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

Phase 3Active Not RecruitingNCT05270837

BioMarin Pharmaceutical55 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Phenylketonuria (PKU)

Interventions

PegvaliaseDRUG

Pegvaliase 2.5mg/10mg/20mg/40mg/60mg self-administered from 1 time up to 7 times a week

Diet OnlyOTHER

Diet Control

Eligibility

Sex: ALLMin age: 12 YearsMax age: 17 Years

Medical Language ↔ Plain English

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.

Locations (16)

Phoenix Children's Hospital

Phoenix, Arizona, United States

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Outcomes

Primary Outcomes

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).

Time frame: 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).

Time frame: 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)

Time frame: 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)

Time frame: Baseline (Day 1), Week 73

Percentage of Participants With Positive PAL IgM Antibody

Data from ClinicalTrials.gov

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Secondary Outcomes

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).

Time frame: 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

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Week 73

Overall: Incidence of Treatment-emergent Adverse Events (Including Part 2)

Time frame: 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)

Time frame: Baseline (Day 1), Week 145

Part 2: Pegvaliase Tmax, Cmax, AUC0-24 and Cavg (Week 145 Intensive PK)

Time frame: Week 145