A Phase 3 Randomized Crossover Study of Sepiapterin vs. Sapropterin in Phenylketonuria Patients Aged 2 Years and Older

The primary objective of this study is to compare the **efficacy** of sepiapterin to sapropterin in reducing blood phenylalanine (Phe) levels in participants with **phenylketonuria** (PKU). This is clinically relevant as managing blood Phe levels is crucial for preventing the neurological complications associated with PKU.

Secondary objectives include: - Evaluating the efficacy of sepiapterin in reducing blood Phe levels. - Assessing the safety and tolerability of sepiapterin. These objectives are important for understanding the potential benefits and risks associated with sepiapterin as a treatment option for PKU.

The clinical trial involves a total of **54 participants** diagnosed with **Phenylketonuria (PKU)**, a metabolic disorder characterized by elevated blood phenylalanine (Phe) levels. The study population includes both male and female participants aged 2 years and older. Participants were selected based on specific criteria, including a clinical diagnosis of PKU with documented hyperphenylalaninemia and a history of blood Phe levels of at least 600 µmol/L. The trial includes individuals who are willing to maintain their current diet throughout the study period. The population comprises a vulnerable group, indicating the inclusion of individuals who may require additional considerations during the trial. Participants are required to provide informed consent, and if applicable, assent with parental or legally designated representative consent. The trial aims to compare the efficacy of sepiapterin to sapropterin in reducing blood Phe levels in this population.

The clinical trial is a **Phase 3**, randomized, crossover, open-label, active-controlled study designed to compare the efficacy of sepiapterin to sapropterin in reducing blood phenylalanine (Phe) levels in participants with **phenylketonuria** (PKU) aged 2 years and older. The trial will involve two medicinal products: PTC923, a powder for oral use, and Kuvan 100 mg soluble tablets, both administered orally. The study is expected to commence recruitment on March 1, 2024, and conclude by March 1, 2025, with an estimated duration of 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, blood Phe levels, and clinical diagnosis of PKU. The trial will include multiple follow-up visits to monitor the primary endpoint, which is the mean change in blood Phe levels from baseline to Weeks 3 and 4 of each treatment period. Secondary endpoints will assess the proportion of participants achieving specific Phe level reductions and monitor adverse events, physical examinations, vital signs, 12-lead ECGs, and routine clinical laboratory assessments.

The expected length of participant involvement is up to 6 months, with conditions for early termination including non-compliance with the protocol, withdrawal of consent, or adverse events that necessitate discontinuation. Participants are required to maintain their current diet throughout the study and adhere to contraceptive guidelines if applicable. The trial's design ensures a robust comparison of the two treatments, with the crossover nature allowing each participant to receive both interventions, thereby serving as their own control.

The clinical trial involves the administration of **PTC923**, a pharmaceutical product in the form of a **powder for oral use**. The active substance in PTC923 is **(S)-2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one**, originating from chemical synthesis. The maximum daily dose is 60 mg/kg, with a total treatment period of up to 6 weeks. The medication is administered orally, and participant compliance is monitored throughout the study. PTC923 is designated as an orphan drug, with the designation number EU/3/21/2435, and is provided by PTC Therapeutics, Inc.

The comparator treatment in this study is **Kuvan 100 mg soluble tablets**, which are administered as an **oral solution**. The active ingredient in Kuvan is **sapropterin dihydrochloride**, also known by synonyms such as dapropterin hydrochloride and tetrahydrobiopterin dihydrochloride. The maximum daily dose for Kuvan is 20 mg/kg, with a treatment duration of up to 4 weeks. This product is manufactured by BioMarin International Limited and is also of chemical origin. The administration route is oral, and adherence to the dosing schedule is closely monitored to ensure accurate comparison with the experimental treatment.

The efficacy of the investigational product in the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the mean change in blood **Phe** (phenylalanine) levels from baseline to Weeks 3 and 4 of each treatment period, specifically the average of the last two weeks of each treatment period in Part 2 of the study. This will provide a direct measure of the treatment's impact on blood Phe levels over time.

Secondary endpoints include the proportion of participants with baseline blood Phe levels ≥600 µmol/L who achieve Phe levels <600 µmol/L after each treatment period in Part 2, and the proportion of participants reaching blood Phe <360 µmol/L after each treatment period in Part 2. These endpoints will help determine the effectiveness of the treatment in achieving clinically significant reductions in blood Phe levels.

Additional assessments will include adverse events (AEs), physical examinations, vital sign assessments, 12-lead ECGs, and routine clinical laboratory assessments. These evaluations will be conducted to monitor the safety and tolerability of the treatment throughout the study.