Evaluation of Pegvaliase Subcutaneous Injections for Safety and Efficacy in Adolescents with Phenylketonuria: A Phase 3 Multi-Center Randomized Study

The primary objectives of this Phase 3 multi-center study are to evaluate the **efficacy** and **safety** of subcutaneous injections of pegvaliase in adolescent subjects aged 12-17 with **Phenylketonuria (PKU)**. Assessing the efficacy of pegvaliase is clinically relevant as it may offer a therapeutic option for managing PKU, a metabolic disorder characterized by elevated levels of phenylalanine, which can lead to neurological complications if untreated. Evaluating the safety profile is crucial to ensure that the treatment does not pose undue risks to the adolescent population.

The secondary objectives include:

• Characterizing total dietary protein intake in adolescent participants with PKU after pegvaliase treatment, which is important for understanding the nutritional management of PKU in conjunction with pharmacotherapy.
• Characterizing the pharmacokinetics (PK) of pegvaliase in adolescent participants with PKU, which provides insights into the drug's absorption, distribution, metabolism, and excretion, informing dosing regimens and optimizing therapeutic outcomes.

The clinical trial involves a total of **51 participants** diagnosed with **Phenylketonuria (PKU)**. The study population comprises both male and female adolescents, aged 12 to 17 years in the United States and 12 to 15 years outside the United States. Participants are generally in good health, as confirmed by physical examinations, clinical laboratory evaluations, and ECG tests conducted during the screening phase. The trial population was selected based on their inability to maintain recommended blood phenylalanine levels despite existing management strategies, including sapropterin dihydrochloride treatment and a phenylalanine-restricted diet. Participants are required to be willing and able to adjust their dietary and medical protein intake according to the study protocol, under the guidance of a study dietician. Additionally, if participants are on medication for ADHD, depression, or other psychiatric disorders, they must have been on a stable dose for at least eight weeks prior to enrollment and be willing to maintain this dose unless medically indicated. The study includes both genders and requires females of childbearing potential to have a negative pregnancy test at screening and to undergo additional pregnancy tests during the study. An adult observer is also required to monitor the participant during and after study drug administration. The trial does not exclude vulnerable populations, ensuring a comprehensive evaluation of the study drug's efficacy and safety in the target demographic.

The clinical trial is designed to evaluate the **safety** and **efficacy** of subcutaneous injections of **pegvaliase** in adolescent subjects aged 12 to 17 years with **phenylketonuria** (PKU). This Phase 3 study employs an open-label, randomized, two-arm design, comparing active treatment with a diet-only control. The trial is expected to span from December 2022 to August 2027, with a maximum treatment period of 215 days for each participant. The study involves multiple visits, starting with a screening visit to confirm eligibility based on criteria such as age, diagnosis of PKU, and failure to maintain recommended blood phenylalanine levels. Participants must also demonstrate willingness to comply with dietary adjustments and study procedures.

Following the screening, eligible participants will be randomized into either the active treatment group receiving **pegvaliase** or the control group adhering to a diet-only regimen. The study includes regular follow-up visits to monitor safety and efficacy outcomes, such as changes in dietary protein intake and plasma phenylalanine levels. Safety assessments will include evaluations of adverse events, laboratory test results, vital signs, physical examinations, and electrocardiograms. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of all study endpoints.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide robust data on the therapeutic potential of **pegvaliase** in managing PKU, contributing to the understanding of its safety and efficacy in the adolescent population.

The clinical trial involves the administration of **Palynziq**, a solution for injection containing the active substance **pegvaliase**. This experimental medication is provided in pre-filled syringes and is available in three different dosages: 2.5 mg, 10 mg, and 20 mg. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous. The maximum daily dose for the 2.5 mg and 10 mg formulations is 10 mg, while the 20 mg formulation has a maximum daily dose of 20 mg. The treatment period for each dosage is up to 215 days. The medication is manufactured by BioMarin International Limited and is specifically labeled for study purposes.

In this study, the experimental treatment is compared against a diet-only control group. The trial is designed to evaluate the safety and efficacy of pegvaliase in adolescent participants with **phenylketonuria** (PKU). No placebo or other comparator treatments are used in this study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The study aims to provide insights into the therapeutic potential of pegvaliase in managing PKU in the specified population.

The efficacy of **pegvaliase** in the clinical trial will be assessed through a series of predefined endpoints. The primary endpoint focuses on safety, evaluated by assessing adverse events (AEs), serious adverse events (SAEs), laboratory test results including chemistry, hematology, and urinalysis, vital signs, physical examination, electrocardiogram (ECG), and anti-BMN165 immunogenicity test results. Secondary endpoints include the change from baseline in total dietary protein intake, encompassing both medical food and intact food, as well as plasma samples for trough pharmacokinetics (PK).