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CompletedNCT00925054Updated Feb 26, 2019Results posted

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

A Phase 2 interventional study of rAvPAL-PEG 0.001 mg/kg and rAvPAL-PEG 0.003 mg/kg in Phenylketonuria, sponsored by BioMarin Pharmaceutical. Completed at 11 sites in United States. Open to participants aged 16 Years to 55 Years. Per ClinicalTrials.gov, last updated 2019-02-26.

Sponsored by BioMarin Pharmaceutical · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
40
Allocation
Non-randomized
Ages
16 Years to 55 Years
Sex
All
01

Study summary

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.

Read the detailed description

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.

02

Conditions studied

  • Phenylketonuria

Browse trials for

Keywords

  • PKU
  • PEG PAL
  • BioMarin
03

In context

Phenylketonurias

187 studies on the registry are indexed under Phenylketonurias; 38 are open to participants now.

This study's enrollment of 40 is above the median of 25 across 117 interventional studies indexed under Phenylketonurias.

Browse Phenylketonurias studies →

Lead sponsor

BioMarin Pharmaceutical is the lead sponsor of 112 studies on the registry; 13 are open to participants now.

Of its 17 completed or terminated interventional studies of FDA-regulated products, 12 (71%) have results posted.

Browse BioMarin Pharmaceutical studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
16 Years to 55 Years
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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

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.
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Sequential assignment
Masking
None (open label)
Enrollment
40 participants (actual)

Study arms

  • Experimental
    rAvPAL-PEG 0.001 mg/kg

    Subjects will start on rAvPAL-PEG 0.001 mg/kg

    Drug: rAvPAL-PEG 0.001 mg/kg

  • Experimental
    rAvPAL-PEG 0.003 mg/kg

    Subjects will start on rAvPAL-PEG 0.003 mg/kg

    Drug: rAvPAL-PEG 0.003 mg/kg

  • Experimental
    rAvPAL-PEG 0.01 mg/kg

    Subjects will start on rAvPAL-PEG 0.01 mg/kg

    Drug: rAvPAL-PEG 0.01 mg/kg

  • Experimental
    rAvPAL-PEG 0.03 mg/kg

    Subjects will start on rAvPAL-PEG 0.03 mg/kg

    Drug: rAvPAL-PEG 0.03 mg/kg

  • Experimental
    rAvPAL-PEG 0.1 mg/kg

    Subjects will start on rAvPAL-PEG 0.1 mg/kg

    Drug: rAvPAL-PEG 0.1 mg/kg

Interventions

  • DrugrAvPAL-PEG 0.001 mg/kg

    Drug page: Pegvaliase

    In Part 1, the planned starting dose levels is 0.001 mg/kg

  • DrugrAvPAL-PEG 0.003 mg/kg

    Drug page: Pegvaliase

    In Part 1, the planned starting dose levels is 0.003 mg/kg

  • DrugrAvPAL-PEG 0.01 mg/kg

    Drug page: Pegvaliase

    In Part 1, the planned starting dose levels is 0.01 mg/kg

  • DrugrAvPAL-PEG 0.03 mg/kg

    Drug page: Pegvaliase

    In Part 1, the planned starting dose levels is 0.03 mg/kg

  • DrugrAvPAL-PEG 0.1 mg/kg

    Drug page: Pegvaliase

    In Part 1, the planned starting dose levels is 0.1 mg/kg

06

What researchers measure

Primary outcomes

  1. Blood Phenylalanine Concentrations

    Time frame: Baseline, Week 1/Day 5, Week 7, Week 16/Day 106

Secondary outcomes

  1. Study Drug Related Adverse Events

    Time frame: Screening, Weeks 1-22

  2. Number of Participants With Positive PAL IgG Antibody

    Antibody against PAL (phenylalanine ammonia lyase) measured over time

    Time frame: Baseline, Week 12

  3. Number of Participants With Positive PAL IgM Antibody

    Antibody positivity over time

    Time frame: Baseline, Week 12

  4. Number of Participants With Positive PEG IgM Antibody

    Antibody positivity over time

    Time frame: Baseline, Week 16

  5. Number of Participants With Positive PEG IgG Antibody

    Antibody positivity over time

    Time frame: Baseline, Week 16

  6. Percentage of Participants With Positive Neutralizing Antibodies [NAb]

    Antibody positivity over time

    Time frame: Baseline, Week 12

  7. Percentage of Participants With Positive PAL IgE Antibody

    Antibody positivity over time

    Time frame: Baselline, Week 12

  8. Percentage of Participants With Positive Anti-PAL-PEG IgE Antibodies

    Antibody positivity over time

    Time frame: Baseline, Week 12

Other outcomes

  1. Trough Concentration of BMN 165

    Plasma concentrations of rAvPAL-PEG (BMN 165)

    Time frame: Baseline, Baseline/pre-dose, Week 7, and Week 16/Day 106

07

Results

Posted Feb 26, 2019

Participant flow

Participant flow — Overall Study
MilestoneStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kg
Started7913110
Completed7812010
Not completed01110

Outcome measures

PrimaryBlood Phenylalanine Concentrations
Time frame:
Baseline, Week 1/Day 5, Week 7, Week 16/Day 106
Reported as:
Mean · umol/L
Blood Phenylalanine Concentrations
umol/LStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline1382.7 ± 191.401336.1 ± 344.871290.5 ± 459.43846.01310.3 ± 319.011310.8 ± 353.86
Week 1 Day 51405.3 ± 190.871276.3 ± 410.221216.5 ± 434.53682.0863.7 ± 307.591158.5 ± 403.63
Week 71436.0 ± 274.081324.8 ± 304.641108.7 ± 510.741849.01321.6 ± 350.781284.5 ± 405.75
week 16 Day 1061284.0 ± 221.731049.4 ± 378.001093.5 ± 445.02—930.7 ± 331.361088.5 ± 367.67
SecondaryStudy Drug Related Adverse Events
Time frame:
Screening, Weeks 1-22
Reported as:
Count of participants · Participants
Study Drug Related Adverse Events
ParticipantsStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Study Drug Related Adverse Events591111036
SecondaryNumber of Participants With Positive PAL IgG Antibody

Antibody against PAL (phenylalanine ammonia lyase) measured over time

Time frame:
Baseline, Week 12
Reported as:
Count of participants · Participants
Number of Participants With Positive PAL IgG Antibody
ParticipantsStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline322007
Week 12781211038
SecondaryNumber of Participants With Positive PAL IgM Antibody

Antibody positivity over time

Time frame:
Baseline, Week 12
Reported as:
Count of participants · Participants
Number of Participants With Positive PAL IgM Antibody
ParticipantsStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline1250412
Week 1243801025
SecondaryNumber of Participants With Positive PEG IgM Antibody

Antibody positivity over time

Time frame:
Baseline, Week 16
Reported as:
Count of participants · Participants
Number of Participants With Positive PEG IgM Antibody
ParticipantsStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline122005
Week 167780934
SecondaryNumber of Participants With Positive PEG IgG Antibody

Antibody positivity over time

Time frame:
Baseline, Week 16
Reported as:
Count of participants · Participants
Number of Participants With Positive PEG IgG Antibody
ParticipantsStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline2571419
Week 1667120934
SecondaryPercentage of Participants With Positive Neutralizing Antibodies [NAb]

Antibody positivity over time

Time frame:
Baseline, Week 12
Reported as:
Count of participants · Participants
Percentage of Participants With Positive Neutralizing Antibodies [NAb]
ParticipantsStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline000000
Week 12001034
SecondaryPercentage of Participants With Positive PAL IgE Antibody

Antibody positivity over time

Time frame:
Baselline, Week 12
Reported as:
Count of participants · Participants
Percentage of Participants With Positive PAL IgE Antibody
ParticipantsStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline000000
Week 12100001
SecondaryPercentage of Participants With Positive Anti-PAL-PEG IgE Antibodies

Antibody positivity over time

Time frame:
Baseline, Week 12
Reported as:
Count of participants · Participants
Percentage of Participants With Positive Anti-PAL-PEG IgE Antibodies
ParticipantsStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline000000
Week 12000000
Other pre-specifiedTrough Concentration of BMN 165

Plasma concentrations of rAvPAL-PEG (BMN 165)

Time frame:
Baseline, Baseline/pre-dose, Week 7, and Week 16/Day 106
Reported as:
Mean · ng/mL
Trough Concentration of BMN 165
ng/mLStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose =0.1 mg/kgTotal
Baseline0 ± 00 ± 00 ± 00—0 ± 0
Baseline, pre-dose————1.6 ± 5.061.6 ± 5.06
Week 70 ± 00 ± 00 ± 000 ± 00 ± 0
Week 16-Day 1067.8 ± 20.523.1 ± 8.706.0 ± 14.54—0 ± 04.2 ± 12.74

Adverse events

Collected over Screening- Week 22. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Starting Dose=0.001 mg/kg0/7 (0%)0/7 (0%)7/7 (100%)
Starting Dose=0.003 mg/kg0/9 (0%)0/9 (0%)9/9 (100%)
Starting Dose=0.01 mg/kg0/13 (0%)1/13 (7.7%)13/13 (100%)
Starting Dose=0.03 mg/kg0/1 (0%)0/1 (0%)1/1 (100%)
Starting Dose=0.1 mg/kg0/10 (0%)1/10 (10%)10/10 (100%)
Most frequent serious events
Most frequent serious events
EventStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kg
DehydrationMetabolism and nutrition disorders0/70/90/130/11/10
HypersensitivityImmune system disorders0/70/91/130/10/10
Most frequent other events
Showing 10 of 132
Most frequent other events
EventStarting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kg
SinusitisInfections and infestations0/70/91/131/10/10
HeadacheNervous system disorders1/75/94/131/15/10
Injection site reactionGeneral disorders1/76/98/130/15/10
ArthralgiaMusculoskeletal and connective tissue disorders0/71/94/130/16/10
NauseaGastrointestinal disorders4/74/94/130/11/10
Upper respiratory tract infectionInfections and infestations0/71/91/130/15/10
Injection site erythemaGeneral disorders1/74/94/130/14/10
Injection site rashGeneral disorders2/73/92/130/13/10
RashSkin and subcutaneous tissue disorders2/73/92/130/10/10
NasopharyngitisInfections and infestations2/72/94/130/11/10

Baseline characteristics

Age, Continuous
Age, Continuous(years)Starting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kgTotal
Mean23.3 ± 3.4529.2 ± 5.9526.5 ± 5.6522.025.2 ± 8.6026.1 ± 6.35
Age, Customized
Age, Customized(Participants)Starting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kgTotal
< 18 years of age000022
> or = 18 years of age79131838
Sex: Female, Male
Sex: Female, Male(Participants)Starting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kgTotal
Female3760420
Male4271620
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Starting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kgTotal
Hispanic or Latino000011
Not Hispanic or Latino79131939
Unknown or Not Reported000000
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Starting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kgTotal
American Indian or Alaska Native000011
Asian001001
Native Hawaiian or Other Pacific Islander000000
Black or African American000000
White79121938
Other000000
Region of Enrollment
Region of Enrollment(Participants)Starting Dose=0.001 mg/kgStarting Dose=0.003 mg/kgStarting Dose=0.01 mg/kgStarting Dose=0.03 mg/kgStarting Dose=0.1 mg/kgTotal
United States791311040
08

Study locations

11 sites
  • The Children's Hospital
    Aurora, Colorado 80045, United States
  • Emory Universty
    Decatur, Georgia 30033, United States
  • Children's Memorial Hospital
    Chicago, Illinois 60614, United States
  • University of Minnesota Medical Center-Fairview
    Minneapolis, Minnesota 55455, United States
  • Washington University Center for Applied Research Sciences
    St Louis, Missouri 63110, United States
  • Albany Medical Center
    Albany, New York 12208, United States
  • Mount Sinai School of Medicine
    New York, New York 10029, United States
  • Akron Children's Hospital
    Akron, Ohio 44308, United States
  • Oregon Health & Science University
    Portland, Oregon 97239, United States
  • University of Pittsburgh Medical Center
    Pittsburgh, Pennsylvania 15213, United States
  • University of Utah Hospital
    Salt Lake City, Utah 84132, United States
09

References and documents

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. PubMed 32593547 ↗
  • Longo N, Harding CO, Burton BK, Grange DK, Vockley J, Wasserstein M, Rice GM, Dorenbaum A, Neuenburg JK, Musson DG, Gu Z, Sile S. Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial. Lancet. 2014 Jul 5;384(9937):37-44. doi: 10.1016/S0140-6736(13)61841-3. Epub 2014 Apr 14. PubMed 24743000 ↗

Individual participant data

Plan to share: No

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 26, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00925054
Lead sponsor
BioMarin Pharmaceutical
Responsible party
Sponsor
First posted
Jun 19, 2009
Start date
Sep 2009
Primary completion
Jun 2015
Completion
Jun 2015
Results posted
Feb 26, 2019
Last update
Feb 26, 2019

Study contacts

Ari Gershman, MD
study director · BioMarin Pharmaceutical

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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