Phenylketonuria
Conditions
Keywords
PEG PAL; PKU; injection;
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.
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.
Interventions
DRUGrAvPAL-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
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Phenylalanine Concentration | Baseline, Week 16 | Plasma Phe |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With PAL IgG Antibody Percentage of Participants With Positive PAL IgG | Baseline, Week 16 | Antibody against phenylalanine ammonia lyase (PAL) |
| Plasma Concentrations of rAvPAL-PEG (BMN 165) | Baseline, Week 8, Week 13 | Measurements taken pre-dose |
| Percentage of Participants With PEG-IgG Antibody Positivity | Baseline, Week 16 | Antibodies against polyethylene glycol (PEG) of the IgG isotype |
| Percentage of Participants With PAL-IgM Antibody Positivity | Baseline, Week 16 | Antibodies against phenylalanine ammonia lyase (PAL) of the IgM isotype |
| Study Drug Related Adverse Events | 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. |
| Percentage of Participants With Neutralizing Antibody Positivity | Baseline, Week 16 | Antibody positivity over time |
| Percentage of Participants With PAL-IgE Antibody Positivity | Baseline, Week 16 | Antibodies against phenylalanine ammonia lyase (PAL) of the IgE isotype |
| Percentage of Participants With PAL-PEG-IgE Antibody Positivity | Baseline, Week 16 | Antibodies against phenylalanine ammonia lyase (PAL)-polyethylene glycol (PEG) of the IgE isotype |
| Percentage of Participants With PEG-IgM Antibody Positivity | Baseline, Week 16 | Antibodies against polyethylene glycol (PEG) of the IgM isotype |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| rAvPAL-PEG rAvPAL-PEG in varying doses | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | rAvPAL-PEG |
|---|---|
| Age, Continuous | 32.2 years STANDARD_DEVIATION 8.27 |
| Age, Customized < 18 years of age | 0 Participants |
| Age, Customized > or = 18 years of age | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 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 | 16 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 1 / 16 |
Outcome results
Primary
Blood Phenylalanine Concentration
Plasma Phe
Time frame: Baseline, Week 16
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 | 1482.1 umol/L | Standard Deviation 363.46 |
| rAvPAL-PEG | Blood Phenylalanine Concentration | Week 16 | 1566.0 umol/L | Standard Deviation 586.11 |
Secondary
Percentage of Participants With Neutralizing Antibody Positivity
Antibody positivity over time
Time frame: Baseline, Week 16
Population: The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With Neutralizing Antibody Positivity | Baseline | 0.0 Percentage |
| rAvPAL-PEG | Percentage of Participants With Neutralizing Antibody Positivity | Week 16 | 0.0 Percentage |
Secondary
Percentage of Participants With PAL-IgE Antibody Positivity
Antibodies against phenylalanine ammonia lyase (PAL) of the IgE isotype
Time frame: Baseline, Week 16
Population: The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With PAL-IgE Antibody Positivity | Baseline | 0.0 Percentage |
| rAvPAL-PEG | Percentage of Participants With PAL-IgE Antibody Positivity | Week 16 | 0.0 Percentage |
Secondary
Percentage of Participants With PAL IgG Antibody Percentage of Participants With Positive PAL IgG
Antibody against phenylalanine ammonia lyase (PAL)
Time frame: Baseline, Week 16
Population: The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With PAL IgG Antibody Percentage of Participants With Positive PAL IgG | Baseline | 12.5 Percentage |
| rAvPAL-PEG | Percentage of Participants With PAL IgG Antibody Percentage of Participants With Positive PAL IgG | Week 16 | 100.0 Percentage |
Secondary
Percentage of Participants With PAL-IgM Antibody Positivity
Antibodies against phenylalanine ammonia lyase (PAL) of the IgM isotype
Time frame: Baseline, Week 16
Population: The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With PAL-IgM Antibody Positivity | Baseline | 12.5 Percentage |
| rAvPAL-PEG | Percentage of Participants With PAL-IgM Antibody Positivity | Week 16 | 75.0 Percentage |
Secondary
Percentage of Participants With PAL-PEG-IgE Antibody Positivity
Antibodies against phenylalanine ammonia lyase (PAL)-polyethylene glycol (PEG) of the IgE isotype
Time frame: Baseline, Week 16
Population: The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With PAL-PEG-IgE Antibody Positivity | Baseline | 0.0 Percentage |
| rAvPAL-PEG | Percentage of Participants With PAL-PEG-IgE Antibody Positivity | Week 16 | 0.0 Percentage |
Secondary
Percentage of Participants With PEG-IgG Antibody Positivity
Antibodies against polyethylene glycol (PEG) of the IgG isotype
Time frame: Baseline, Week 16
Population: The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With PEG-IgG Antibody Positivity | Baseline | 25.0 Percentage |
| rAvPAL-PEG | Percentage of Participants With PEG-IgG Antibody Positivity | Week 16 | 75.0 Percentage |
Secondary
Percentage of Participants With PEG-IgM Antibody Positivity
Antibodies against polyethylene glycol (PEG) of the IgM isotype
Time frame: Baseline, Week 16
Population: The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With PEG-IgM Antibody Positivity | Baseline | 31.3 Percentage |
| rAvPAL-PEG | Percentage of Participants With PEG-IgM Antibody Positivity | Week 16 | 50.0 Percentage |
Secondary
Plasma Concentrations of rAvPAL-PEG (BMN 165)
Measurements taken pre-dose
Time frame: Baseline, Week 8, Week 13
Population: The PK population will consist of all subjects who received any amount of study drug and have post-treatment plasma BMN 165 concentration measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rAvPAL-PEG | Plasma Concentrations of rAvPAL-PEG (BMN 165) | Baseline-Day 1, 1 Hour Predose | 0.000 ng/mL | Standard Deviation 0 |
| rAvPAL-PEG | Plasma Concentrations of rAvPAL-PEG (BMN 165) | Week 13-Day 89, Predose | 1116.364 ng/mL | Standard Deviation 2013.9676 |
| rAvPAL-PEG | Plasma Concentrations of rAvPAL-PEG (BMN 165) | Week 8-Day 52, 1 Hour Predose | 2425.608 ng/mL | Standard Deviation 8532.2431 |
Secondary
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.
Time frame: Weekly
Population: The safety population will consist of all subjects who receive any amount of study drug throughout the study duration and have post-treatment safety information (laboratory values, vital signs, adverse events, 12-lead electrocardiogram, chest x-ray, antibodies, and physical examinations).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rAvPAL-PEG | Study Drug Related Adverse Events | 16 Participants |