■精氨酸酶1缺乏症(ARG1-D)是一种罕见的衰弱,进步,继承,代谢性疾病的特征是血浆精氨酸(pArg)及其代谢物的显着增加,随着发病率的增加,生活质量大幅下降,过早死亡。目前缺乏能够降低精氨酸并改善临床结果的有效治疗方法。聚乙二醇精氨酸酶是一种新型的人类精氨酸酶1酶疗法。本试验旨在证明聚乙二醇精氨酸酶对pArg和关键移动性结果的疗效。
■这个阶段3随机,双盲,安慰剂对照,平行组临床试验(临床试验.govNCT03921541,EudraCT2018-004837-34),将接受ARG1-D2:1治疗的患者随机分配至静脉/皮下每周一次的聚乙二醇精氨酸酶或安慰剂,并结合个体化疾病管理.它在7个国家进行;美国,英国,加拿大,奥地利,法国,德国,意大利。主要终点是24周后pArg相对于基线的变化;关键次要终点是粗大运动功能测量E部分(GMFM-E)和2分钟步行测试(2MWT)中第24周相对于基线的变化。全分析集用于分析。
■从2019年5月1日至2021年3月29日,32名患者被纳入并随机分组(pegzilinginase,n=21;安慰剂,n=11)。Pegziloginase在第24周将几何平均pArg从354.0μmol/L降低至86.4μmol/L,而安慰剂为464.7至426.6μmol/L(95%CI:-67.1%,-83.5%;p<0.0001)和90.5%的患者的正常水平(安慰剂为0%)。此外,pegzilarginase治疗证实了临床相关的功能移动性改善.这些影响通过额外的24周的后续暴露长期持续。聚乙二醇精氨酸酶耐受性良好,不良事件大多为一过性,严重程度为轻度/中度。
■这些结果支持pegziloginase作为使ARG1-D中的pArg正常化并在功能运动性方面实现临床上有意义的改善的第一种潜在治疗方法。
■AegleaBioTherapeutics。
UNASSIGNED: Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes.
UNASSIGNED: This Phase 3 randomized, double-blind, placebo-controlled, parallel-group clinical trial (clinicaltrials.govNCT03921541, EudraCT 2018-004837-34), randomized patients with ARG1-D 2:1 to intravenously/subcutaneously once-weekly pegzilarginase or placebo in conjunction with their individualized disease management. It was conducted in 7 countries; United States, United Kingdom, Canada, Austria, France, Germany, Italy. Primary endpoint was change from baseline in pArg after 24 weeks; key secondary endpoints were change from baseline at Week 24 in Gross Motor Function Measure part E (GMFM-E) and 2-min walk test (2MWT). Full Analysis Set was used for the analyses.
UNASSIGNED: From 01 May 2019 to 29 March 2021, 32 patients were enrolled and randomized (pegzilarginase, n = 21; placebo, n = 11). Pegzilarginase lowered geometric mean pArg from 354.0 μmol/L to 86.4 μmol/L at Week 24 vs 464.7 to 426.6 μmol/L for placebo (95% CI: -67.1%, -83.5%; p < 0.0001) and normalized levels in 90.5% of patients (vs 0% with placebo). In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. Pegzilarginase was well-tolerated, with adverse events being mostly transient and mild/moderate in severity.
UNASSIGNED: These results support pegzilarginase as the first potential treatment to normalize pArg in ARG1-D and achieve clinically meaningful improvements in functional mobility.
UNASSIGNED: Aeglea BioTherapeutics.