Phase 3 Open-Label Evaluation of PTC923 (Sepiapterin) for Long-Term Safety and Dietary Impact in Phenylketonuria Patients

Trial ID: 2023-509229-31-00
Protocol: PTC923-MD-004-PKU
Sponsor: PTC Therapeutics Inc.

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Diseases & Conditions

Phenylketonuria

Objectives

The primary objective of this Phase 3 open-label study is to evaluate the long-term **safety** of PTC923 in subjects with **Phenylketonuria** (PKU). This is clinically relevant as it aims to ensure that the treatment is safe for long-term use in managing this metabolic disorder. Additionally, the study seeks to assess changes from baseline in dietary phenylalanine/protein consumption, which is crucial for understanding the impact of PTC923 on dietary management in PKU patients.

Secondary objectives include:

Evaluating the effect of PTC923 on quality of life (QOL) using the Phenylketonuria-quality of life (PKU-QOL) questionnaire in subjects whose primary language is English, Turkish, Dutch, German, Spanish, Italian, Portuguese, or French, across various age groups.
Assessing the effect of PTC923 on QOL using the European Quality of Life - 5 Dimensions (EQ-5D) across different age groups.
Evaluating the pharmacokinetics of sepiapterin and tetrahydrobiopterin (BH4) following PTC923 dosing.
Assessing the taste, palatability, and acceptability of PTC923 in non-feeder subjects under 18 years of age.

These secondary objectives are important for understanding the broader impacts of PTC923 on patient well-being and treatment adherence.

Participants

The clinical trial involves a total of **160 participants** diagnosed with **Phenylketonuria (PKU)**, a metabolic disorder. The study population includes both male and female subjects of any age, encompassing a broad age range. Participants were selected based on a clinical diagnosis of PKU, with documented hyperphenylalaninemia (HPA) evidenced by at least two past blood phenylalanine (Phe) measurements equal to or greater than 600 µmol/L. The trial includes individuals who are willing to maintain their current diet throughout the study unless instructed otherwise by the investigator. The study population is characterized by its inclusion of a vulnerable population, indicating special considerations in the trial design. Participants are required to comply with the protocol and study procedures, and specific contraceptive measures are mandated for women of childbearing potential and sexually active males to ensure safety during the trial period. The trial aims to evaluate the long-term safety of PTC923 and assess changes in dietary Phe/protein consumption among the participants.

Plans and Procedures

The clinical trial is designed as a **Phase 3 open-label study** to evaluate the long-term safety and efficacy of **PTC923** in individuals diagnosed with **phenylketonuria (PKU)**. The trial will assess changes from baseline in dietary phenylalanine/protein consumption and monitor the safety profile of the treatment. The study is expected to span approximately four years, with an estimated end date in March 2026. Participants will be involved in the trial for a maximum treatment period of 24 months, during which they will receive **PTC923** in the form of a **powder for oral use**. The maximum daily dose is set at 60 mg/kg.

The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to conclude participation. The screening visit will involve obtaining informed consent, verifying the clinical diagnosis of PKU, and ensuring compliance with inclusion criteria, such as maintaining a stable diet and using effective contraception for women of childbearing potential. Follow-up visits will occur at predetermined intervals to assess treatment-emergent adverse events, conduct clinical laboratory tests, and evaluate changes in dietary intake. The end-of-study visit will finalize data collection and ensure participant safety post-treatment.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or choose to discontinue participation. The primary endpoints include the number and severity of treatment-emergent adverse events and changes in dietary phenylalanine/protein consumption. Secondary endpoints will assess quality of life changes using the PKU-QOL questionnaire and EQ-5D, as well as pharmacokinetic assessments of sepiapterin and BH4 concentrations. The study aims to provide comprehensive data on the long-term use of **PTC923** in managing PKU, contributing valuable insights into its safety and efficacy profile.

Treatment

The clinical trial involves the administration of the experimental medication **PTC923**, which is a **powder for oral use**. The active substance in PTC923 is **(S)-2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one**, also known as synthetic sepiapterin. This compound is of chemical origin and is provided by PTC Therapeutics, Inc. The medication is administered orally, with a maximum daily dose of 60 mg/kg. The treatment period extends up to 24 weeks. The study aims to evaluate the long-term safety of PTC923 in subjects with phenylketonuria (PKU) and assess changes from baseline in dietary phenylalanine/protein consumption.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy or a placebo, although specific details on these are not provided in the data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the efficacy and safety of PTC923, with a focus on its potential as an orphan drug for the treatment of PKU.

Efficacy

The efficacy of the clinical trial evaluating PTC923 (Sepiapterin) in patients with **Phenylketonuria** (PKU) will be assessed through several primary and secondary endpoints. The primary efficacy endpoint is the change from baseline in dietary phenylalanine (Phe) and protein consumption, which will be measured during the Dietary Phe Tolerance Assessment period. This assessment aims to determine the impact of PTC923 on the dietary management of PKU.

Secondary efficacy endpoints include changes from baseline in quality of life (QOL) using the PKU-QOL questionnaire for subjects whose primary language is English, Turkish, Dutch, German, Spanish, Italian, Portuguese, or French. The questionnaire is tailored to different age groups: Parent PKU-QOL for ages 6 to 8, Child PKU-QOL for ages 9 to 11, Adolescent PKU-QOL for ages 12 to 17, and Adult PKU-QOL for ages 18 and older. Additionally, changes in QOL will be assessed using the EQ-5D tool, with versions adapted for different age groups: EQ-5D-Y Proxy Version 1 for ages 3 to 7, EQ-5D-Y for ages 8 to 15, and EQ-5D-5L for ages 16 and older. Further secondary endpoints include pharmacokinetic assessments of sepiapterin and BH4 concentrations in plasma following dosing, as well as acceptability scores for taste and palatability in subjects under 18 years of age.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Informed consent and assent (if necessary, at the investigator’s discretion [ie, for children]) with parental/legal guardian consent
Male or female subjects of any age
Clinical diagnosis of PKU with HPA documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L
Women of childbearing potential, as defined in the Clinical Trial Facilitation Group guidance (CTFG 2020), must have a negative pregnancy test at study entry and agree to abstinence or the use of at least one highly effective form of contraception (with a failure rate of <1% per year when used consistently and correctly): • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: − Oral − Intravaginal − Transdermal • Progestogen-only hormonal contraception associated with inhibition of ovulation: − Oral − Injectable − Implantable • Intrauterine device • Intrauterine hormone-releasing system • Bilateral tubal occlusion • Vasectomized partner with confirmed azoospermia Highly effective contraception or abstinence must be continued for the duration of the study and for up to 90 days after the last dose of the study drug. All females will be considered of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group without other known or suspected cause) or have been permanently sterilized surgically (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy).
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 and able to comply with the protocol and study procedures.
Willing to continue current diet unchanged while participating in the study (unless specifically instructed to change diet during the study by the investigator).
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.

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Exclusion Criteria

The individual, in the opinion of the investigator, is unwilling or unable to adhere to the requirements of the study
Inability to tolerate oral medication
A female who is pregnant or breastfeeding, or considering pregnancy
Serious neuropsychiatric illness (eg, major depression) not currently under medical control, that in the opinion of the investigator or PTC, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject
Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 mL/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 subject’s ability to participate in the study or increase the risk of participation for that subject
Requirement for concomitant treatment with any drug known to inhibit folate synthesis (eg, methotrexate)
Concomitant treatment with BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ)
Additional criteria for subjects 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
Additional criteria for subjects who did not participate in a feeder study: History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy
Additional criteria for subjects who did not participate in a feeder study: History of allergies or adverse reactions to synthetic BH4 or sepiapterin
Additional criteria for subjects who did not participate in a feeder study: Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to Screening
Additional criteria for subjects who did not participate in a feeder study: 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
Additional criteria for subjects who did not participate in a feeder study: Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR <60 mL/min/1.73 m2. In subjects ≥18 years of age, the Modification of Diet in Renal Disease Equation should be used to determine GFR. In subjects <18 years of age, the Bedside Schwartz Equation should be used to determine GFR.
Additional criteria for subjects who did not participate in a feeder study: 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-alpha-carbinolamine dehydratase genes
Additional criteria for subjects who did not participate in a feeder study: Major surgery within the prior 90 days of screening
Additional criteria for subjects who did not participate in a feeder study: Unwillingness to washout from BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ)

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Czechia	Not Recruiting	14 Feb 2022	6
Denmark	Not Recruiting	14 Feb 2022	3
France	Not Recruiting	14 Feb 2022	10
Germany	Not Recruiting	14 Feb 2022	14
Italy	Not Recruiting	14 Feb 2022	4
The Netherlands	Not Recruiting	14 Feb 2022	—
Poland	Not Recruiting	14 Feb 2022	18
Portugal	Not Recruiting	14 Feb 2022	4
Slovenia	Not Recruiting	14 Feb 2022	6
Spain	Not Recruiting	14 Feb 2022	7