Long-Term Extension of Previous rAvPAL-PEG Protocols in Subjects With PKU (PAL-003)

Study Overview
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Brief Summary
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This study is an extension of previous rAvPAL-PEG studies. 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.

Detailed Description
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PAL-003 is designed to evaluate long-term treatment of subjects who are continuing to take rAvPAL-PEG. Subjects'previous rAvPAL-PEG dosing will continue in PAL-003. In PAL-003, each subject's dose will be adjusted as needed to attain or maintain blood Phe concentrations of 60-600 µmol/L. rAvPAL-PEG dose will be based on either a subject's weight or will be a fixed dose (subjects who have maintained blood Phe levels to 60-600 µmol/L for at least 2 consecutive weeks and who have maintained a stable rAvPAL-PEG dose for at least 2 consecutive weeks). Doses will be evaluated on an individual basis.

Official Title
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Long-term Extension of a Phase 2, Open-Label Dose-Finding Study to Evaluate the Safety, Efficacy, and Tolerability of Multiple Subcutaneous Doses of rAvPAL-PEG in Subjects With PKU

Conditions
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Phenylketonuria

Intervention / Treatment
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* Drug: rAvPAL-PEG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have completed participation in previous rAvPAL-PEG studies. 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 previous rAvPAL-PEG studies. Alanine aminotransferase (ALT) concentration > 2 times the upper limit of normal. Creatinine > 1.5 times the upper limit of normal.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rAvPAL-PEG<br>rAvPAL-PEG in varying doses dependent on safety and efficacy. | Drug: rAvPAL-PEG<br>* The doses are planned to be in the same range as those tested in PAL-002 or PAL-004 and then modified either by increasing or decreasing the dose, adhering to an upper limit up to 5.0 mg/kg per week or 375 mg/week, considering each subject's individual responses related to safety and efficacy.<br>* Other names: Pegvaliase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Blood Phenylalanine (Phe) Concentration | Blood Phe Concentration (Change from Baseline) and Daily Dose in PAL-003 Subjects by Disposition (PAL-003 Population) | At Baseline and Change from Baseline to Week 48, Week 96, Week 144, Week 216, and Week 240 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics-Plasma Pegvaliase Concentration | Steady-state Pharmacokinetics (PK) of pegvaliase was measured in subjects who have achieved and maintained target blood Phe | At Baseline, Week 48, Week 96, Week 144, Week 216 and Week 240 | 
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | A treatment-emergent AE was defined as any adverse event (AE) newly appearing or worsened in severity following initiation of study drug until 4 weeks after last dose of pegvaliase (PAL-003) | Up to 109 months. | 
| Percentage of Participants With Positive PEG IgG Antibody | The presence of IgG Antibodies against PEG (polyethylene glycol) is measured overtime | At Baseline and Change from Baseline to Week 24, Week 52, Week 104 and Week 156 | 
| Percentage of Participants With Positive PAL IgG Antibody | The presence of IgG Antibodies against PAL (phenylalanine ammonia lyase) is measured overtime | At Baseline and Change from Baseline to Week 24, Week 52, Week 104 and Week 156 |