Evaluation of Long-Term Neurocognitive Outcomes in Pediatric Phenylketonuria Patients Treated with (S)-2-Amino-6-(2-Hydroxypropanoyl)-7,8-Dihydropteridin-4(3H)-one
- Trial ID
- 2024-514435-20-00
- Protocol
- PTC923-PKU-401
- Sponsor
- PTC Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the long-term efficacy of **sepiapterin** in preserving neurocognitive functioning in children diagnosed with **phenylketonuria** (PKU) when treatment is initiated in early childhood. This is clinically relevant as maintaining neurocognitive function is crucial for the developmental outcomes and quality of life in children with PKU, a metabolic disorder that can lead to intellectual disability if not managed effectively.
Secondary objectives include evaluating the effect of sepiapterin on the quality of life (QOL) of the participants. Assessing QOL is important to understand the broader impact of the treatment on daily living and overall well-being, beyond the primary neurocognitive outcomes.
Participants
The clinical trial involves a total of **55 participants** diagnosed with **phenylketonuria** (PKU). The study population includes both male and female outpatients who are less than 10 years of age at the time of informed consent or assent form signature. Participants are required to have an established diagnosis of PKU with hyperphenylalaninemia, evidenced by specific blood phenylalanine (Phe) levels. The trial population was selected based on specific inclusion criteria, including age and baseline Full Scale Intelligence Quotient (FSIQ) scores for certain age groups. Participants must be willing to maintain a prescribed daily protein and Phe intake during the screening and part of the study. The trial also considers lifestyle factors such as dietary management, which is crucial for individuals with PKU. The study aims to evaluate the long-term efficacy of sepiapterin on preserving neurocognitive functioning in children when treatment is initiated in early childhood. The trial includes a vulnerable population, given the young age of the participants.
Plans and Procedures
The clinical trial is designed to evaluate the long-term efficacy of **sepiapterin** in preserving neurocognitive functioning in children diagnosed with **phenylketonuria** (PKU). This is a Phase 3b, open-label study, focusing on participants under the age of 10 years. The trial employs a controlled design, with participants receiving the investigational product, PTC923, in the form of a powder for oral use. The study aims to assess the mean change in full-scale intelligence quotient (FSIQ) over a two-year period, with secondary endpoints including changes in quality of life and phenylalanine levels.
The trial is expected to span from July 2025 to July 2032, with participant involvement lasting up to 72 months. The study begins with an inclusion visit, where eligibility is confirmed based on criteria such as age, baseline FSIQ score, and blood phenylalanine levels. Participants must have a documented diagnosis of PKU with hyperphenylalaninemia. Follow-up visits will occur periodically to monitor neurocognitive outcomes and other health parameters. The end-of-study visit will conclude the participant's involvement, assessing the long-term impact of the treatment.
Participants may be withdrawn from the study if they fail to comply with the study protocol, experience adverse effects, or if the investigator deems it necessary for their safety. The trial's primary objective is to determine the efficacy of sepiapterin in maintaining neurocognitive function, with the ultimate goal of improving the quality of life for children with PKU. The study's design ensures rigorous monitoring and data collection to support the evaluation of the investigational product's long-term benefits.
Treatment
The clinical trial involves the administration of the experimental medication **PTC923**, which is formulated as a **powder for oral use**. The active substance in PTC923 is **(S)-2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one**, a chemical compound. The medication is administered orally, with a maximum daily dose of 60 mg/kg. The treatment period extends up to 72 weeks. PTC923 is not a pediatric formulation, and it has been designated as an orphan drug under the designation number EU/3/21/2435. The medication is provided by PTC Therapeutics, Inc., and is intended for use in children with **phenylketonuria** (PKU) to evaluate its long-term efficacy in preserving neurocognitive functioning when treatment is initiated in early childhood.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of PTC923. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the impact of PTC923 on neurocognitive outcomes in the target population over the specified treatment duration.
Efficacy
The efficacy of the investigational product, **sepiapterin**, in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the mean change in full-scale intelligence quotient (FSIQ) over a 2-year period. This will be measured using the Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition (WPPSI-IV) for participants aged 30 months to less than 6 years, and the Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) for participants aged 6 to 16 years. These validated scales are designed to evaluate neurocognitive functioning in children with phenylketonuria (PKU).
Secondary endpoints include changes from baseline in the phenylketonuria quality of life (PKU-QOL) questionnaire score and the European Quality of Life - 5 Dimensions (EQ-5D) score over time. Additionally, the mean change in FSIQ will be assessed over a 4-year period, and changes in phenylalanine (Phe) levels will be monitored over time. These assessments will provide a comprehensive evaluation of the long-term efficacy of sepiapterin in preserving neurocognitive functioning and improving quality of life in the pediatric population with PKU.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Informed consent, and if necessary, assent (with parent/legally designated representative consent).
- Male or female outpatients <10 years of age at the time of informed consent/assent form signature.
- Parent(s) or legally designated representative(s) willing and able to comply with all study procedures.
- Women of childbearing potential, as defined in CTCG 2024: see protocol for more details; must have a negative pregnancy test at Screening and agree to abstinence or the use of at least 1 highly effective form of contraception (with a failure rate of <1% per year when used consistently and correctly); Highly effective contraception or abstinence must be continued for the duration of the study and for at least 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 at least 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period. Males who are abstinent will not be required to use a contraceptive method unless they become sexually active. Males who have undergone a vasectomy are not required to use a contraceptive method if at least 16 weeks post procedure.
- Willing to maintain prescribed daily protein/Phe during Screening and Part 1.
- For participants ≥1 month of age at Screening: Established diagnosis of PKU with hyperphenylalaninemia evidenced by at least 2 blood Phe measurement ≥600 μmol/L as documented in the medical history.
- For participants ≥1 month of age at Screening: A minimum of 1 documented blood Phe measurement <480 μmol/L within 1 month prior to Screening.
- For participants ≥1 month of age at Screening: Two screening blood Phe concentration values must be in the range ≥120 to ≤480 μmol/L.
- For participants <1 month of age at the time of informed consent/assent only: Blood Phe at newborn screening ≥600 μmol/L.
- For participants ≥30 months to <10 years of age: Baseline FSIQ score ≥80.
Exclusion Criteria
- The individual and/or parent(s)/legally designated representative(s), in the opinion of the investigator, is/are unwilling or unable to adhere to the requirements of the 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.
- Any clinically significant laboratory abnormality as determined by the investigator. In general, each laboratory value from screening and baseline chemistry and hematology panels should fall within the limits of the normal laboratory reference range, unless deemed not clinically significant by the investigator.
- Any past medical history of an abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated (Bedside Schwartz Equation) glomerular filtration rate <60 mL/min/1.73 m2.
- Major surgery within 90 days prior to Screening visit.
- History of allergies or adverse reactions to any of the ingredients or excipients of synthetic tetrahydrobiopterin (BH4) or sepiapterin.
- Inability to tolerate oral medication.
- A female who is pregnant or breastfeeding or considering pregnancy.
- Current use of methotrexate, pemetrexed, trimetrexate, or other dihydrofolate reductase inhibitors.
- Serious neuropsychiatric illness (eg, major depression) not currently under medical control or other concurrent disease or condition 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.
- Treatment with BH4 supplementation (sapropterin, KUVAN) within 3 months prior to Screening.
- Current participation in another investigational drug study or use of any investigational agent within 30 days prior to Screening.
- 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.
- Previous treatment for >6 weeks with sepiapterin (ie, SEPHIENCE™)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Jul 2025 | 15 |
 Ireland | Recruiting | 01 Jul 2025 | 15 |
 Poland | Recruiting | 01 Jul 2025 | 15 |
 Sweden | Not Yet Recruiting | 01 Jul 2025 | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Sephience 1 000 mg oral powder in sachet | Test | ORAL POWDER IN SACHET | ORAL | 60 | 72 | PRD12584325 |
Sephience 250 mg oral powder in sachet | Test | ORAL POWDER IN SACHET | ORAL | 60 | 72 | PRD12584229 |