Principal Investigator: Nicola Longo
Keywords: Arginase 1 Deficiency , PEACE study Department: Pediatric Genetics
IRB Number: 00124126
Specialty: Pediatric Genetics
Sub Specialties: Medical Genetics
Recruitment Status: Recruiting

Contact Information

Carrie Bailey
carrie.bailey@hsc.utah.edu
8015873605

Brief Summary

Study Purpose:

Pegzilarginase is being investigated as an enzyme therapy for ARG1-D. Biological activity of pegzilarginase has been demonstrated based on non-clinical studies and clinical data from the CAEB1102-101A and CAEB1102-102A studies in ARG1-D subjects. The current study seeks to confirm the clinical utility of pegzilarginase for the treatment of patients with ARG1-D. Lowering plasma arginine levels into the normal range via pegzilarginase administration may allow the potential to slow or halt the progression of neuromotor, neurocognitive, and/or adaptive behavioral deterioration in patients with ARG1-D.

Primary Objectives:

  • Demonstrate the efficacy of pegzilarginase relative to placebo based on a statistically significant decrease from baseline in plasma arginine concentrations after 24 weeks of study treatment

Key Secondary Objective:

  • Demonstrate the efficacy of pegzilarginase relative to placebo based on a statistically significantly greater proportion of clinical responders

Secondary Objectives:

  • Compare the proportions of subjects with response in the individual components of the key secondary endpoint between pegzilarginase and placebo
  • Compare pegzilarginase with placebo with respect to other aspects of mobility
  • Compare pegzilarginase with placebo with respect to adaptive behavior
  • Compare pegzilarginase with placebo with respect to the number of individual components of the key secondary endpoint exhibiting response
  • Compare pegzilarginase with placebo with respect to the proportion of subjects whose endpoint arginine value falls below target goal of 200 µmol/L
  • Compare pegzilarginase with placebo with respect to the proportions of subjects whose endpoint arginine value falls within the normal range of 40-115µmol/L
  • Compare pegzilarginase with placebo for changes in guanidino compounds
  • Evaluate the safety and immunogenicity of pegzilarginase
  • Further characterize the pharmacokinetic profile of pegzilarginase

Tertiary Objectives:

  • Describe caregiver and clinician global impression of the impact of pegzilarginase on motor function
  • Describe caregiver and clinician global impression of the impact of pegzilarginase on adaptive behavior
  • Describe the impact of pegzilarginase on other aspects of motor function
  • Describe the impact of pegzilarginase on quality of life
  • Describe the impact of pegzilarginase on neurocognition and memory
  • Describe the diets maintained by subjects in the study
  • Describe the effect of pegzilarginase on plasma ammonia
  • Evaluate the effects of pegzilarginase on growth in pediatric subjects

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 RBC arginase activity. For entry into this study, subjects must also fulfill the following plasma arginine criteria:
a. 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 μM.
b. If a subject is re-screened (see Section 5.3), 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 1 component of 1 assessment included in the key secondary endpoints. To be considered assessable, the subject must be able to complete the assessment, and must have a Baseline deficit in at least 1 component as defined in Table 18.

5. The subject must 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 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).

 

Pregnant Partner and Infants:  Inclusion of a participant’s partner and their child, if they were to become pregnant while the participant is receiving Pegzilarginase as part of the study.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

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 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 (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 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 on this study.

10. Previous liver or hematopoietic transplant procedure.