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

A Phase 2, Open-Label Study to Evaluate the Safety, Tolerability, and Efficacy of Subcutaneous Dose Levels of rAvPAL-PEG Administered Daily in Subjects With Phenylketonuria

The purpose of this study is to evaluate the effect of daily administration of rAvPAL-PEG on the reduction of blood Phe concentrations in subjects with 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.