PDF(Pubmed)
Abstract：
Adenosine deaminase (ADA) deficiency is an ultrarare inherited purine metabolism disorder characterized by severe combined immunodeficiency. Elapegademase-lvlr is a new pegylated recombinant bovine ADA used in enzyme-replacement therapy (ERT) for ADA deficiency. Therefore, replacement with the new drug may eliminate the infectious risks associated with the currently used bovine intestinal-derived product, pegademase.
We conducted a multicenter, single-arm, open-label, phase 3, and postmarketing clinical study of elapegademase for patients with ADA deficiency. The following biochemical markers were monitored to determine an appropriate dose of elapegademase: the trough deoxyadenosine nucleotide (dAXP) level ≤0.02 μmol/mL in erythrocytes or whole blood and the trough serum ADA activity ≥1100 U/L (equivalent to plasma levels ≥15 μmol/h/mL) indicated sufficient enzyme activity and detoxification as efficacy endpoints and monitored adverse events during the study as safety endpoints.
A total of four patients (aged 0-25 years) were enrolled. One infant patient died of pneumonia caused by cytomegalovirus infection whereas the other three completed the study and have been observed in the study period over 3 years. The infant patient had received elapegademase at 0.4 mg/kg/week until decease and the others received elapegademase at maximum doses of 0.3 mg/kg/week for 164-169 weeks. As a result, all four patients achieved undetectable levels of dAXPs together with sufficient enzyme activity, increased T and B cell numbers, and slightly elevated and maintained IgM and IgA immunoglobulin levels. Serious adverse events occurred in three patients, all of which were assessed as unrelated to elapegademase.
This study showed that elapegademase had comparable safety and efficacy to pegademase as ERT for ADA deficiency by demonstrating stable maintenance of sufficient ADA activity and lowering dAXP to undetectable levels, while no drug-related adverse events were reported (Trial registration: JapicCTI-163204).
We conducted a multicenter, single-arm, open-label, phase 3, and postmarketing clinical study of elapegademase for patients with ADA deficiency. The following biochemical markers were monitored to determine an appropriate dose of elapegademase: the trough deoxyadenosine nucleotide (dAXP) level ≤0.02 μmol/mL in erythrocytes or whole blood and the trough serum ADA activity ≥1100 U/L (equivalent to plasma levels ≥15 μmol/h/mL) indicated sufficient enzyme activity and detoxification as efficacy endpoints and monitored adverse events during the study as safety endpoints.
A total of four patients (aged 0-25 years) were enrolled. One infant patient died of pneumonia caused by cytomegalovirus infection whereas the other three completed the study and have been observed in the study period over 3 years. The infant patient had received elapegademase at 0.4 mg/kg/week until decease and the others received elapegademase at maximum doses of 0.3 mg/kg/week for 164-169 weeks. As a result, all four patients achieved undetectable levels of dAXPs together with sufficient enzyme activity, increased T and B cell numbers, and slightly elevated and maintained IgM and IgA immunoglobulin levels. Serious adverse events occurred in three patients, all of which were assessed as unrelated to elapegademase.
This study showed that elapegademase had comparable safety and efficacy to pegademase as ERT for ADA deficiency by demonstrating stable maintenance of sufficient ADA activity and lowering dAXP to undetectable levels, while no drug-related adverse events were reported (Trial registration: JapicCTI-163204).
摘要：
背景：腺苷脱氨酶（ADA）缺乏症是一种以严重的联合免疫缺陷为特征的遗传性嘌呤代谢紊乱。Elapegademase-lvlr是一种新的聚乙二醇化重组牛ADA，用于ADA缺乏症的酶替代疗法（ERT）。因此,用新药替代可能消除与目前使用的牛肠衍生产品相关的感染风险，pegademase.
方法：我们进行了多中心，单臂,开放标签，3期，以及ADA缺乏症患者elapegademase的上市后临床研究。监测以下生化标志物以确定适当剂量的elapegademase：红细胞或全血中的脱氧腺苷核苷酸（dAXP）谷水平≤0.02μmol/mL，血清ADA活性谷≥1100U/L（相当于血浆水平≥15μmol/h/mL）表明足够的酶活性和解毒作用作为终点，并在研究期间监测不良事件作为安全性终点。
结果：共纳入4例患者（0-25岁）。一名婴儿患者死于巨细胞病毒感染引起的肺炎，而其他三人完成了研究，并在研究期间观察到超过3年。婴儿患者以0.4mg/kg/周的剂量接受了elapegademase，直到死亡，其他人则以0.3mg/kg/周的最大剂量接受了elapegemase，持续164-169周。因此,所有四名患者都达到了检测不到的dAXPs水平以及足够的酶活性，T细胞和B细胞数量增加，略有升高并维持IgM和IgA免疫球蛋白水平。3例患者发生严重不良事件，所有这些都被评估为与elapegademase无关。
结论：这项研究表明，通过证明稳定维持足够的ADA活性并将dAXP降低至无法检测的水平，elapegademase与pegademase相比，对ADA缺乏症具有与ERT相当的安全性和有效性。而未报告药物相关的不良事件（试验注册：JapicCTI-163204）。
方法：我们进行了多中心，单臂,开放标签，3期，以及ADA缺乏症患者elapegademase的上市后临床研究。监测以下生化标志物以确定适当剂量的elapegademase：红细胞或全血中的脱氧腺苷核苷酸（dAXP）谷水平≤0.02μmol/mL，血清ADA活性谷≥1100U/L（相当于血浆水平≥15μmol/h/mL）表明足够的酶活性和解毒作用作为终点，并在研究期间监测不良事件作为安全性终点。
结果：共纳入4例患者（0-25岁）。一名婴儿患者死于巨细胞病毒感染引起的肺炎，而其他三人完成了研究，并在研究期间观察到超过3年。婴儿患者以0.4mg/kg/周的剂量接受了elapegademase，直到死亡，其他人则以0.3mg/kg/周的最大剂量接受了elapegemase，持续164-169周。因此,所有四名患者都达到了检测不到的dAXPs水平以及足够的酶活性，T细胞和B细胞数量增加，略有升高并维持IgM和IgA免疫球蛋白水平。3例患者发生严重不良事件，所有这些都被评估为与elapegademase无关。
结论：这项研究表明，通过证明稳定维持足够的ADA活性并将dAXP降低至无法检测的水平，elapegademase与pegademase相比，对ADA缺乏症具有与ERT相当的安全性和有效性。而未报告药物相关的不良事件（试验注册：JapicCTI-163204）。
