Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency

• ClinicalTrials.gov Identifier: NCT03921541
• Recruitment Status: Recruiting
• First Posted: April 19, 2019
• Last Update Posted: December 4, 2019
• Sponsor: Aeglea Biotherapeutics
• Information provided by (Responsible Party): Aeglea Biotherapeutics

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Arginase I Deficiency; Hyperargininemia	Drug: Pegzilarginase; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: April 10, 2019
• Estimated Primary Completion Date: March 2021
• Estimated Study Completion Date: June 2023

Arms and Interventions

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 Name: 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 24 weeks, weekly IV infusions of pegzilarginase plus individualized disease management for for an additional 150 weeks	Drug: Pegzilarginase; Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated; Other Name: Co-ArgI-PEG; AEB1102

Outcome Measures

Primary Outcome Measures :

1. Change in plasma arginine concentration [ Time Frame: Baseline through 24 weeks ]
   The primary analysis will test the change in the level of plasma arginine between baseline and week 24. It will compare the level of plasma arginine between participants treated with pegzilarginase and those treated with placebo.

Secondary Outcome Measures :

1. Clinical response in any of the mobility or adaptive behavior [ Time Frame: Baseline, week 12 and week 24 ]
   The Key Secondary outcome measure will compare the proportion of participants in either the pegzilarginase or the placebo arm who have a Clinical Response after 12 and 24 weeks of treatment. A Clinical Response is defined by either a Mobility Response or an Adaptive Behavior Response in at least one of the component assessments. The component assessments are the 2 Minute Walk Test, Functional Mobility Assessment or the Vineland Adaptive Behavior Scale II.
2. Clinical Response in each individual mobility and adaptive behavior assessment [ Time Frame: Baseline, week 12 and week 24 ]
   Each participant will be measured on whether or not (yes/no) they have a Clinical Response at week 12 and week 24 on each of the individual component assessments from the Key Secondary Outcome Measure above (2). Mobility is measured by the 2 Minute Walk Test and the Functional Mobility Assessment and adaptive behavior is measured by the Vineland Adaptive Behavior Scale II."
3. Number of assessments where a Clinical Response is seen [ Time Frame: Baseline, week 12 and week 24 ]
   The number of individual components of the Key Secondary Outcome Measure where a Clinical Response is demonstrated in each participant will be measured (0, 1, 2 or 3) at week 12 and week 24 and will be compared between pegzilarginase and placebo arms.
4. Proportion of participants with plasma arginine levels below target guidance [ Time Frame: Baseline, week 12 and week 24 ]
   Proportion of participants with plasma arginine levels below 200umol/L (target level set in disease management guidelines) at week 24.
5. Proportion of participants with plasma arginine levels in normal range [ Time Frame: week 24 ]
   Proportion of participants with plasma arginine levels between 40 - 115 umol/L (normal range for plasma arginine) at week 24.
6. Change in guanidino compounds [ Time Frame: Baseline and week 24 ]
   Guanidino compounds (direct or indirect breakdown products from arginine) have been shown to be elevated in patients with Arg1-D. This analysis will measure the change in the level of guanidino compounds between baseline and week 24.
7. Immunogenicity of pegzilarginase [ Time Frame: Baseline, week 1, week 7, week 12, week 17, week 24 ]
   The proportion of participants who develop antibodies to pegzilarginase will be measured over the period of the clinical trial.
8. Pharmacokinetic profile of pegzilarginase [ Time Frame: Baseline, week 12, week 24 ]
   The pharmacokinetic profile of pegzilarginase will be characterized by measuring plasma concentration at several time points at baseline, week 12 and week 24. The time points are pre-infusion and then 1 hr, 2 hr, 4 hr, 24 hr, 96 hr and 168 hr after infusion.
9. Determine if adverse events occur [ Time Frame: Reporting will be from 1st dose through follow-up (assessed for up to 174 weeks) ]
   Number of participants developing treatment related adverse events.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

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. For entry into this study, subjects must also fulfill the following plasma arginine criterion:

   1. The average of all measured values of plasma arginine during the screening period prior to the randomization visit (Visit 1, Study Day 0) 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 endpoint. To be considered assessable, the subject must be able to complete the assessment, and must have a baseline deficit in the specific component as defined in the protocol
5. Have received documented confirmation from the investigator and/or dietician that the subject is capable of maintaining their diet in accordance with dietary information presented in the protocol, i.e., is capable of maintaining their current level of protein consumption including natural protein and essential amino acid supplementation
6. Subjects receiving ammonia scavenger therapy, anti-epileptic drugs, and/or medications for spasticity (e.g., 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 child-bearing 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 (female), 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); or intrauterine hormone-releasing system (IUS)

Exclusion Criteria:

1. Hyperammonemic episode (defined as an event in which a subject has an ammonia level > 100 umol/L 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 in 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 (e.g., 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 within last 6 months for spasticity related complications
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 on this study
10. Previous liver or hematopoietic transplant procedure.

Contacts and Locations

Contacts

Contact: Aeglea Clinical Department; 1.855.509.9921; raredisease@aegleabio.com

Locations

United States, District of Columbia

Children's National Medical Center; Recruiting

Washington, District of Columbia, United States, 20010

Contact: Nicholas Ah Mew, MD

Principal Investigator: Nicholas Ah Mew, MD

United States, New York

Icahn School of Medicine at Mount Sinai; Recruiting

New York, New York, United States, 10029

Contact: George Diaz, MD

Principal Investigator: George Diaz, MD

Cohen Children's Medical Center (Northwell Health); Recruiting

Queens, New York, United States, 11040

Contact: Laura Pisani, MD

Principal Investigator: Laura Pisani, MD

United States, Texas

UT Southwestern Medical Center; Recruiting

Dallas, Texas, United States, 75390

Contact: Markey McNutt, MD

Principal Investigator: Markey McNutt, MD

United States, Washington

Seattle Children's Hospital; Recruiting

Seattle, Washington, United States, 98105

Contact: Angela Sun, MD

Principal Investigator: Angela Sun, MD

Austria

LKH Bregenz; Recruiting

Bregenz, Austria

Contact: Martina Huemer, MD

Principal Investigator: Martina Huemer, MD

Medizinische Universität Innsbruck; Recruiting

Innsbruck, Austria

Contact: Daniela Karall, MD

Principal Investigator: Daniela Karall, MD

United Kingdom

Birmingham Children's Hospital; Recruiting

Birmingham, United Kingdom

Contact: Suresh Vijayaraghavan, MD

Principal Investigator: Suresh Vijayaraghavan, MD

University Hospital of Wales; Recruiting

Cardiff, United Kingdom

Contact: Graham Shortland, MD

Principal Investigator: Graham Shortland, MD

Great Ormond Street Hospital for Children; Recruiting

London, United Kingdom

Contact: Spyros Batzios, MD

Principal Investigator: Spyros Batzios, MD

Salford Royal; Recruiting

Salford, United Kingdom

Contact: Reena Sharma, MD

Principal Investigator: Reena Sharma, MD

Sponsors and Collaborators

Aeglea Biotherapeutics

Investigators

• Study Director: Josie Gayton; Aeglea Biotherapeutics, Inc.

More Information

• Responsible Party: Aeglea Biotherapeutics
• ClinicalTrials.gov Identifier: NCT03921541 History of Changes
• Other Study ID Numbers: CAEB1102-300A
• First Posted: April 19, 2019
• Last Update Posted: December 4, 2019
• Last Verified: December 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Aeglea Biotherapeutics:

ARG1-D

Additional relevant MeSH terms:

Hyperargininemia; Urea Cycle Disorders, Inborn; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases