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.Trial registration number: NCT02488044 and NCT03378531.

Safety, PK/PD and preliminary anti-tumor activities of pegylated recombinant human arginase 1 (BCT-100) in patients with advanced arginine auxotrophic tumors

“…Apart from minor grade 1 skin reactions at injection sites, none of these side effects have been reported in our studies of BCT-100. Pegzilarginase (pegylated human recombinant arginase with cobalt as co-factor instead of the naturally occurring Manganese) has a seemingly different toxicity profile to BCT-100, and to date its use has focused on developing the drug as an enzyme replacement therapy [19].…”

Natural history of arginase 1 deficiency and the unmet needs of patients: A systematic review of case reports

“…Novel treatment options addressing the underlying disease of ARG1‐D, such as the human enzyme therapy pegzilarginase, could have the potential to improve clinical outcomes and reduce disease manifestations in patients with ARG1‐D. 42 The FDA granted breakthrough therapy designation to pegzilarginase for the treatment of ARG1‐D in 2019 43 based on results of a phase I/II clinical trial (NCT02488044) that suggest treatment with pegzilarginase rapidly and sustainably reduces plasma arginine levels in patients with ARG1‐D to within treatment guideline levels. 44 , 45 , 46…”

Current status of surviving patients with arginase 1 deficiency in Japan

“…Interventions for ARG1 deficiency include ammonia scavengers such as sodium benzoate and sodium phenylbutyrate, arginine-free formula, and restriction of protein intake. More recently, pegzilarginase has been reported to be effective as arginase replacement therapy, and is able to reduce blood arginine and glutamic acid levels [40] . Arginase replacement therapy is expected to prevent deterioration of mobility and neurological dysfunction because blood arginine is a major factor with adverse effects on neurodevelopmental outcomes.…”