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

NCT00925054 | Completed Phase 2 Results DMC

• 1 other identifier: PAL-002
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 11

Brief 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.

Conditions

Phenylketonuria

Keywords

PKU; PEG PAL; BioMarin

Outcome Measures

Primary Outcomes (1)

• Blood Phenylalanine Concentrations

  Baseline, Week 1/Day 5, Week 7, Week 16/Day 106

Secondary Outcomes (8)

• Study Drug Related Adverse Events

  Screening, Weeks 1-22

• Number of Participants With Positive PAL IgG Antibody

  Baseline, Week 12

• Number of Participants With Positive PAL IgM Antibody

  Baseline, Week 12

• Number of Participants With Positive PEG IgM Antibody

  Baseline, Week 16

• Number of Participants With Positive PEG IgG Antibody

  Baseline, Week 16

Other Outcomes (1)

• Trough Concentration of BMN 165

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

Study Arms (5)

rAvPAL-PEG 0.001 mg/kg

EXPERIMENTAL

Subjects will start on rAvPAL-PEG 0.001 mg/kg

Drug: rAvPAL-PEG 0.001 mg/kg

rAvPAL-PEG 0.003 mg/kg

EXPERIMENTAL

Subjects will start on rAvPAL-PEG 0.003 mg/kg

Drug: rAvPAL-PEG 0.003 mg/kg

rAvPAL-PEG 0.01 mg/kg

EXPERIMENTAL

Subjects will start on rAvPAL-PEG 0.01 mg/kg

Drug: rAvPAL-PEG 0.01 mg/kg

rAvPAL-PEG 0.03 mg/kg

EXPERIMENTAL

Subjects will start on rAvPAL-PEG 0.03 mg/kg

Drug: rAvPAL-PEG 0.03 mg/kg

rAvPAL-PEG 0.1 mg/kg

EXPERIMENTAL

Subjects will start on rAvPAL-PEG 0.1 mg/kg

Drug: rAvPAL-PEG 0.1 mg/kg

Interventions

rAvPAL-PEG 0.001 mg/kg DRUG

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

rAvPAL-PEG 0.001 mg/kg

rAvPAL-PEG 0.003 mg/kg DRUG

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

rAvPAL-PEG 0.003 mg/kg

rAvPAL-PEG 0.01 mg/kg DRUG

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

rAvPAL-PEG 0.01 mg/kg

rAvPAL-PEG 0.03 mg/kg DRUG

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

rAvPAL-PEG 0.03 mg/kg

rAvPAL-PEG 0.1 mg/kg DRUG

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

rAvPAL-PEG 0.1 mg/kg

Eligibility Criteria

• Age: 16 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (11)

The Children's Hospital

Aurora, Colorado, 80045, United States

Location

Emory Universty

Decatur, Georgia, 30033, United States

Location

Children's Memorial Hospital

Chicago, Illinois, 60614, United States

Location

University of Minnesota Medical Center-Fairview

Minneapolis, Minnesota, 55455, United States

Location

Washington University Center for Applied Research Sciences

St Louis, Missouri, 63110, United States

Location

Albany Medical Center

Albany, New York, 12208, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

Akron Children's Hospital

Akron, Ohio, 44308, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Utah Hospital

Salt Lake City, Utah, 84132, United States

Location

Related Publications (2)

• 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.

  PMID: 32593547 DERIVED

• 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.

  PMID: 24743000 DERIVED

MeSH Terms

Conditions

Phenylketonurias

Interventions

pegvaliase

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Medical Director
• Organization: BioMarin Pharmaceutical Inc.

ari.gershman@bmrn.com

415-475-5854

Study Officials

• Ari Gershman, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 19, 2009
• Study Start: September 1, 2009
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: February 26, 2019
• Results First Posted: February 26, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (11)