Long-Term Extension of a Dose Finding Study to Evaluate the Safety, Efficacy, and Tolerability of Multiple Doses of rAvPAL-PEG in Subjects With Phenylketonuria (PKU) (PAL-003)

• Safety based on the incidence of adverse events and clinically significant changes in vital signs [ Time Frame: Screening and weekly thereafter ] [ Designated as safety issue: Yes ]
• Antibody response [ Time Frame: Week 1 and monthly thereafter (eg. Week 4, 8, etc.) ] [ Designated as safety issue: No ]
  The presence of antibodies will be assessed.
• Pharmacokinetics [ Time Frame: Week 1 and weekly thereafter ] [ Designated as safety issue: No ]
  Plasma concentrations of rAvPAL-PEG will be measured when steady-state levels of Phe are attained.
• Safety based on clinically significant changes in laboratory test results [ Time Frame: Screening and monthly thereafter ] [ Designated as safety issue: Yes ]

• To evaluate the safety and tolerability of long-term administration of SC injections of rAvPAL-PEG in subjects with PKU. [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
• To evaluate the immune response to long-term administration of SC injections of rAvPAL-PEG in subjects with PKU who participated in Study PAL-002. [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
• To evaluate steady-state PK of rAvPAL-PEG in subjects with PKU. [ Time Frame: 24 months ] [ Designated as safety issue: No ]

This study is an extension of the dose-finding study (PAL-002), and also as an extension for the dose and frequency finding study (PAL-004). Administration of rAvPAL-PEG will be continued to assess whether long-term dosing of rAvPAL-PEG is safe and can maintain reduced blood Phe concentrations in PKU subjects.

Inclusion Criteria:

• Must have completed participation in PAL-002, PAL-004 or 165-205.
• 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.
• Willing and able to comply with all study procedures.
• 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.
• In generally good health as evidenced by physical examination, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and electrocardiogram (ECG) at Screening.

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 during study participation.
• A prior reaction that included systemic symptoms (eg, generalized hives, respiratory or gastrointestinal problems, hypotension, angioedema, anaphylaxis) to rAvPAL-PEG or a PEG-containing product.
• 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.
• Known hypersensitivity to rAvPAL-PEG or its excipients, including hypersensitivity reactions that necessitated early termination from PAL-002.
• Alanine aminotransferase (ALT) concentration > 2 times the upper limit of normal.
• Creatinine > 1.5 times the upper limit of normal.