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.

Study Overview

• Status: Completed
• Conditions: Phenylketonuria
• Intervention / Treatment: Drug: rAvPAL-PEG

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children'S Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Weisskopf Child Evaluation Center / University of Louisville
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Center for Applied Research Sciences
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin-Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Recombinant Anabaena variabilis phenylalanine ammonia lyase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Phenylalanine Concentration	Plasma Phe	Baseline, Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study Drug Related Adverse Events	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.	Weekly
Percentage of Participants With PAL IgG Antibody Percentage of Participants With Positive PAL IgG	Antibody against phenylalanine ammonia lyase (PAL)	Baseline, Week 16
Plasma Concentrations of rAvPAL-PEG (BMN 165)	Measurements taken pre-dose	Baseline, Week 8, Week 13
Percentage of Participants With PEG-IgG Antibody Positivity	Antibodies against polyethylene glycol (PEG) of the IgG isotype	Baseline, Week 16
Percentage of Participants With PAL-IgM Antibody Positivity	Antibodies against phenylalanine ammonia lyase (PAL) of the IgM isotype	Baseline, Week 16
Percentage of Participants With PEG-IgM Antibody Positivity	Antibodies against polyethylene glycol (PEG) of the IgM isotype	Baseline, Week 16
Percentage of Participants With Neutralizing Antibody Positivity	Antibody positivity over time	Baseline, Week 16
Percentage of Participants With PAL-IgE Antibody Positivity	Antibodies against phenylalanine ammonia lyase (PAL) of the IgE isotype	Baseline, Week 16
Percentage of Participants With PAL-PEG-IgE Antibody Positivity	Antibodies against phenylalanine ammonia lyase (PAL)-polyethylene glycol (PEG) of the IgE isotype	Baseline, Week 16

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical

Publications and helpful links

General Publications

• Burton BK, Longo N, Vockley J, Grange DK, Harding CO, Decker C, Li M, Lau K, Rosen O, Larimore K, Thomas J; PAL-002 and PAL-004 Investigators. Pegvaliase for the treatment of phenylketonuria: Results of the phase 2 dose-finding studies with long-term follow-up. Mol Genet Metab. 2020 Aug;130(4):239-246. doi: 10.1016/j.ymgme.2020.06.006. Epub 2020 Jun 16.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: September 29, 2010
• First Submitted That Met QC Criteria: September 30, 2010
• First Posted (Estimate): October 1, 2010

Study Record Updates

• Last Update Posted (Actual): February 26, 2019
• Last Update Submitted That Met QC Criteria: February 4, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: PEG PAL; PKU; injection
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: PAL-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No