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

A Phase II, Multi-center, Open-label, Dose-finding Study to Evaluate Safety, Efficacy and Tolerability of Subcutaneously (SC) Administered rAvPAL-PEG in Patients With PKU for 24 Weeks

The primary objective of the study is to evaluate the effect of dosing regimens of multiple subcutaneous (SC) doses of rAvPAL-PEG to induce an early and sustained Phe reduction while decreasing the frequency and severity of hypersensitivity reactions in patients with PKU.

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.