Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Arginase I Deficiency, Hyperargininemia

Intervention / Treatment
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* Drug: Pegzilarginase
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: 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 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.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pegzilarginase<br>Weekly IV infusions of pegzilarginase plus individualized disease management for 24 weeks | Drug: Pegzilarginase<br>* Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated<br>* Other names: Co-ArgI-PEG; AEB1102;|
| Placebo Comparator: Placebo<br>Weekly IV infusions of placebo plus individualized disease management for 24 weeks | Drug: Placebo<br>* Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated<br>|
| Experimental: Pegzilarginase Long Term Extension<br>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<br>* Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated<br>* Other names: Co-ArgI-PEG; AEB1102;|

What is the study measuring?
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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 and 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. | Baseline and 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. | Week 24 | 
| Change in ornithine and guanidino compounds | This analysis will measure the change from baseline in the level of ornithine and guanidino compounds after 24 weeks of treatment. | Baseline and 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. | Baseline, week 12 and 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. | Baseline, week 12 and 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. | Baseline, week 12 and 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. | Baseline, week 12 and week 24 | 
| Evaluate safety of pegzilarginase | Number of participants developing treatment related adverse events. | Reporting will be from signing consent through follow-up (assessed for up to 174 weeks) | 
| 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, week 2, week 7, week 12, week 17, week 24 | 
| Pharmacokinetic profile of pegzilarginase | 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. | Baseline, week 12, week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARG1-D