Phenylketonuria (PKU)
Conditions
Brief summary
This is a Phase 3 open-label extension study enrolling adult patients with PKU who were previously treated with pegvaliase in Studies PAL-003 (NCT00924703) or 165-302 (NCT02468570). The study is designed to evaluate the long-term safety and efficacy of pegvaliase administered at doses \> 40 mg/day to 60 mg/day.
Detailed description
Pegvaliase dosing will continue without interruption from Parent Study 165-302 (NCT02468570) or Parent Study PAL-003 (NCT00924703). Beginning on Day 1, subjects will receive the same dose and regimen of pegvaliase they were receiving in either 165-302 or PAL-003. A subject who reduces to a dose of 40 mg/day or lower for 32 consecutive weeks will be discontinued from study drug and withdrawn from the study as they will have the option to transition to commercial drug. Dose reductions may be performed if warranted due to AEs or hypophenylalaninemia. Dose increases to up to 60 mg/day may be performed per investigator discretion in consultation with the sponsor's medical monitor. Dosing will continue for approximately 121 weeks.
Interventions
DRUGPegvaliase
40-60mg/day
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Must be enrolled in PAL-003 or 165-302 Part 4 at the time of screening for 165-304 and most recently receiving pegvaliase at a dose \> 40 mg/day. * Has identified a competent person or persons ≥ 18 years of age who can observe the subject during study drug administration and for a minimum of 1 hour following administration in situations required per protocol. * For females with childbearing potential, must have negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. * If sexually active and not planning to become pregnant (self or partner), must be willing to use 2 acceptable methods of contraception while participating in the study and for 4 weeks after the study. * Is 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; a legally authorized representative may provide written consent and assent may be requested. * Is willing and able to comply with all study procedures. * Is in generally good health, as evidenced by physical examination and/or clinical laboratory evaluations (hematology, chemistry, and urinalysis).
Exclusion criteria
* Use of any investigational product (except pegvaliase) 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 (except pegvaliase) intended to treat PKU, including the use of large neutral amino acids, within 2 days prior to the administration of pegvaliase (Day 1). * Use or planned use of any injectable drugs containing PEG (other than pegvaliase), including medroxyprogesterone injection, within 3 months prior to screening and during study participation. * A history of organ transplantation or on chronic immunosuppressive therapy * A history of substance abuse (as defined by the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders \[DSM\]) in the past 12 months or current alcohol or drug abuse * Current participation in the Kuvan® registry study (PKU Demographics, Outcomes and Safety \[PKUDOS\]) * 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 terminating early from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0 | Up to Day 741 (approximately Week 106) | 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 |
| Change in Blood Phe Concentration | The Outcome Measure Data Table below uses the 'analysis visit' as defined by the mapping rule in the SAP. The last Phe measurement was mapped to 'analysis visit' week 121. The actual date of the last Phe measurement was day 836 (approximately Week 119). | Change in blood phenylalanine (Phe) concentration from Parent Study baseline (naïve/pretreatment). |
Countries
United States
Participant flow
Recruitment details
This was a multicenter study, conducted in 17 study centers in the United States involving subjects from either Parent Study 165-302 (NCT02468570) or Parent Study PAL-003 (NCT00924703).
Participants by arm
| Arm | Count |
|---|---|
| All Subjects Self administered subcutaneous pegvaliase injection using a prefilled syringe. | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Subject received <= 40 mg/day for > 32 weeks | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 28.84 years STANDARD_DEVIATION 9.02 |
| Age, Customized 16 to < 18 years | 2 Participants |
| Age, Customized >/= 66 years | 0 Participants |
| Age, Customized Between 18 and < 66 years | 35 Participants |
| Baseline Blood Phe | 1376.9 umol/L STANDARD_DEVIATION 289.77 |
| Body Mass Index (BMI) | 32 kg/m^2 STANDARD_DEVIATION 8.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 36 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 22 Participants |
| Weight | 94.9 kg STANDARD_DEVIATION 29.75 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 37 |
| other Total, other adverse events | 36 / 37 |
| serious Total, serious adverse events | 7 / 37 |
Outcome results
Primary
Change in Blood Phe Concentration
Change in blood phenylalanine (Phe) concentration from Parent Study baseline (naïve/pretreatment).
Time frame: The Outcome Measure Data Table below uses the 'analysis visit' as defined by the mapping rule in the SAP. The last Phe measurement was mapped to 'analysis visit' week 121. The actual date of the last Phe measurement was day 836 (approximately Week 119).
Population: Efficacy population consisted of all subjects receiving at least one dose of pegvaliase during the study and having a post-treatment blood Phe concentration measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 121 | -1123 µmol/L | — |
| All Subjects | Change in Blood Phe Concentration | Parent Study Baseline (naïve/pretreatment) | 1376.9 µmol/L | Standard Deviation 289.77 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline to Screening/Day 1 | -761 µmol/L | Standard Deviation 506.7 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at week 9 | -970.6 µmol/L | Standard Deviation 513.6 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 17 | -963.4 µmol/L | Standard Deviation 454 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 25 | -830.6 µmol/L | Standard Deviation 599.8 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 33 | -999.8 µmol/L | Standard Deviation 528 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 41 | -984.1 µmol/L | Standard Deviation 545.6 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 49 | -1001.7 µmol/L | Standard Deviation 518.3 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 57 | -867 µmol/L | Standard Deviation 569.2 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 65 | -913.2 µmol/L | Standard Deviation 445 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 73 | -896 µmol/L | Standard Deviation 582.8 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 81 | -847.8 µmol/L | Standard Deviation 504 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 89 | -962.3 µmol/L | Standard Deviation 482.6 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 97 | -865.6 µmol/L | Standard Deviation 567.4 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 105 | -817.4 µmol/L | Standard Deviation 584.9 |
| All Subjects | Change in Blood Phe Concentration | Change from Baseline at Week 113 | -1319 µmol/L | Standard Deviation 123 |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0
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
Time frame: Up to Day 741 (approximately Week 106)
Population: Population consisted of all subjects receiving at least one dose of pegvaliase during the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Subjects | Number of Participants With Treatment-emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0 | TEAE | 36 Participants |
| All Subjects | Number of Participants With Treatment-emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0 | Related TEAE | 17 Participants |
| All Subjects | Number of Participants With Treatment-emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0 | Serious TEAE | 7 Participants |
| All Subjects | Number of Participants With Treatment-emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0 | Related Serious TEAE | 1 Participants |