Conditions: Phenylketonuria
Keywords: PKU PEG-PAL BioMarin rAv-PAL PEG BMN 165 open label Prism301 Pegvaliase
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 261
Healthy volunteers: no

Brief summary:
The BMN 165 clinical development program has been designed to demonstrate the safety and efficacy of BMN 165 in reducing blood Phe concentrations in patients 18 to 70 years old with hyperphenylalaninemia due to PKU. Study BMN 165-301 is a Phase 3, open-label, randomized study designed to further characterize the safety of BMN 165 during two induction, titration, and maintenance dose regimens in adults with PKU who have not had previous exposure to BMN 165 (naive). Subjects will be randomized (1:1) to titrate up to one of two dose regimens. Other key features of this study are the dose regimens chosen for induction and titration; the study duration; self administration of study drug; and the chosen tertiary objectives.

Detailed description:
Primary and Secondary Outcomes:

The primary objective of the study is the following:

* To characterize the safety and tolerability during induction, titration, and maintenance dosing in BMN 165-naïve subjects who self administer BMN 165 at dose levels of 20 mg/day and 40 mg/day

The secondary objective of the study is the following:

* To evaluate blood Phe concentration during induction, titration, and maintenance dosing in BMN 165-naïve subjects who self administer BMN 165 at dose levels of 20 mg/day and 40 mg/day

The tertiary objectives of the study are the following:

* Percentage of daily recommended intake for age of natural protein intake
* Dietary protein intake from medical food and intact food
* The ADHD-RS score (-Investigator Rated; inattentive subscale score, total score, and hyperactivity/impulsivity subscale score)
* POMS scores (-Observer Rated and -Subject Rated)
* Trough plasma concentrations of BMN 165

Primary Analysis:

All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The incidence of AEs will be summarized by system organ class, preferred term, relationship to study drug, and severity for the subjects who are randomized to the 40 mg/day dose, the 20 mg/day dose, and overall. A by-subject listing will be provided for those subjects who experience an SAE, including death, or experience an AE associated with early withdrawal from the study or study drug. Hypersensitivity AEs and AEs that result in dosing interruption or dose reduction are of interest, and the percentage of subjects who report these AEs will be presented.

Clinical laboratory data will be summarized by the type of laboratory test for the subjects who are randomized to the 40 mg/day dose, the 20 mg /day dose, and overall. Frequency and percentage of subjects who experience abnormal (ie, outside of reference range) and/or clinically significant abnormalities after study drug administration will be presented for each clinical laboratory test. For each clinical laboratory test, descriptive statistics will be provided for baseline and all subsequent post-baseline visits. Changes from baseline to the post-baseline visits will also be provided. Descriptive statistics, including clinically significant changes from baseline, of vital signs, physical examination results, ECG test results, and immunogenicity test results will also be provided in a similar manner. Additionally, antibodies and titers will be summarized at the scheduled time point.

Detailed statistical methods will be provided in the Statistical Analysis Plan (SAP).

Secondary Analysis:

The secondary efficacy endpoint is change from baseline to end of study in blood Phe concentration.

Baseline is defined as the average of blood Phe concentrations collected prior to dosing at the Screening Visit and on Day 1.

The primary analysis method for the secondary endpoint will use a repeated measures model, with change from baseline Phe as the dependent variable and dose (40 mg/day or 20 mg/day), study week, and baseline Phe as independent variables.

A responder analysis will be presented as a cumulative distribution function. The percentage of subjects with blood Phe concentration below "X" umol/L at the end of the study will be plotted and summarized for various "X" as a cumulative distribution function for each of the 2 doses and overall.

Detailed statistical methods will be provided in the SAP.

Tertiary Analyses:

The statistical analysis method for tertiary endpoints (protein intake; the ADHD-RS IV score) will be descriptive. More details regarding the analysis methods for the tertiary endpoints will be provided in the SAP.

Trough plasma concentrations of BMN 165 will be evaluated.

DMC The Data Monitoring Committee (DMC) will act in an advisory capacity to

BioMarin to monitor subject safety and the efficacy of BMN 165 in subjects who participate in Study BMN 165-301 .The DMC responsibilities may include the following:

* Review the study protocol, informed consent and assent documents, and plans for data monitoring
* Evaluate the progress of the trial; study data quality; timeliness; subject recruitment, accrual and retention; subjects' risk versus benefit; and other factors that could affect the study outcome
* Consider relevant information that may have an effect on the safety of the participants or the ethics of the study
* Protect the safety of the study participants in accordance with the stopping rules as defined in study protocol
* Make recommendations to BioMarin concerning continuation or termination of the study or other modifications of the study based on their observations
* If appropriate, conduct interim analysis of safety and efficacy

Arms:
arm 1: Subjects who meet the eligibility criteria will be randomized 1:1 to titrate to one of two dose regimens: 20 mg/day or 40 mg/day. The randomization will be stratified by the last available blood Phe concentration prior to Day 1 (600 to 900 μmol/L and \> 900 μmol/L). arm 2: Subjects who meet the eligibility criteria will be randomized 1:1 to titrate to one of two dose regimens: 20 mg/day or 40 mg/day. The randomization will be stratified by the last available blood Phe concentration prior to Day 1 (600 to 900 μmol/L and \> 900 μmol/L).

Interventions: intervention 1: BMN 165
Intervention descriptions: intervention 1: After informed consent, eligible subjects will be randomized (1:1) to titrate up to one of two dose regimens: 20 mg/day or 40 mg/day. All subjects will initiate IP at a fixed-dose of 2.5 mg/week for 4 weeks (Induction). After the Induction Period, subjects will enter the Titration Period (Weeks 5 up to 34) where they will increase their weekly BMN 165 dose to a daily dose regimen of 20 mg/day or 40 mg/day. The Titration Period will be individualized to each subject based on a minimum of 6 weeks (the amount of time it takes to reach a dose regimen of 20 mg/day with no dose interruptions) and up to 30 weeks (accounts for dose reduction or interruption due to AEs). Subjects will stop titration once they have achieved either the 20 mg/day or 40 mg/day dose regimen. The majority of subjects will maintain the 20 or 40 mg/day dose regimen for at least an additional 2 weeks until a minimum of approximately 26 weeks or a maximum of 36 weeks in the study.

Protocol document: