Phenylketonuria
Conditions
Brief summary
This study is an extension of previous rAvPAL-PEG studies. Administration of rAvPAL-PEG will be continued to assess whether long-term dosing of rAvPAL-PEG is safe and can maintain reduced blood Phe concentrations in PKU subjects.
Detailed description
PAL-003 is designed to evaluate long-term treatment of subjects who are continuing to take rAvPAL-PEG. Subjects'previous rAvPAL-PEG dosing will continue in PAL-003. In PAL-003, each subject's dose will be adjusted as needed to attain or maintain blood Phe concentrations of 60-600 µmol/L. rAvPAL-PEG dose will be based on either a subject's weight or will be a fixed dose (subjects who have maintained blood Phe levels to 60-600 µmol/L for at least 2 consecutive weeks and who have maintained a stable rAvPAL-PEG dose for at least 2 consecutive weeks). Doses will be evaluated on an individual basis.
Interventions
DRUGrAvPAL-PEG
The doses are planned to be in the same range as those tested in PAL-002 or PAL-004 and then modified either by increasing or decreasing the dose, adhering to an upper limit up to 5.0 mg/kg per week or 375 mg/week, considering each subject's individual responses related to safety and efficacy.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Must have completed participation in previous rAvPAL-PEG studies. * 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. * Willing and able to comply with all study procedures. * 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. * In generally good health as evidenced by physical examination, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and electrocardiogram (ECG) at Screening.
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 during study participation. * A prior reaction that included systemic symptoms (eg, generalized hives, respiratory or gastrointestinal problems, hypotension, angioedema, anaphylaxis) to rAvPAL-PEG or a PEG-containing product. * 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. * Known hypersensitivity to rAvPAL-PEG or its excipients, including hypersensitivity reactions that necessitated early termination from previous rAvPAL-PEG studies. * 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 |
|---|---|---|
| Change From Baseline in the Blood Phenylalanine (Phe) Concentration | At Baseline and Change from Baseline to Week 48, Week 96, Week 144, Week 216, and Week 240 | Blood Phe Concentration (Change from Baseline) and Daily Dose in PAL-003 Subjects by Disposition (PAL-003 Population) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics-Plasma Pegvaliase Concentration | At Baseline, Week 48, Week 96, Week 144, Week 216 and Week 240 | Steady-state Pharmacokinetics (PK) of pegvaliase was measured in subjects who have achieved and maintained target blood Phe |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Up to 109 months. | A treatment-emergent AE was defined as any adverse event (AE) newly appearing or worsened in severity following initiation of study drug until 4 weeks after last dose of pegvaliase (PAL-003) |
| Percentage of Participants With Positive PEG IgG Antibody | At Baseline and Change from Baseline to Week 24, Week 52, Week 104 and Week 156 | The presence of IgG Antibodies against PEG (polyethylene glycol) is measured overtime |
| Percentage of Participants With Positive PAL IgG Antibody | At Baseline and Change from Baseline to Week 24, Week 52, Week 104 and Week 156 | The presence of IgG Antibodies against PAL (phenylalanine ammonia lyase) is measured overtime |
Countries
United States
Participant flow
Recruitment details
This was a multicenter study, conducted in 14 study centers of United States.
Participants by arm
| Arm | Count |
|---|---|
| rAvPAL-PEG rAvPAL-PEG 0.001 to a maximum dose of 5.0 mg/kg/week or 375 mg/week by subcutaneous injection | 68 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Physician Decision | 5 |
| Overall Study | Withdrawal by Sponsor | 1 |
| Overall Study | Withdrawal by Subject | 11 |
Baseline characteristics
| Characteristic | rAvPAL-PEG |
|---|---|
| Age, Continuous | 28.31 years STANDARD_DEVIATION 8.66 |
| Baseline blood Phe | 1022.4 μmol/L STANDARD_DEVIATION 530.39 |
| Body mass index (BMI) | 29.2 kg/m^2 STANDARD_DEVIATION 8.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized White | 66 Participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 28 Participants |
| Weight | 83.0 kg STANDARD_DEVIATION 26.39 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 68 |
| other Total, other adverse events | 68 / 68 |
| serious Total, serious adverse events | 12 / 68 |
Outcome results
Primary
Change From Baseline in the Blood Phenylalanine (Phe) Concentration
Blood Phe Concentration (Change from Baseline) and Daily Dose in PAL-003 Subjects by Disposition (PAL-003 Population)
Time frame: At Baseline and Change from Baseline to Week 48, Week 96, Week 144, Week 216, and Week 240
Population: Efficacy population consisted of all subjects who received at least one dose of study drug and have post-treatment blood Phe concentration measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rAvPAL-PEG | Change From Baseline in the Blood Phenylalanine (Phe) Concentration | Baseline | 1022.4 μmol/L | Standard Deviation 530.39 |
| rAvPAL-PEG | Change From Baseline in the Blood Phenylalanine (Phe) Concentration | Change from Baseline to Week 48 | -553.5 μmol/L | Standard Deviation 652.95 |
| rAvPAL-PEG | Change From Baseline in the Blood Phenylalanine (Phe) Concentration | Change from Baseline to Week 96 | -653.3 μmol/L | Standard Deviation 637.81 |
| rAvPAL-PEG | Change From Baseline in the Blood Phenylalanine (Phe) Concentration | Change from Baseline to Week 144 | -672.3 μmol/L | Standard Deviation 621.06 |
| rAvPAL-PEG | Change From Baseline in the Blood Phenylalanine (Phe) Concentration | Change from Baseline to Week 216 | -535.9 μmol/L | Standard Deviation 573.08 |
| rAvPAL-PEG | Change From Baseline in the Blood Phenylalanine (Phe) Concentration | Change from Baseline to Week 240 | -574.9 μmol/L | Standard Deviation 549.9 |
Secondary
Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
A treatment-emergent AE was defined as any adverse event (AE) newly appearing or worsened in severity following initiation of study drug until 4 weeks after last dose of pegvaliase (PAL-003)
Time frame: Up to 109 months.
Population: Analysis population consisted of subjects from the study of PAL-003 only
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| rAvPAL-PEG | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any adverse event | 68 Participants |
| rAvPAL-PEG | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any serious adverse events | 12 Participants |
| rAvPAL-PEG | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any treatment-related adverse event | 65 Participants |
| rAvPAL-PEG | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any treatment-related serious adverse event | 6 Participants |
| rAvPAL-PEG | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Death | 0 Participants |
Secondary
Percentage of Participants With Positive PAL IgG Antibody
The presence of IgG Antibodies against PAL (phenylalanine ammonia lyase) is measured overtime
Time frame: At Baseline and Change from Baseline to Week 24, Week 52, Week 104 and Week 156
Population: As PAL-003 is an extension of parent Phase 2 studies (PAL-002, PAL-004 \& 165-205), the parent Phase 2 treatment naïve baseline data (N=80) was used for the vital signs, immunogenicity \& PK analyses to monitor changes in vital signs mediated by pegvaliase, understand development \& maturation of immune response against pegvaliase, \& the resulting impact on PK. Refer to NCT00925054-PAL-002, NCT01212744-PAL-004 \& NCT01560286-165-205 for parent Ph2 demographic data (N=80).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With Positive PAL IgG Antibody | Change from Baseline to Week 156 | 45 Participants |
| rAvPAL-PEG | Percentage of Participants With Positive PAL IgG Antibody | Baseline | 10 Participants |
| rAvPAL-PEG | Percentage of Participants With Positive PAL IgG Antibody | Change from Baseline to Week 24 | 63 Participants |
| rAvPAL-PEG | Percentage of Participants With Positive PAL IgG Antibody | Change from Baseline to Week 52 | 60 Participants |
| rAvPAL-PEG | Percentage of Participants With Positive PAL IgG Antibody | Change from Baseline to Week 104 | 48 Participants |
Secondary
Percentage of Participants With Positive PEG IgG Antibody
The presence of IgG Antibodies against PEG (polyethylene glycol) is measured overtime
Time frame: At Baseline and Change from Baseline to Week 24, Week 52, Week 104 and Week 156
Population: As PAL-003 is an extension of parent Phase 2 studies (PAL-002, PAL-004 \& 165-205), the parent Phase 2 treatment naïve baseline data (N=80) was used for the vital signs, immunogenicity \& PK analyses to monitor changes in vital signs mediated by pegvaliase, understand development \& maturation of immune response against pegvaliase, \& the resulting impact on PK. Refer to NCT00925054-PAL-002, NCT01212744-PAL-004 \& NCT01560286-165-205 for parent Ph2 demographic data (N=80).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| rAvPAL-PEG | Percentage of Participants With Positive PEG IgG Antibody | Baseline | 29 Participants |
| rAvPAL-PEG | Percentage of Participants With Positive PEG IgG Antibody | Change from Baseline to Week 24 | 24 Participants |
| rAvPAL-PEG | Percentage of Participants With Positive PEG IgG Antibody | Change from Baseline to Week 52 | 14 Participants |
| rAvPAL-PEG | Percentage of Participants With Positive PEG IgG Antibody | Change from Baseline to Week 104 | 2 Participants |
| rAvPAL-PEG | Percentage of Participants With Positive PEG IgG Antibody | Change from Baseline to Week 156 | 7 Participants |
Secondary
Pharmacokinetics-Plasma Pegvaliase Concentration
Steady-state Pharmacokinetics (PK) of pegvaliase was measured in subjects who have achieved and maintained target blood Phe
Time frame: At Baseline, Week 48, Week 96, Week 144, Week 216 and Week 240
Population: As PAL-003 is an extension of parent Phase 2 studies (PAL-002, PAL-004 \& 165-205), the parent Phase 2 treatment naïve baseline data (N=80) was used for the vital signs, immunogenicity \& PK analyses to monitor changes in vital signs mediated by pegvaliase, understand development \& maturation of immune response against pegvaliase, \& the resulting impact on PK. Refer to NCT00925054-PAL-002, NCT01212744-PAL-004 \& NCT01560286-165-205 for parent Ph2 demographic data (N=80).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rAvPAL-PEG | Pharmacokinetics-Plasma Pegvaliase Concentration | At Baseline | 961.5 ng/mL | Standard Deviation 3013.43 |
| rAvPAL-PEG | Pharmacokinetics-Plasma Pegvaliase Concentration | Week 48 | 4127.3 ng/mL | Standard Deviation 6116.72 |
| rAvPAL-PEG | Pharmacokinetics-Plasma Pegvaliase Concentration | Week 96 | 7457.7 ng/mL | Standard Deviation 10685.02 |
| rAvPAL-PEG | Pharmacokinetics-Plasma Pegvaliase Concentration | Week 144 | 7196.1 ng/mL | Standard Deviation 11678.89 |
| rAvPAL-PEG | Pharmacokinetics-Plasma Pegvaliase Concentration | Week 216 | 7764.4 ng/mL | Standard Deviation 9292.34 |
| rAvPAL-PEG | Pharmacokinetics-Plasma Pegvaliase Concentration | Week 240 | 6557.8 ng/mL | Standard Deviation 9220.95 |