Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency

Phase 3

Completed

Conditions: Arginase I Deficiency
Hyperargininemia

Interventions: Drug: Placebo
Drug: Pegzilarginase

Registration Number: NCT03921541

Lead Sponsor: Aeglea Biotherapeutics

Brief Summary: 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.

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

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

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
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
Subjects must be ≥ 2 years of age on the date of informed consent/assent
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
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
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
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

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
Active infection requiring anti-infective therapy within 3 weeks prior to first dose
Known active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
Extreme mobility deficit, defined as either the inability to be assessed on the GFAQ or a score of 1 on the GFAQ
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)
Has participated in a previous interventional study with pegzilarginase
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
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
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
Previous liver or hematopoietic transplant procedure.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Weekly IV infusions of placebo plus individualized disease management for 24 weeks
Pegzilarginase	Pegzilarginase	Weekly IV infusions of pegzilarginase plus individualized disease management for 24 weeks
Pegzilarginase Long Term Extension	Pegzilarginase	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Plasma Arginine Concentration After 24 Weeks of Treatment	Baseline through Week 24	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.

Secondary Outcome Measures

Name	Time	Method
Mean Change From Baseline in the Mobility Assessments of the Key Secondary Outcome Measure of the 2 Minute Walk Test	Baseline through Week 24	The Key Secondary outcome measure is the mean change from baseline in the 2 Minute Walk Test.
Mean Change From Baseline in the Mobility Assessments of the Key Secondary Outcome Measure of GMFM-E	Baseline through Week 24	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
Proportion of Participants With Plasma Arginine Levels Below Target Guidance	Baseline and week 24	Proportion of participants with plasma arginine levels below 200umol/L (target level set in disease management guidelines) after 24 weeks of treatment.
Proportion of Participants With Plasma Arginine Levels in Normal Range	Baseline to Week 24	Proportion of participants with plasma arginine levels between 40 - 115 umol/L (normal range for plasma arginine) after 24 weeks.
Change in Ornithine	Baseline and week 24	This analysis will measure the change from baseline in the level of ornithine after 24 weeks of treatment.
Change in Guanidino Compound-ARGA	Baseline to week 24	This analysis will measure the change from baseline in the level of ARGA after 24 weeks of treatment.
Change in Guanidino Compound - GAA	Baseline to week 24	This analysis will measure the change from baseline in the level of GAA compound after 24 weeks of treatment.
Change in Guanidino Compound - GVA	Baseline to week 24	This analysis will measure the change from baseline in the level of GVA compound after 24 weeks of treatment.
Change in Guanidino Compound - NAArg	Baseline to week 24	This analysis will measure the change from baseline in the level of NAArg compound after 24 weeks of treatment.
Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by GMFM-D	Baseline to week 24	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
Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Functional Mobility Scale (FMS)	Baseline to week 24	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.
Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Gillette Functional Assessment Questionnaire (GFAQ)	Baseline to week 24	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).
Mean Change From Baseline at Week 24 in Adaptive Behavior Assessed Using the Vineland Adaptive Behavior Scales (VABS)-II	Baseline to week 24	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.
Evaluate Safety of Pegzilarginase	Reporting will be from signing consent through follow-up (Baseline to Week 24)	Number of participants developing treatment related adverse events.
Evaluate Immunogenicity of Pegzilarginase	Baseline to week 24	The proportion of participants who develop (ADA) anti-drug antibodies to pegzilarginase will be measured over the period of the clinical trial.

Trial Locations

Locations (32): Emory University
🇺🇸
Atlanta, Georgia, United States
Harvey Pediatrics
🇺🇸
Rogers, Arkansas, United States
University of Florida College of Medicine
🇺🇸
Gainesville, Florida, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
Stanford University School of Medicine
🇺🇸
Stanford, California, United States
Hopital des Enfants
🇫🇷
Talence, France
LKH Bregenz
🇦🇹
Bregenz, Austria
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
UT Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
University of Utah Hospitals & Clinics
🇺🇸
Salt Lake City, Utah, United States
University Hospital of Wales
🇬🇧
Cardiff, United Kingdom
Birmingham Children's Hospital
🇬🇧
Birmingham, United Kingdom
Great Ormond Street Hospital for Children
🇬🇧
London, United Kingdom
Azienda Ospedaliera Città della Salute e della Scienza di Torino
🇮🇹
Torino, Italy
Salford Royal
🇬🇧
Salford, United Kingdom
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
McGill University Health Center
🇨🇦
Montreal, Quebec, Canada
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸
Chicago, Illinois, United States
Cohen Children's Medical Center (Northwell Health)
🇺🇸
Queens, New York, United States
University of Pittsburgh Medical Center
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Texas Health Science Center Medical School at Houston
🇺🇸
Houston, Texas, United States
Hôpital Necker - Enfants Malades
🇫🇷
Paris, France
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
🇩🇪
Mainz, Rheinland Pfalz, Germany
Universitaetsklinikum Muenster
🇩🇪
Muenster, Nordrhein Westfalen, Germany
Fondazione MBBM
🇮🇹
Monza, Italy
Ospedale Pediatrico Bambino Gesù
🇮🇹
Roma, Italy
Willink Biochemical Genetics Unit
🇬🇧
Manchester, United Kingdom
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Medizinische Universität Innsbruck
🇦🇹
Innsbruck, Austria