Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency

PEACE (Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints): A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Efficacy and Safety of Pegzilarginase in Children and Adults With Arginase 1 Deficiency

CAEB1102-300A is a multi-center randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of pegzilarginase in patients with ARG1-D. This study will consist of a screening period; a randomized, double-blind treatment period; a long-term extension; and a follow up visit for final safety assessments.

Study Overview

• Status: Completed
• Conditions: Arginase I Deficiency; Hyperargininemia
• Intervention / Treatment: Drug: Pegzilarginase; Drug: Placebo

Detailed Description

CAEB1102-300A is a multi-center randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of pegzilarginase in patients with ARG1-D. This study will consist of a screening period; a randomized, double-blind treatment period; a long-term extension; and a follow up visit for final safety assessments.

Subjects will be randomized to treatment following completion of all screening assessments and confirmation of study eligibility in a 2:1 ratio to receive weekly IV infusions of pegzilarginase plus individualized disease management (IDM) or placebo plus IDM during the 24-week double blind treatment period. After completion of the 24-week double-blind treatment period, each subject will enter the long term, open-label extension, the first 8 weeks of which are blinded. During the long-term extension, all subjects receive pegzilarginase plus IDM. After 8 weeks of the LTE study, patients have the option to receive treatment by subcutaneous administration (SC).

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Bregenz, Austria
    • LKH Bregenz
  • Innsbruck, Austria
    • Medizinische Universität Innsbruck
• Canada
  • Quebec
    • Montreal, Quebec, Canada
      • McGill University Health Center
• France
  • Paris, France
    • Hôpital Necker - Enfants Malades
  • Talence, France
    • Hopital Des Enfants
• Germany
  • Nordrhein Westfalen
    • Muenster, Nordrhein Westfalen, Germany
      • Universitaetsklinikum Muenster
  • Rheinland Pfalz
    • Mainz, Rheinland Pfalz, Germany
      • Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
• Italy
  • Monza, Italy
    • Fondazione MBBM
  • Roma, Italy
    • Ospedale Pediatrico Bambino Gesu
  • Torino, Italy
    • Azienda Ospedaliera Città della Salute e della Scienza di Torino
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Children's Hospital
  • Cardiff, United Kingdom
    • University Hospital of Wales
  • London, United Kingdom
    • Great Ormond Street Hospital for Children
  • Manchester, United Kingdom
    • Willink Biochemical Genetics Unit
  • Salford, United Kingdom
    • Salford Royal
• United States
  • Arkansas
    • Rogers, Arkansas, United States, 72758
      • Harvey Pediatrics
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • Queens, New York, United States, 11040
      • Cohen Children's Medical Center (Northwell Health)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center Medical School at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Hospitals & Clinics
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Subjects are eligible to be included in the study only if all the following criteria apply:

1. The subject and/or parent/guardian provides written informed consent/assent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

2. A current diagnosis of ARG1 D as documented in medical records, which must include 1 of the following: elevated plasma arginine levels, a mutation analysis that results in a pathogenic variant, or reduced RBC arginase activity. For entry into this study, subjects must also fulfill the following plasma arginine criteria:

   1. The average of all measured values of plasma arginine during the screening period prior to the randomization visit (Visit 1, Study Day 1) is ≥ 250 µmol/L
   2. If a subject is re-screened, the only values that are considered for eligibility assessment are those in the current screening period
3. Subjects must be ≥ 2 years of age on the date of informed consent/assent
4. The subject must be assessable for clinically meaningful within-subject change (clinical response) on at least one component of one assessment included in the key secondary/other secondary endpoints. To be considered assessable, the subject must be able to complete the assessment, and must have a baseline deficit in at least one component as defined in the protocol
5. Have received documented confirmation from the investigator and/or dietician that the subject can maintain their diet in accordance with dietary information presented in the protocol, ie, can maintain the current level of protein consumption, including natural protein and EAA supplementation
6. Subjects receiving ammonia scavenger therapy, anti-epileptic drugs, and/or medications for spasticity (eg, baclofen) must be on a stable dose of the medication for at least 4 weeks prior to randomization and be willing to remain on a stable dose during the double-blind portion and blinded follow-up portions of the study
7. Female and male subjects may participate. Female subjects of childbearing potential must have a negative serum pregnancy test during the screening period before receiving the first dose of study treatment, and a negative urine pregnancy test on the day of the first dose, prior to the first dose. If the subject (male or female) is engaging in sexual activity that could lead to pregnancy, must be surgically sterile, postmenopausal (no menses for 12 months without an alternative medical cause or a high FSH level in the postmenopausal range in women not using hormonal contraception or hormonal replacement therapy), or must agree to use a highly effective method of birth control during the study and for a minimum of 30 days after the last study drug administration. Highly effective methods of contraception include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation; progesterone-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); or abstinence (refraining from heterosexual intercourse during the entire period of risk associated with study treatment).

Exclusion Criteria:

1. Hyperammonemic episode (defined as an event in which a subject has an ammonia level ≥100 µM with one or more symptoms related to hyperammonemia requiring hospitalization or emergency room management) within the 6 weeks before the first dose of study drug is administered
2. Active infection requiring anti-infective therapy within 3 weeks prior to first dose
3. Known active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
4. Extreme mobility deficit, defined as either the inability to be assessed on the GFAQ or a score of 1 on the GFAQ
5. Other medical conditions or comorbidities that, in the opinion of the investigator would interfere with study compliance or data interpretation (eg, severe intellectual disability precluding required study assessments)
6. Has participated in a previous interventional study with pegzilarginase
7. Has a history of hypersensitivity to polyethylene glycol (PEG) that, in the judgment of the investigator, puts the subject at unacceptable risk for adverse events
8. Subject is being treated with botulinum toxin-containing regimens or plans to initiate such regimens during the double-blind or blinded follow-up portions of the study or received surgical or botulinum-toxin treatment for spasticity-related complications within the 16 weeks prior to the first dose of study treatment in this study
9. Is currently participating in another therapeutic clinical trial or has received any investigational agent within 30 days (or 5 half-lives whichever is longer) prior to the first dose of study treatment in this study
10. Previous liver or hematopoietic transplant procedure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pegzilarginase; Weekly IV infusions of pegzilarginase plus individualized disease management for 24 weeks	Drug: Pegzilarginase; Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated; Other Names: Co-ArgI-PEG; AEB1102
Placebo Comparator: Placebo; Weekly IV infusions of placebo plus individualized disease management for 24 weeks	Drug: Placebo; Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated
Experimental: Pegzilarginase Long Term Extension; After completion of 24 weeks DB treatment, weekly IV infusions of pegzilarginase plus individualized disease management for an additional 150 weeks, with the option to receive treatment by SC after 8 weeks of the LTE study.	Drug: Pegzilarginase; Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated; Other Names: Co-ArgI-PEG; AEB1102

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Plasma Arginine Concentration After 24 Weeks of Treatment	The primary analysis will test the change in the level of plasma arginine between baseline and completion of week 24 assessments. It will compare the change from baseline in plasma arginine between participants treated with pegzilarginase and those treated with placebo.	Baseline through Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in the Mobility Assessments of the Key Secondary Outcome Measure of the 2 Minute Walk Test	The Key Secondary outcome measure is the mean change from baseline in the 2 Minute Walk Test.	Baseline through Week 24
Mean Change From Baseline in the Mobility Assessments of the Key Secondary Outcome Measure of GMFM-E	The Key Secondary outcome measure is the mean change from baseline in GMFM-E The Gross Motor Function Measure (GMFM) utilize a 4-point scoring system for each item across dimensions A-E. GMFM-E assesses walking, running, and jumping. The minimum score for GMFM-E is 0; the maximum score is 72, with a higher score representing better gross motor function	Baseline through Week 24
Proportion of Participants With Plasma Arginine Levels Below Target Guidance	Proportion of participants with plasma arginine levels below 200umol/L (target level set in disease management guidelines) after 24 weeks of treatment.	Baseline and week 24
Proportion of Participants With Plasma Arginine Levels in Normal Range	Proportion of participants with plasma arginine levels between 40 - 115 umol/L (normal range for plasma arginine) after 24 weeks.	Baseline to Week 24
Change in Ornithine	This analysis will measure the change from baseline in the level of ornithine after 24 weeks of treatment.	Baseline and week 24
Change in Guanidino Compound-ARGA	This analysis will measure the change from baseline in the level of ARGA after 24 weeks of treatment.	Baseline to week 24
Change in Guanidino Compound - GAA	This analysis will measure the change from baseline in the level of GAA compound after 24 weeks of treatment.	Baseline to week 24
Change in Guanidino Compound - GVA	This analysis will measure the change from baseline in the level of GVA compound after 24 weeks of treatment.	Baseline to week 24
Change in Guanidino Compound - NAArg	This analysis will measure the change from baseline in the level of NAArg compound after 24 weeks of treatment.	Baseline to week 24
Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by GMFM-D	To compare pegzilarginase with placebo with respect to other aspects of mobility. The Gross Motor Function Measure (GMFM) utilize a 4-point scoring system for each item across dimensions A-E. GMFM-D assesses tasks related to standing. The minimum score for GMFM-D is 0; the maximum score is 39 with a higher score representing better gross motor function	Baseline to week 24
Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Functional Mobility Scale (FMS)	To compare pegzilarginase with placebo with respect to other aspects of mobility utilizing the FMS-5 Score. The functional mobility scale (FMS) is a 6-point scale from Level 1 (uses wheelchair, stroller, scooter, shopping cart, wagon, or is carried OR walks for exercise only with highly specialized/ supportive walker OR does limited stepping with substantial support/assistance from another person) to Level 6 (independent walking and running on all surfaces without assistive devices or help from another person) that assesses the need for assistive devices for walks of 3 different lengths: 5 meters, 50 meters, and 500 meters.	Baseline to week 24
Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Functional Mobility Scale (FMS)	To compare pegzilarginase with placebo with respect to other aspects of mobility utilizing the FMS-50 Score. The functional mobility scale (FMS) is a 6-point scale from Level 1 (uses wheelchair, stroller, scooter, shopping cart, wagon, or is carried OR walks for exercise only with highly specialized/ supportive walker OR does limited stepping with substantial support/assistance from another person) to Level 6 (independent walking and running on all surfaces without assistive devices or help from another person) that assesses the need for assistive devices for walks of 3 different lengths: 5 meters, 50 meters, and 500 meters.	Baseline to week 24
Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Functional Mobility Scale (FMS)	To compare pegzilarginase with placebo with respect to other aspects of mobility utilizing the FMS-500 Score. The functional mobility scale (FMS) is a 6-point scale from Level 1 (uses wheelchair, stroller, scooter, shopping cart, wagon, or is carried OR walks for exercise only with highly specialized/ supportive walker OR does limited stepping with substantial support/assistance from another person) to Level 6 (independent walking and running on all surfaces without assistive devices or help from another person) that assesses the need for assistive devices for walks of 3 different lengths: 5 meters, 50 meters, and 500 meters.	Baseline to week 24
Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Gillette Functional Assessment Questionnaire (GFAQ)	To compare pegzilarginase with placebo with respect to other aspects of mobility. The Gillette Functional Assessment Questionnaire (GFAQ) is a parent/caregiver assessment consisting of a single question describing a child's ability to walk using a 10-point scale from Level 1 (cannot take any steps at all) to Level 10 (walks, runs, and climbs on uneven terrain and does stairs without difficulty or assistance; is typically able to keep up with peers).	Baseline to week 24
Mean Change From Baseline at Week 24 in Adaptive Behavior Assessed Using the Vineland Adaptive Behavior Scales (VABS)-II	To compare pegzilarginase with placebo with respect to adaptive behavior. The Vineland Adaptive Behavior Scales (VABS-II) is a scale designed to measure adaptive behavior of individuals from birth to age 90 years. The VABS-II contains 4 domains: communication, daily living skills, socialization, and motor skills. The domains are made up of 11 subdomains in which the scores are added to form the domain composite scores. The 4 domain composite scores then combine to form the adaptive behavior composite for those individuals aged birth to 6 years 11 months. Three domain composite scores (communication, daily living skills, and socialization) combine to form the adaptive behavior composite for those ages 7 through 90 years. The VABS-II scoring system describes adequate adaptive behavior by subdomain as 13 to 17 and 86 to 114 for the composite score, with higher scores indicating better adaptive functioning.	Baseline to week 24
Evaluate Safety of Pegzilarginase	Number of participants developing treatment related adverse events.	Reporting will be from signing consent through follow-up (Baseline to Week 24)
Evaluate Immunogenicity of Pegzilarginase	The proportion of participants who develop (ADA) anti-drug antibodies to pegzilarginase will be measured over the period of the clinical trial.	Baseline to week 24

Collaborators and Investigators

• Sponsor: Aeglea Biotherapeutics
• Investigators: Study Director: Cortney Caudill, Aeglea BioTherapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2019
• Primary Completion (Actual): January 27, 2023
• Study Completion (Actual): January 27, 2023

Study Registration Dates

• First Submitted: April 9, 2019
• First Submitted That Met QC Criteria: April 16, 2019
• First Posted (Actual): April 19, 2019

Study Record Updates

• Last Update Posted (Estimated): November 19, 2024
• Last Update Submitted That Met QC Criteria: November 13, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: ARG1-D
• 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; Urea Cycle Disorders, Inborn; Hyperargininemia
• Other Study ID Numbers: CAEB1102-300A

Drug and device information, study documents

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