Study to Evaluate the Safety and Efficacy of Pegvaliase in Adolescents (Ages 12-17) With Phenylketonuria (PEGASUS)

A Phase 3 Multi-Center Study to Evaluate the Safety and Efficacy of Subcutaneous Injections of Pegvaliase in Adolescent Subjects (Ages 12-17) With Phenylketonuria- Open-Label Randomized Two-Arm (Active vs Diet-Only Control)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Phenylketonuria (PKU)
• Intervention / Treatment: Drug: Pegvaliase; Other: Diet Only

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.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • Charité - Universitätsmedizin Berlin
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf
  • Mainz, Germany
    • Universitat Mainz
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • IU Health University Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • University of Kentucky College of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth)
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia School of Medicine
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Diet Only; Participants will be managing their PKU with diet alone. Participants in the diet-only control arm will be required to maintain and adjust dietary and medical protein food intake through Week 72, initiating pegvaliase treatment beginning Week 73 and, from Weeks 73 through 215.	Other: Diet Only; Diet Control
Experimental: Pegvaliase; Treatment Arm	Drug: Pegvaliase; Pegvaliase 2.5mg/10mg/20mg/40mg/60mg self-administered from 1 time up to 7 times a week; Other Names: PEG PAL; BMN 165

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Blood Phe Concentration Following 72 Weeks (Average of the Week 69 and Week 73) on Study.	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).	Baseline to Week 72 (average of the Week 69 and Week 73)
Incidence of Treatment-emergent Adverse Events (Part 1)	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).	Up to Week 73
Percentage of Participants With Positive Anti-pegvaliase Total Antibody (TAb)	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)	Baseline (Day 1), Week 73
Percentage of Participants With Positive PAL IgG Antibody	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)	Baseline (Day 1), Week 73
Percentage of Participants With Positive PAL IgM Antibody	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)	Baseline (Day 1), Week 73
Percentage of Participants With Positive PEG IgG Antibody	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)	Baseline (Day 1), Week 73
Percentage of Participants With Positive PEG IgM Antibody	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)	Baseline (Day 1), Week 73
Percentage of Participants With Positive Neutralizing Antibodies (NAb)	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)	Baseline (Day 1), Week 73

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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).	Baseline to Week 72 (average of Week 69 and week 73)
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	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).	Baseline to Week 72 (average of Week 69 and week 73)
Pegvaliase Tmax (Week 73 Intensive PK)	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)	Week 73
Pegvaliase Cmax (Week 73 Intensive PK)	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.	Week 73
Pegvaliase AUC0-24 (Week 73 Intensive PK)	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.	Week 73
Pegvaliase Cavg (Week 73 Intensive PK)	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.	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

Other Outcome Measures

Outcome Measure	Time Frame
Characterize area under plasma concentration time curve (AUC) of pegvaliase	Baseline to 215 weeks
Characterize maximum plasma concentration (Cmax) of pegvaliase	Baseline to 215 weeks
Characterize trough plasma concentration (Ctrough) of pegvaliase	Baseline to 215 weeks
Characterize time to reach maximum plasma concentration (Tmax) of pegvaliase	Baseline to 215 weeks

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Chair: Study Director, BioMarin Pharmaceutical

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2022
• Primary Completion (Actual): January 14, 2025
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: February 1, 2022
• First Submitted That Met QC Criteria: February 25, 2022
• First Posted (Actual): March 8, 2022

Study Record Updates

• Last Update Posted (Actual): July 21, 2026
• Last Update Submitted That Met QC Criteria: June 23, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Phenylketonuria; PKU; BioMarin; Pegvaliase; BMN165; PAL; Subcutaneous Injections; adolescent PKU
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Amino Acid Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Phenylketonurias; pegvaliase
• Other Study ID Numbers: 165-306

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No