Phenylketonuria (PKU)
Conditions
Keywords
PKU, BioMarin, Phenylketonuria, BMN165, PAL, Subcutaneous Injections, Pegvaliase, adolescent PKU
Brief summary
This is a Phase 3 open-label randomized controlled study enrolling approximately 54 adolescents with PKU. The study is designed to assess the safety and efficacy of pegvaliase injections.
Detailed description
This Phase 3 multicenter study is designed to evaluate the safety and efficacy of pegvaliase administered daily to adolescents (ages 12 to 17 years old (US), inclusive, and 12 to 15 years old (EU), inclusive 12-17) with phenylketonuria (PKU). Participants will be randomized in a 2:1 ratio to the active (pegvaliase) and control (diet-only) treatment arms, respectively, with 36 participants receiving pegvaliase and 18 participants managing their PKU with diet alone.
Interventions
DRUGPegvaliase
Pegvaliase 2.5mg/10mg/20mg/40mg/60mg self-administered from 1 time up to 7 times a week
OTHERDiet Only
Diet Control
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Is 12 to 17 years old (US), inclusive, or 12 to 15 years (EU), inclusive, at the start of the Screening/Run-in Period (Day -28). * Diagnosis of PKU and failure to maintain recommended blood Phe levels on existing management (sapropterin dihydrochloride and Phe-restricted diet) demonstrated by 2 blood Phe concentration measurements \> 600 μmol/L during the Screening/Run-in Period (7 to 10 days in between blood Phe assessments) and average blood Phe concentration \> 600 μmol/L over the past 12 months (per available data). * Willing and able to maintain and adjust dietary and medical protein food intake according to the study protocol under the supervision of a study dietician or adequately trained designee per investigator discretion during study participation. * If on medication for ADHD, depression, or other psychiatric disorder, stable dose of medication for ≥ 8 weeks prior to enrollment and willing to maintain stable dose unless a change is medically indicated. * An adult (≥ 18 years of age) has been identified who is willing and competent to observe the participant during study drug administration and for a minimum of 1 hour following administration. * Participants must be capable of giving signed informed consent * If sexually active, male or female participants must not plan to become pregnant (self or partner) and must use 2 acceptable methods of contraception while participating in the study beginning at Screening and for 4 weeks after discontinuing study drug.
Exclusion criteria
* Previous treatment with pegvaliase. * Use of any medication that is intended to treat PKU, including the use of large neutral amino acids, within 14 days prior to the administration of study drug on Day 1. * Use or planned use of any injectable drugs containing polyethylene glycol (PEG; other than pegvaliase), including medroxyprogesterone injection, within 3 months prior to the start of Screening/Run-in and during study participation with the exception of COVID-19 vaccinations. * A history of organ transplantation or on chronic immunosuppressive therapy. * Use of any investigational product or investigational medical device within 30 days prior to Screening/Run-in or requirement for any investigational agent prior to completion of all scheduled study assessments. * A positive test for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody. * Alanine aminotransferase (ALT) concentration \> 2 × the upper limit of normal (ULN). * Creatinine \> 1.5 × ULN. * Inability to identify and/or communicate to others that the participant is experiencing symptoms of potential anaphylaxis due to cognitive impairment or other reasons.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Blood Phe Concentration Following 72 Weeks (Average of the Week 69 and Week 73) on Study. | Baseline to Week 72 (average of the Week 69 and Week 73) | The blood Phe measurement following 72 weeks on study is defined as the average of the Week 69 and Week 73 blood Phe measurements. Change from baseline in blood Phe will be compared between participants in the active (pegvaliase) and the control (diet-only) treatment arms. Baseline blood Phe concentration at Part 1 was defined as the average of 3 pre-treatment measurements collected between Screening/Run-in (2) and Day 1 pre-dose (1). |
| Incidence of Treatment-emergent Adverse Events (Part 1) | Up to Week 73 | Treatment-emergent adverse events (TEAE) is defined as any AE that newly appeared or worsened in severity after first dose of pegvaliase (pegvaliase arm) or on or after study day 1 (diet-only arm) until 30 days after last dose of the study. Serious adverse event (SAE). |
| Percentage of Participants With Positive Anti-pegvaliase Total Antibody (TAb) | Baseline (Day 1), Week 73 | The anti-pegvaliase total antibody (TAb) method captures drug-binding antibodies comprised of different isotypes and specificities. Antibody Positivity = number of subjects testing positive at any study visit / total number of subjects at study visit. The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm) |
| Percentage of Participants With Positive PAL IgG Antibody | Baseline (Day 1), Week 73 | The presence of immunoglobulin G (IgG) Antibodies against phenylalanine ammonia lyase (PAL) is measured overtime. The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm) |
| Percentage of Participants With Positive PAL IgM Antibody | Baseline (Day 1), Week 73 | The presence of immunoglobulin M (IgM) Antibodies against PAL (phenylalanine ammonia lyase) is measured overtime. PAL IgM was positive if the titer value was greater than or equal to the median of all baseline PAL IgM titers. The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm) |
| Percentage of Participants With Positive PEG IgG Antibody | Baseline (Day 1), Week 73 | The presence of IgG Antibodies against polyethylene glycol (PEG) is measured overtime The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm) |
| Percentage of Participants With Positive PEG IgM Antibody | Baseline (Day 1), Week 73 | The presence of IgM Antibodies against PEG (polyethylene glycol) is measured overtime The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm) |
| Percentage of Participants With Positive Neutralizing Antibodies (NAb) | Baseline (Day 1), Week 73 | Neutralizing antibodies (NAbs) capable of inhibiting the enzymatic activity of pegvaliase were measured. The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Dietary Protein Intake (i.e., Medical Food and/or Intact Food) Following 72 Weeks (Average of Week 69 and Week 73) on Study | Baseline to Week 72 (average of Week 69 and week 73) | The total dietary protein intake following 72 weeks on study is defined as the mean total dietary protein intake calculated from the 3-day diet diaries collected at Week 69 and Week 73 visits. Total dietary protein is measured in grams/kilogram (g/kg). Baseline total protein intake at Part 1 was defined as the mean total dietary protein intake calculated from the 3 separate 3-day diet diaries collected during Screening/Run-in (2) and Day 1 (1). |
| Percentage Change From Baseline in Total Dietary Protein Intake (i.e., Medical Food and/or Intact Food) Following 72 Weeks (Average of Week 69 and Week 73) on Study | Baseline to Week 72 (average of Week 69 and week 73) | The total dietary protein intake following 72 weeks on study is defined as the mean total dietary protein intake calculated from the 3-day diet diaries collected at Week 69 and Week 73 visits. Total dietary protein is measured in grams/kilogram (g/kg). Baseline total protein intake at Part 1 was defined as the mean total dietary protein intake calculated from the 3 separate 3-day diet diaries collected during Screening/Run-in (2) and Day 1 (1). |
| Pegvaliase Tmax (Week 73 Intensive PK) | Week 73 | Time to maximum observed plasma concentration (Tmax) for pegvaliase during the Week 73 intensive PK assessment, defined as the elapsed time from dosing to the sampling time at which the highest observed pegvaliase plasma concentration (Cmax) occurs based on the Week 73 plasma concentration-time profile. Pharmacokinetic (PK) |
| Pegvaliase Cmax (Week 73 Intensive PK) | Week 73 | Maximum observed plasma concentration (Cmax) of pegvaliase during the Week 73 intensive PK assessment, defined as the highest measured pegvaliase plasma concentration across the Week 73 postdose sampling interval. Cmax is summarized in ng/mL concentration units based on observed values from the Week 73 concentration-time profile. |
| Pegvaliase AUC0-24 (Week 73 Intensive PK) | Week 73 | Area under the plasma concentration-time curve from 0-24 hours postdose (AUC0-24) for pegvaliase during the Week 73 intensive PK assessment. AUC0-24 was calculated form the Week 73 plasma concentration-time data using noncompartmental methods and reported in ng\*h/mL units. |
| Pegvaliase Cavg (Week 73 Intensive PK) | Week 73 | Average plasma concentration over the 0 to 24 hour postdose interval for pegvaliase during the Week 73 intensive PK assessment, reported in ng/mL concentration units, representing the mean pegvaliase exposure across the 24 hour postdose interval at Week 73. |
| Overall: Incidence of Treatment-emergent Adverse Events (Including Part 2) | Up to Week 153 | — |
| Part 2: Percentage of Participants With Anti-pegvaliase Total Antibody (TAb), Positive PAL IgG Antibody, Positive PAL IgM Antibody, Positive PEG IgG Antibody, Positive PEG IgM Antibody and Positive Neutralizing Antibodies (NAb) | Baseline (Day 1), Week 145 | — |
| Part 2: Pegvaliase Tmax, Cmax, AUC0-24 and Cavg (Week 145 Intensive PK) | Week 145 | — |
Countries
Germany, United States
Contacts
STUDY_CHAIRStudy Director
BioMarin Pharmaceutical
Participant flow
Recruitment details
This study was conducted by 13 principal investigators at 13 study centers in the United States of America and 3 principal investigators at 3 study centers in Germany.
Pre-assignment details
Approximately 54 participants planned (36 pegvaliase; 18 diet-only); 55 participants randomized (36 pegvaliase; 19 diet-only) and 49 participants completed Part 1 (32 pegvaliase; 17 diet-only); the other 6 participants discontinued from study before reaching Week 73.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 14.3 years STANDARD_DEVIATION 1.27 |
| Age, Customized 12 years | 7 Participants |
| Age, Customized 13 years | 5 Participants |
| Age, Customized 14 years | 19 Participants |
| Age, Customized 15 years | 16 Participants |
| Age, Customized 16 years | 6 Participants |
| Age, Customized 17 years | 2 Participants |
| Blood Phe Concentration | 1025.3 µmol/L STANDARD_DEVIATION 254.05 |
| BMI | 24.0 kg/m^2 STANDARD_DEVIATION 6.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| PAL IgG | 11 Participants |
| PAL IgM | 18 Participants |
| PEG IgG | 26 Participants |
| PEG IgM | 10 Participants |
| Protein from intact food | 0.2 g/kg STANDARD_DEVIATION 0.15 |
| Protein from medical food | 0.8 g/kg STANDARD_DEVIATION 0.34 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment Germany | 8 participants |
| Region of Enrollment United States | 44 participants |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 8 Participants |
| Total protein intake | 1.1 g/kg STANDARD_DEVIATION 0.41 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 19 |
| other Total, other adverse events | 36 / 36 | 17 / 19 |
| serious Total, serious adverse events | 2 / 36 | 1 / 19 |
Outcome results
None listed