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.

中文翻译：

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pegzilarginase 在精氨酸酶 1 缺乏症患者中的临床效果和安全性

精氨酸酶 1 缺乏症 (ARG1-D) 患者的高精氨酸血症被认为是疾病表现的关键驱动因素，包括痉挛、发育迟缓和癫痫发作。Pegzilarginase (AEB1102) 是一种研究性酶疗法，正在开发为一种新型精氨酸降低方法。我们在一项 1/2 期研究 (101A) 和一项开放标签扩展研究 (102A) 的前 12 周报告了静脉 (IV) 给予 pegzilarginase 在儿科和成人 ARG1-D 患者 (n = 16) 中的安全性和有效性）。基线时的重大疾病负担包括分别有 75%、56% 和 44% 的患者出现下肢痉挛、发育迟缓和既往高氨血症发作。在标准疾病管理中，基线血浆精氨酸 (pArg) 升高（中位数 389 μM，范围 238-566）。每周一次重复给药导致 20 次累积剂量 (n = 14) 后 pArg 的中位下降 277 μM，给药后 168 小时，50% 的患者 pArg 在正常范围内 (40 至 115 μM)（平均 pegzilarginase 剂量 0.10毫克/公斤）。在 79% 的患者中，降低 pArg 伴随着一项或多项关键活动性评估（6MWT、GMFM-D 和 E）的改善。在 101A 中，4 名患者（在 162 次输注中）发生了 7 次超敏反应。其他常见的治疗相关不良事件 (AE) 包括呕吐、高氨血症、瘙痒和腹痛。在 101A 中观察到了 5 名患者发生的与治疗相关的严重 AE。Pegzilarginase 可有效降低 pArg 水平，并伴有 ARG1-D 患者的临床反应。