Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency

Abstract

Hyperargininemia in patients with arginase 1 deficiency (ARG1- D) is considered a key driver of disease manifestations, including spasticity, developmental delay, and seizures. Pegzilarginase (AEB1102) is an investigational enzyme therapy which is being developed as a novel arginine lowering approach. We report the safety and efficacy of intravenously (IV) administered pegzilarginase in pediatric and adult ARG1- D patients (n = 16) from a Phase 1/2 study (101A) and the first 12- weeks of an open- label extension study (102A). Substantial disease burden at baseline included lower- limb spasticity, developmental delay, and previous hyperammonemic episodes in 75%, 56%, and 44% of patients, respectively. Baseline plasma arginine (pArg) was elevated (median 389- μM, range 238- 566) on standard disease management. Once weekly repeat dosing resulted in a median decrease of pArg of 277- μM after 20 cumulative doses (n = 14) with pArg in the normal range (40 to 115- μM) in 50% of patients at 168- hours post dose (mean pegzilarginase dose 0.10 mg/kg). Lowering pArg was accompanied by improvements in one or more key mobility assessments (6MWT, GMFM- D & E) in 79% of patients. In 101A, seven hypersensitivity reactions occurred in four patients (out of 162 infusions administered). Other common treatment- related adverse events (AEs) included vomiting, hyperammonemia, pruritus, and abdominal pain. Treatment- related serious AEs that occurred in five patients were all observed in 101A. Pegzilarginase was effective in lowering pArg levels with an accompanying clinical response in patients with ARG1- D. The improvements with pegzilarginase occurred in patients receiving standard treatment approaches, which suggests that pegzilarginase could offer benefit over existing disease management.