A Study to Evaluate Subcutaneously Administered rAvPAL-PEG in Patients With Phenylketonuria for 24 Weeks

A Phase II, Multi-center, Open-label, Dose-finding Study to Evaluate Safety, Efficacy and Tolerability of Subcutaneously (SC) Administered rAvPAL-PEG in Patients With PKU for 24 Weeks

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01560286

Enrollment

Registered

2012-03-22

Start date

2012-05-31

Completion date

2015-07-31

Last updated

2019-08-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Phenylketonuria

Keywords

PKU, Injections, PEG-PAL, PAL

Brief summary

The primary objective of the study is to evaluate the effect of dosing regimens of multiple subcutaneous (SC) doses of rAvPAL-PEG to induce an early and sustained Phe reduction while decreasing the frequency and severity of hypersensitivity reactions in patients with PKU.

Detailed description

The primary rationale for this study is to define an optimal rAvPAL-PEG dose regimen by establishing the therapeutic effect within the shortest time possible time for induction, titration and maintenance phases while reducing the severity and frequency of hypersensitivity reactions that may lead to dose interruptions. It is hypothesized that these goals can be achieved by keeping rAvPAL-PEG doses low when anti-PEG IgM response is predicted to be high and titrating to an efficacious dose once the IgG response to PAL has developed. Further investigation is needed to determine how early and quickly patients can titrate safely to lower blood Phe; therefore, this protocol proposes to assess two Groups using an induction/titration and maintenance schedule with an aim towards establishing the therapeutic effect safety within an optimal period of time.

Interventions

BIOLOGICALBMN 165 (rAvPAL-PEG)

Subcutaneous injection of rAvPAL-PEG administered from 1 time up to 5 times per week between 2.5mg up to a maximum of 375mg for 24 weeks.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

16 Years to 70 Years

Healthy volunteers

Inclusion criteria

1. A diagnosis of PKU, with the following: * Current blood Phe concentration of ≥ 600 µmol/L at Screening. * Average blood Phe concentration of ≥ 600 µmol/L over the past 6 months, using available data. * Naïve to prior treatment with rAvPAL-PEG. 2. Evidence that the patient is a non responder to Kuvan® treatment (ie, 4 weeks of treatment with 20 mg/kg/day of Kuvan, insufficient response per investigator determination, unsuitable for Kuvan® per Investigator determination, and treatment end date ≥ 2 days prior to Day 1 \[ie, first dose\]). Patients 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. 3. Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures. In the case of participants under the age of 18 or participants who have been deemed mentally unable to provide informed consent, a parent or legal guardian may provide written informed consent (and, if required, the patient will provide written assent). 4. Willing and able to comply with all study procedures. 5. Between the ages of 16 and 70 years, inclusive. 6. 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. 7. Sexually active patients must be willing to use an acceptable method of contraception while participating in the study. 8. Maintained a stable diet with no significant modifications during the 4 weeks preceding the administration of study drug and willing to continue with the diet while on study so as to avoid potential variability of response due to variations in dietary intake. 9. In generally good health as evidenced by physical examination, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and electrocardiogram (ECG) at Screening.

Exclusion criteria

1. 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. 2. Use of any medication that is intended to treat PKU, including use of large amino acids, within 2 days prior to the administration of study drug. 3. 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. 4. A prior reaction that included systemic symptoms (eg, respiratory or gastrointestinal problems, hypotension, angioedema, anaphylaxis) to a PEG containing product. Patients 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. 5. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) or to breastfeed at any time during the study. 6. 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). 7. Any condition that, in the view of the PI, places the patient at high risk of poor treatment compliance or of not completing the study. 8. Alanine aminotransferase (ALT) concentration \> 2 times the upper limit of normal. 9. Creatinine \> 1.5 times the upper limit of normal. 10. A positive test for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen and hepatitis C antibody.

Design outcomes

Primary

Measure	Time frame	Description
Blood Phenylalanine Concentration	Baseline, Week 24	All patients will have their plasma Phenylalanine (Phe) assessed. Please note that Pharmacokinetics Sub-study was not performed, and thus no results are available.

Secondary

Measure	Time frame	Description
Number of Participants With Study Drug Related Adverse Events	Minimum Weekly Assessment of Injection Sites, Vital Signs and Adverse Events. Other Safety Assessments will be performed at other intervals (below):	—
Percentage of Participants With Positive Anti-PAL Immunoglobulin G [IgG]	Baseline, Week 24	Antibody Positivity
Trough Concentration of BMN 165	Week 1, Week 24	PK assessment from pre-dose blood draw.
Percentage of Participants With Positive Anti-PEG IgG	Baseline, Week 24	Antibody Positivity
Percentage of Participants With Positive PAL-IgM	Baseline, Week 24	Antibody Positivity
Percentage of Participants With Positive Anti-PEG-IgM	Baseline, Week 24	Antibody positivity
Percentage of Participants With Positive Neutralizing Antibodies [Nab]	Baseline, Week 24	Antibody positivity
Percentage of Participants With Positive Anti-PAL-IgE Antibodies	Baseline, Week 24	Antibody positivity
Percentage of Participants With Positive Anti-PAL-PEG IgE Antibodies	Baseline, Week 24	Antibody positivity

Countries

United States

Participant flow

Participants by arm

Arm	Count
rAvPAL-PEG All 24 Enrolled Subjects	24
Total	24

Baseline characteristics

Characteristic	rAvPAL-PEG
Age, Continuous	29.3 years STANDARD_DEVIATION 11.43
Age, Customized < 18 years	1 Participants
Age, Customized > or = 18 years	23 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	24 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants
Race/Ethnicity, Customized Asian	0 Participants
Race/Ethnicity, Customized Black or African American	0 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants
Race/Ethnicity, Customized Other	0 Participants
Race/Ethnicity, Customized White	24 Participants
Region of Enrollment United States	24 Participants
Sex: Female, Male Female	13 Participants
Sex: Female, Male Male	11 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 24
other Total, other adverse events	23 / 24
serious Total, serious adverse events	1 / 24

Outcome results

Primary

Blood Phenylalanine Concentration

All patients will have their plasma Phenylalanine (Phe) assessed. Please note that Pharmacokinetics Sub-study was not performed, and thus no results are available.

Time frame: Baseline, Week 24

Population: The efficacy population will consist of all subjects who received any amount of study drug and have post-treatment blood Phe concentration measurements.

Arm	Measure	Group	Value (MEAN)	Dispersion
rAvPAL-PEG	Blood Phenylalanine Concentration	Baseline	1168.8 umol/L	Standard Deviation 290.98
rAvPAL-PEG	Blood Phenylalanine Concentration	Week 24	617.6 umol/L	Standard Deviation 529.28

Secondary

Number of Participants With Study Drug Related Adverse Events

Time frame: Minimum Weekly Assessment of Injection Sites, Vital Signs and Adverse Events. Other Safety Assessments will be performed at other intervals (below):