Clinical trial NCT02488044: A Phase 1/2 Study of AEB1102 in Patients With Arginase I Deficiency
Official title: A Phase 1/2 Open-label Study in Patients With Arginase I Deficiency to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous AEB1102
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Arginase I Deficiency
Hyperargininemia
Lead sponsor: Aeglea Biotherapeutics
Sponsor class: INDUSTRY
First posted: 2015-07-02
Enrollment: 16
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A Phase 1/2 Open-label Study in Patients with Arginase I Deficiency to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous AEB1102. This study is designed to evaluate the safety and tolerability of IV administration of AEB1102 for the treatment of pediatric and adult patients with Arginase I deficiency and hyperargininemia. This study will be conducted in 2 parts: Part 1 (Single Ascending Dose Escalation) and Part 2 (Repeated Dosing). Each part will be preceded by a baseline assessment of arginine levels. All patients who participate in Part 1 may continue AEB1102 dosing in Part 2 if they qualify for continued dosing. A data safety monitoring board (DSMB) will provide independent review of study safety data and recommend whether the sponsor should continue the study as planned, modify the study protocol, or discontinue the study.


Eligibility criteria: Inclusion Criteria:

* Documented diagnosis of Arginase I deficiency
* Adequate organ function: Hgb ≥ 10 g/dL, ANC ≥ 1.5 x 109/L, plt count ≥ 100,000/µL; liver transaminase levels ≤ 2.5x ULN, total bilirubin ≤ 2.0 mg/dL; serum creatinine \<1.5 x ULN
* If female and of child-bearing potential, has a negative serum pregnancy test within 7 days before enrollment
* If a sexually active (male or female), must be surgically sterile, post-menopausal (female), or must agree to use a physician-approved method of birth control during the study and for a minimum of 30 days after the last study drug administration
* Patient or legal guardian is able and willing to provide written informed consent and to comply with all requirements of study participation (including all study procedures and continuation of prescribed diet without modification) prior to any screening procedures

Exclusion Criteria:

* Transfusion of ≥ 2 u RBC within 60 days
* Active infection requiring systemic treatment
* Known infection with HIV, Hep B or Hep C
* Severe hyperammonemia requiring hospitalization within 14 days. Had more than one episode of hyperammonemia requiring hospitalization within the 30 days prior to enrollment.
* Current uncontrolled hyperammonemia
* Has a history of hypersensitivity to PEG or any other component of the AEB1102 (Co-ArgI-PEG) formulation
* If female, is lactating or breast feeding

PART 2 INCLUSION CRITERION:

1. Did not experience any safety or tolerability event in Part 1 which would preclude continued participation and dosing of AEB1102

Primary outcomes:
measure: Number of subjects with adverse events
timeFrame: weekly throughout the study, up to 14 weeks
Secondary outcomes:
measure: Number of subjects with a decrease from baseline in plasma arginine level
timeFrame: Baseline to 2, 4, 6, 8 weeks
measure: Pharmacokinetic profile including Cmax, AUC, Tmax, T1/2 for each subject
timeFrame: At 15 min, 1, 2, 4, 8, 12, 24, 48, 72, and 120 hours following dose escalation
measure: Number of subjects with a decrease from baseline in plasma guanidino compound levels
timeFrame: Baseline to 2, 4, 6, 8 weeks
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Dallas
country: United States
facility: UTSW
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Porto
country: Portugal
facility: Centro Hospitalar S. Joao
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Aeglea Biotherapeutics, Inc.
name: Josie Gayton
role: STUDY_DIRECTOR
References:
citation: Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. 2005 Mar;84(3):243-51. doi: 10.1016/j.ymgme.2004.11.004. Epub 2004 Dec 19.
citation: Glazer ES, Stone EM, Zhu C, Massey KL, Hamir AN, Curley SA. Bioengineered human arginase I with enhanced activity and stability controls hepatocellular and pancreatic carcinoma xenografts. Transl Oncol. 2011 Jun;4(3):138-46. doi: 10.1593/tlo.10265. Epub 2011 Jun 1.
citation: Diaz GA, Schulze A, McNutt MC, Leao-Teles E, Merritt JL 2nd, Enns GM, Batzios S, Bannick A, Zori RT, Sloan LS, Potts SL, Bubb G, Quinn AG. Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency. J Inherit Metab Dis. 2021 Jul;44(4):847-856. doi: 10.1002/jimd.12343. Epub 2021 Jan 26.