Dose-Finding Study to Evaluate the Safety, Efficacy, & Tolerability of Multiple Doses of rAvPAL-PEG in Subjects With PKU

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether weekly injections of phenylalanine ammonia lyase (rAvPAL-PEG) can reduce blood phenylalanine concentrations in PKU subjects and whether repeated administration is safe.

Detailed Description
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This is a 2 part, Phase 2, open-label dose-finding study in approximately 35 subjects with PKU. Seven dose cohorts are planned, each consisting of 5 subjects. In Part 1, the planned starting dose levels are those tested in PAL 001 (0.001, 0.003, 0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg), provided no dose limiting toxicity was observed in PAL 001. In Parts 1 and 2, study drug will be administered by clinic staff. Subjects who completed participation in PAL 001 will receive priority to participate in PAL 002. rAvPAL PEG naïve subjects will be enrolled to fill any dose cohort vacancies resulting from subjects who did not complete PAL 001 or who chose not to continue into PAL 002. In addition, if the number of dose cohorts determined in PAL 001 is less than 7, additional naïve subjects may be added to the existing dose cohorts to provide a total of approximately 35 subjects entering Part 1 of PAL 002. Furthermore, if serial dosing of cohorts in Part 1 of PAL 002 is stopped, additional subjects (either naïve subjects or PAL 001 subjects) may be added to the existing cohorts so that total study enrollment is approximately 35 subjects. In any of these cases, additional subjects will be enrolled sequentially from lowest to highest dose cohort. Diet will not be altered during the course of this study, except as necessary for safety. Subjects will be evaluated for safety and for blood Phe concentrations throughout the study. Toxicity will be measured according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3. A Data Monitoring Committee will monitor the study.

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

Conditions
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Phenylketonuria

Intervention / Treatment
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* Drug: rAvPAL-PEG 0.001 mg/kg
* Drug: rAvPAL-PEG 0.003 mg/kg
* Drug: rAvPAL-PEG 0.01 mg/kg
* Drug: rAvPAL-PEG 0.03 mg/kg
* Drug: rAvPAL-PEG 0.1 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For subjects who did not participate in PAL-001, diagnosis of PKU with both of the following: Current blood Phe concentration of ≥ 600 mmol/L at Screening and average blood Phe concentration of ≥ 600 µmol/L over the past 3 years, using available data. For subjects who did not participate in PAL-001, 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 ≥ 6 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 parent or legal guardian, after the nature of the study has been explained, and prior to any research-related procedures. Between the ages of 16 and 55 years, inclusive. 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 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 electrocardiogram (ECG) at Screening. Willing and able to comply with study procedures. 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, within 3 months prior to Screening and during study participation. A prior reaction that included systemic symptoms (eg, respiratory or gastrointestinal problems, hypotension, angioedema, anaphylaxis) to rAvPAL-PEG or a PEG containing product. Subjects 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. 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. 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rAvPAL-PEG 0.001 mg/kg<br>Subjects will start on rAvPAL-PEG 0.001 mg/kg | Drug: rAvPAL-PEG 0.001 mg/kg<br>* In Part 1, the planned starting dose levels is 0.001 mg/kg<br>|
| Experimental: rAvPAL-PEG 0.003 mg/kg<br>Subjects will start on rAvPAL-PEG 0.003 mg/kg | Drug: rAvPAL-PEG 0.003 mg/kg<br>* In Part 1, the planned starting dose levels is 0.003 mg/kg<br>|
| Experimental: rAvPAL-PEG 0.01 mg/kg<br>Subjects will start on rAvPAL-PEG 0.01 mg/kg | Drug: rAvPAL-PEG 0.01 mg/kg<br>* In Part 1, the planned starting dose levels is 0.01 mg/kg<br>|
| Experimental: rAvPAL-PEG 0.03 mg/kg<br>Subjects will start on rAvPAL-PEG 0.03 mg/kg | Drug: rAvPAL-PEG 0.03 mg/kg<br>* In Part 1, the planned starting dose levels is 0.03 mg/kg<br>|
| Experimental: rAvPAL-PEG 0.1 mg/kg<br>Subjects will start on rAvPAL-PEG 0.1 mg/kg | Drug: rAvPAL-PEG 0.1 mg/kg<br>* In Part 1, the planned starting dose levels is 0.1 mg/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Phenylalanine Concentrations |  | Baseline, Week 1/Day 5, Week 7, Week 16/Day 106 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study Drug Related Adverse Events |  | Screening, Weeks 1-22 | 
| Number of Participants With Positive PAL IgG Antibody | Antibody against PAL (phenylalanine ammonia lyase) measured over time | Baseline, Week 12 | 
| Number of Participants With Positive PAL IgM Antibody | Antibody positivity over time | Baseline, Week 12 | 
| Number of Participants With Positive PEG IgM Antibody | Antibody positivity over time | Baseline, Week 16 | 
| Number of Participants With Positive PEG IgG Antibody | Antibody positivity over time | Baseline, Week 16 | 
| Percentage of Participants With Positive Neutralizing Antibodies [NAb] | Antibody positivity over time | Baseline, Week 12 | 
| Percentage of Participants With Positive PAL IgE Antibody | Antibody positivity over time | Baselline, Week 12 | 
| Percentage of Participants With Positive Anti-PAL-PEG IgE Antibodies | Antibody positivity over time | Baseline, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PKU, PEG PAL, BioMarin