Safety, Tolerability, and Efficacy Study of rAvPAL-PEG Administered Daily in Subjects With Phenylketonuria (PKU)

This 16-week multi-center, open-label, Phase 2 study is designed to evaluate the safety,
tolerability,and efficacy of daily SC injections of rAvPAL-PEG in subjects with PKU. Subjects
who are naïve to prior treatment with rAvPAL-PEG and who have met the other study eligibility
criteria will be enrolled at approximately 8 sites in the US and Canada. Up to 6 daily dose
levels of rAvPAL-PEG are planned and may be assessed during this study (0.06 mg/kg/day, 0.1
mg/kg/day, 0.2 mg/kg/day;0.4 mg/kg/day, 0.6 mg/kg/day, or 0.8 mg/kg/day). Enrollment will
begin with the 0.4 mg/kg/day dose level and additional higher or lower doses may be added.
The additional dose levels chosen for assessment will be based on the safety (systemic
reaction or clinically significant abnormal laboratory test results assessed as related to
study drug) and efficacy (blood Phe reduction to less than or equal to 60 μmol/L) information
of at least 3 subjects with at least 2 weeks of daily dosing with rAvPAL-PEG. Initiation of
dosing at higher or lower dose levels will be per the determination of the Sponsor's Medical
Officer in consultation with the Investigator.

Inclusion Criteria:

- Diagnosis of PKU with both of the following: current blood Phe concentration of ≥ 600
micromol/L at screening and average blood Phe concentration of ≥ 600 micromol/L over
the past 3 years, using available data

- 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 ≥ 4 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 legally authorized representative, 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.

- Between the ages of 16 and 70 years, inclusive.

- Negative pregnancy test at screening and willing to have additional pregnancy tests
performed during the study for females of childbearing potential only. Females
considered not of childbearing potential are those who have been in menopause for at
least 2 years or have had a tubal ligation at least 1 year prior to screening, or who
have had a total hysterectomy.

- Willing to use an acceptable method of contraception while participating in the study
(sexually active subjects only).

- 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 ECG at screening.

Exclusion Criteria:

- Prior use of rAvPAL-PEG.

- Use of any investigational product 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.

- Known hypersensitivity to rAvPAL-PEG excipients.

- 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 investigator, 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.