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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01212744
Recruitment Status : Completed
First Posted : October 1, 2010
Results First Posted : February 26, 2019
Last Update Posted : February 26, 2019
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Phenylketonuria Drug: rAvPAL-PEG Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : March 2011
Actual Primary Completion Date : April 2015
Actual Study Completion Date : April 2015

Arm Intervention/treatment
Experimental: rAvPAL-PEG
rAvPAL-PEG in varying doses
Drug: rAvPAL-PEG
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, 0.8 mg/kg/day
Other Name: Recombinant Anabaena variabilis phenylalanine ammonia lyase

Primary Outcome Measures :
  1. Blood Phenylalanine Concentration [ Time Frame: Baseline, Week 16 ]
    Plasma Phe

Secondary Outcome Measures :
  1. Study Drug Related Adverse Events [ Time Frame: Weekly ]
    Safety will be evaluated on the incidence of AEs and clinically significant changes in vital signs as well as clinical labs and ECG. Please refer to AE section below for comprehensive listing of all adverse events recorded during study.

  2. Percentage of Participants With PAL IgG Antibody Percentage of Participants With Positive PAL IgG [ Time Frame: Baseline, Week 16 ]
    Antibody against phenylalanine ammonia lyase (PAL)

  3. Plasma Concentrations of rAvPAL-PEG (BMN 165) [ Time Frame: Baseline, Week 8, Week 13 ]
    Measurements taken pre-dose

  4. Percentage of Participants With PEG-IgG Antibody Positivity [ Time Frame: Baseline, Week 16 ]
    Antibodies against polyethylene glycol (PEG) of the IgG isotype

  5. Percentage of Participants With PAL-IgM Antibody Positivity [ Time Frame: Baseline, Week 16 ]
    Antibodies against phenylalanine ammonia lyase (PAL) of the IgM isotype

  6. Percentage of Participants With PEG-IgM Antibody Positivity [ Time Frame: Baseline, Week 16 ]
    Antibodies against polyethylene glycol (PEG) of the IgM isotype

  7. Percentage of Participants With Neutralizing Antibody Positivity [ Time Frame: Baseline, Week 16 ]
    Antibody positivity over time

  8. Percentage of Participants With PAL-IgE Antibody Positivity [ Time Frame: Baseline, Week 16 ]
    Antibodies against phenylalanine ammonia lyase (PAL) of the IgE isotype

  9. Percentage of Participants With PAL-PEG-IgE Antibody Positivity [ Time Frame: Baseline, Week 16 ]
    Antibodies against phenylalanine ammonia lyase (PAL)-polyethylene glycol (PEG) of the IgE isotype

Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01212744

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United States, Colorado
The Children's Hospital
Aurora, Colorado, United States, 80045
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
United States, Kentucky
Weisskopf Child Evaluation Center / University of Louisville
Louisville, Kentucky, United States, 40202
United States, Missouri
University of Missouri
Columbia, Missouri, United States, 65212
Washington University Center for Applied Research Sciences
Saint Louis, Missouri, United States, 63110
United States, New York
Albany Medical Center
Albany, New York, United States, 12208
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
United States, Wisconsin
University of Wisconsin-Madison
Madison, Wisconsin, United States, 53705
Sponsors and Collaborators
BioMarin Pharmaceutical
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Study Director: Ari Gershman, MD BioMarin Pharmaceutical
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: BioMarin Pharmaceutical Identifier: NCT01212744    
Other Study ID Numbers: PAL-004
First Posted: October 1, 2010    Key Record Dates
Results First Posted: February 26, 2019
Last Update Posted: February 26, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by BioMarin Pharmaceutical:
PEG PAL; PKU; injection;
Additional relevant MeSH terms:
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Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases