Dose-Finding Study to Evaluate the Safety, Efficacy, & Tolerability of Multiple Doses of rAvPAL-PEG in Subjects With PKU
Condition: Phenylketonuria
MeSH terms: Phenylketonurias
Intervention: rAvPAL-PEG 0.001 mg/kg; rAvPAL-PEG 0.003 mg/kg; rAvPAL-PEG 0.01 mg/kg; rAvPAL-PEG 0.03 mg/kg; rAvPAL-PEG 0.1 mg/kg
Intervention description: In Part 1, the planned starting dose levels is 0.001 mg/kg; In Part 1, the planned starting dose levels is 0.003 mg/kg; In Part 1, the planned starting dose levels is 0.01 mg/kg; In Part 1, the planned starting dose levels is 0.03 mg/kg; In Part 1, the planned starting dose levels is 0.1 mg/kg
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 16 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: PKU; PEG PAL; BioMarin

Summary:

      The purpose of this study is to evaluate whether weekly injections of phenylalanine ammonia
      lyase (rAvPAL-PEG) can reduce blood phenylalanine concentrations in PKU subjects and whether
      repeated administration is safe.
    

Eligibility criteria:

        Inclusion Criteria:

          -  For subjects who did not participate in PAL-001, diagnosis of PKU with both of the
             following: Current blood Phe concentration of ≥ 600 mmol/L at Screening and average
             blood Phe concentration of ≥ 600 µmol/L over the past 3 years, using available data.

          -  For subjects who did not participate in PAL-001, evidence that the subject is a
             non-responder to Kuvan® treatment (ie, 4 weeks of treatment with 20 mg/kg/day of
             Kuvan®, insufficient response per investigator determination, and treatment end date ≥
             14 days prior to Day 1 [ie, first dose]). Subjects who have had a previous response to
             Kuvan® treatment but are not currently taking Kuvan® because of noncompliance and have
             been off treatment for ≥ 6 months prior to Screening are eligible for participation.

          -  Willing and able to provide written, signed informed consent, or, in the case of
             participants under the age of 18, provide written assent (if required) and written
             informed consent by a parent or legal guardian, after the nature of the study has been
             explained, and prior to any research-related procedures.

          -  Between the ages of 16 and 55 years, inclusive.

          -  Females of childbearing potential must have a negative pregnancy test at Screening and
             be willing to have additional pregnancy tests during the study. Females considered not
             of childbearing potential include those who have been in menopause at least 2 years,
             or had tubal ligation at least 1 year prior to Screening, or who have had total
             hysterectomy.

          -  Sexually active subjects must be willing to use an acceptable method of contraception
             while participating in the study.

          -  Maintained a stable diet with no significant modifications during the 4 weeks
             preceding the administration of study drug.

          -  In generally good health as evidenced by physical examination, clinical laboratory
             evaluations (hematology, chemistry, and urinalysis), and electrocardiogram (ECG) at
             Screening.

          -  Willing and able to comply with study procedures.

        Exclusion Criteria:

          -  Use of any investigational product (with the exception of rAvPAL-PEG) or
             investigational medical device within 30 days prior to Screening, or requirement for
             any investigational agent prior to completion of all scheduled study assessments.

          -  Use of any medication that is intended to treat PKU within 14 days prior to the
             administration of study drug.

          -  Use or planned use of any injectable drugs containing PEG (other than rAvPAL-PEG),
             including Depo-Provera, within 3 months prior to Screening and during study
             participation.

          -  A prior reaction that included systemic symptoms (eg, respiratory or gastrointestinal
             problems, hypotension, angioedema, anaphylaxis) to rAvPAL-PEG or a PEG containing
             product. Subjects with a prior systemic reaction of generalized rash may be eligible
             for participation per the discretion of the Principal Investigator in consultation
             with the Sponsor's Medical Officer.

          -  Pregnant or breastfeeding at Screening or planning to become pregnant (self or
             partner) or to breastfeed at any time during the study.

          -  Concurrent disease or condition that would interfere with study participation or
             safety (eg, history or presence of clinically significant cardiovascular, pulmonary,
             hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic,
             neurological, oncologic, or psychiatric disease).

          -  Any condition that, in the view of the PI, places the subject at high risk of poor
             treatment compliance or of not completing the study.

          -  Alanine aminotransferase (ALT) concentration > 2 times the upper limit of normal.

          -  Creatinine > 1.5 times the upper limit of normal.