatability will be indirectly assessed by the parent(s)/caregiver(s) of participants using the following: On the basis of the reaction/facial expression of your child, do you think that the medication is (pleasant, not sure, unpleasant)?	Month 1 Day 1
Acceptability/Ease of Administration of PTC923	For all participants <12 years of age, parent(s)/caregiver(s) will rate the acceptability/ease of administration, with the following question: Do you sometimes have problems in giving the medication to your child because he/she refuses to take it or throws it up? (Yes/No).	Month 1 Day 1
Taste/Flavor Assessment Using a Facial Hedonic Scale	For participants ≥5 to <18 years of age who are able to comply with the instructions, the participant will rate the taste/flavor using a facial hedonic scale (5=really good; 4=good; 3=not sure; 2=bad; 1=really bad).	Month 1 Day 1
Plasma Sepiapterin Concentration		Month 1 Day 1 up to Month 11 Day 1
Plasma BH4 Concentration		Month 1 Day 1 up to Month 11 Day 1

Collaborators and Investigators

• Sponsor: PTC Therapeutics

Publications and helpful links

General Publications

• van Spronsen F, Peters H, Margvelashvili L, Agladze D, Schwartz IVD, Gizewska M, Hamazaki T, Guilder L, MacDonald A, Vijay S, Inwood A, Minami M, Fjellbirkeland O, Lund A, Lah M, Thomas JA, Longo N, Kiykim E, Ishige M, Burlina A, Belanger-Quintana A, Rutsch F, Opladen T, Mungan H, Ezgu F, Bratkovic D, Chakrapani A, Ito T, Guimas A, Zori R, Tchan M, Sacharow S, Oliveira A, Janeiro P, Guerra IC, Plana JC, Yildiz Y, Canda E, Khan A, Vockley J, Breilyn MS, Manti F, Larkin A, Hughes C, Liu E, Gao L, Ingalls K, Smith N, Muntau AC. Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: Interim results from the phase 3 APHENITY Extension Study. Genet Med. 2026 Apr;28(4):101683. doi: 10.1016/j.gim.2026.101683. Epub 2026 Jan 12.

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2022
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: December 8, 2021
• First Submitted That Met QC Criteria: December 8, 2021
• First Posted (Actual): December 21, 2021

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 22, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Amino Acid Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Phenylketonurias; sepiapterin
• Other Study ID Numbers: PTC923-MD-004-PKU; 2021-000497-28 (EudraCT Number); 2023-509229-31-00 (Other Identifier: CTIS 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