A Study to Evaluate Subcutaneously Administered rAvPAL-PEG in Patients With Phenylketonuria for 24 Weeks

The primary rationale for this study is to define an optimal rAvPAL-PEG dose regimen by
establishing the therapeutic effect within the shortest time possible time for induction,
titration and maintenance phases while reducing the severity and frequency of
hypersensitivity reactions that may lead to dose interruptions. It is hypothesized that these
goals can be achieved by keeping rAvPAL-PEG doses low when anti-PEG IgM response is predicted
to be high and titrating to an efficacious dose once the IgG response to PAL has developed.
Further investigation is needed to determine how early and quickly patients can titrate
safely to lower blood Phe; therefore, this protocol proposes to assess two Groups using an
induction/titration and maintenance schedule with an aim towards establishing the therapeutic
effect safety within an optimal period of time.

Inclusion Criteria:

1. A diagnosis of PKU, with the following:

- Current blood Phe concentration of ≥ 600 µmol/L at Screening.

- Average blood Phe concentration of ≥ 600 µmol/L over the past 6 months, using
available data.

- Naïve to prior treatment with rAvPAL-PEG.

2. Evidence that the patient is a non responder to Kuvan® treatment (ie, 4 weeks of
treatment with 20 mg/kg/day of Kuvan, insufficient response per investigator
determination, unsuitable for Kuvan® per Investigator determination, and treatment end
date ≥ 2 days prior to Day 1 [ie, first dose]). Patients 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.

3. Willing and able to provide written, signed informed consent after the nature of the
study has been explained and prior to any research-related procedures. In the case of
participants under the age of 18 or participants who have been deemed mentally unable
to provide informed consent, a parent or legal guardian may provide written informed
consent (and, if required, the patient will provide written assent).

4. Willing and able to comply with all study procedures.

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

6. 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.

7. Sexually active patients must be willing to use an acceptable method of contraception
while participating in the study.

8. Maintained a stable diet with no significant modifications during the 4 weeks
preceding the administration of study drug and willing to continue with the diet while
on study so as to avoid potential variability of response due to variations in dietary
intake.

9. In generally good health as evidenced by physical examination, clinical laboratory
evaluations (hematology, chemistry, and urinalysis), and electrocardiogram (ECG) at
Screening.

Exclusion Criteria:

1. 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.

2. Use of any medication that is intended to treat PKU, including use of large amino
acids, within 2 days prior to the administration of study drug.

3. 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.

4. A prior reaction that included systemic symptoms (eg, respiratory or gastrointestinal
problems, hypotension, angioedema, anaphylaxis) to a PEG containing product. Patients
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.

5. Pregnant or breastfeeding at Screening or planning to become pregnant (self or
partner) or to breastfeed at any time during the study.

6. 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).

7. Any condition that, in the view of the PI, places the patient at high risk of poor
treatment compliance or of not completing the study.

8. Alanine aminotransferase (ALT) concentration > 2 times the upper limit of normal.

9. Creatinine > 1.5 times the upper limit of normal.

10. A positive test for human immunodeficiency virus (HIV) antibody, hepatitis B surface
antigen and hepatitis C antibody.