Arginase 1 Deficiency Hyperargininemia MedDRA version: 20.0 Level: PT Classification code 10062695 Term: Arginase deficiency System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: Pegzilarginase
Product Code: AEB1102
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEGZILARGINASE
CAS Number: 1659310-95-8
Current Sponsor code: AEB1102
Other descripti
Sponsors
Aeglea Biotherapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion 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 as documented in medical records, which must include 1 of the following: elevated plasma arginine levels, a mutation analysis that results in s pathogenic variant, or reduced 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 µmol/L. b. 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 1 component of 1 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 1 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 essential amino acid 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). Are the trial subjects under 18? yes Number of subjects for this age range: 30 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 10 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 followup 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate the efficacy of pegzilarginase relative to placebo based on a statistically significant decrease in plasma arginine (Arg) concentrations;Secondary Objective: To further demonstrate the clinical and biochemical efficacy of pegzilarginase (IMP) relative to placebo (Pbo). -Demonstrate the efficacy of IMP relative to Pbo based on key mobility outcome measures -Compare IMP with Pbo with respect to the proportion of subjects whose endpoint Arg value falls below target guidance of 200 µM -Compare IMP with Pbo with respect to the proportions of subjects whose endpoint Arg value falls within the normal range of 40 to 115 µM -Compare IMP with Pbo for changes in ornithine and guanidino compounds (GCs) -Compare IMP with Pbo with respect to other aspects of mobility -Compare IMP with Pbo with respect to adaptive behavior -To evaluate the safety and immunogenicity of IMP -To further characterize the pharmacokinetic (PK) profile of IMP;Primary end point(s): Change from baseline in plasma arginine after 24 weeks of study treatment;Timepoint(s) of evaluation of this end point: After 24 weeks of study treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: After 24 weeks of study treatment.;Secondary end point(s): To further demonstrate the clinical and biochemical efficacy of pegzilarginase relative to placebo 1) Mean change from baseline at Week 24 in the 2-Minute Walk Test (2MWT) 2) Mean change from Baseline at Week 24 in the Gross Motor Function Measure-88 (GMFM) Part E 3) A subject is considered a responder if their endpoint arginine value is <200 µM after 24 weeks of study treatment, and a non-responder otherwise 4) A subject is considered a responder if their endpoint arginine value is in the normal range (=40 µM to =115 µM) after 24 weeks of study treatment, and a non-responder otherwise 5) Change from Baseline in ornithine and GCs after 24 weeks of study treatment 6) Mean change from Baseline at Week 24 in the GMFM Part D Mean change from Baseline at Week 24 in Functional Mobility Scale (FMS) and Gillette Functional Assessment Questionnaire (GFAQ) 7) Mean change from Baseline at Week 24 in Vineland Adaptive Behavior Scales (VABS)-II 8) Adverse events (AEs) and anti-drug antibodies (ADAs) will be collected 9) PK and PD data will be analyzed | — |
Countries
Austria, Canada, France, Germany, Italy, United Kingdom, United States
Contacts
Public ContactArg1-D Trial Information
Aeglea Biotherapeutics, Inc.
Outcome results
None listed