An Open-Label Phase 3 Study of BMN 165 for Adults With PKU Not Previously Treated w/ BMN 165
Condition: Phenylketonuria
MeSH terms: Phenylketonurias
Study type: Interventional
Phase: Phase 3

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
    

Intervention name(s): BMN 165
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): rAvPAL-PEG; Pegvaliase
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: PKU; PEG-PAL; BioMarin; rAv-PAL PEG; BMN 165; open label; Prism301; Pegvaliase