Ptushkin V V, Kulagin A D, Lukina E A, Davydkin I L, Konstantinova T S, Shamrai V S, Minaeva N V, Kudlay D A, Gapchenko E V, Markova O A, Borozinets A Y
Botkin City Clinical Hospital.
Pavlov First Saint Petersburg State Medical University.
Ter Arkh. 2020 Sep 1;92(7):77-84. doi: 10.26442/00403660.2020.07.000818.
Currently, the main pathogenetic method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is the treatment with recombinant monoclonal antibodies that block the C5 component of the complement system. Eculizumab is the first biotechnological drug, which is a monoclonal antibody, with proven clinical efficacy and safety for the treatment of patients with PNH, which is used in world clinical practice. In Russia, in the framework of the state program Development of the pharmaceutical and medical industry for 20132020 was developed Elizaria (JSC GENERIUM) the first biosimilar of the original drug eculizumab.
To evaluate the pharmacokinetic and pharmacodynamic parameters, as well as safety and immunogenicity parameters of the drug Elizara in the induction phase of therapy in previously untreated patients with PNH.
The study included 11 patients with PNH aged 26 to 75 years who had not previously received eculizumab. Each of the study participants was injected with the studied drug Elizaria at a dose of 600 mg intravenously once a week for 4 weeks.
During the clinical study, it was noted that the concentration of the studied drug significantly increased by the time the infusion was completed and then gradually decreased to a minimum at the end of the dosing interval. The average concentration of eculizumab 5 minutes before the administration of the study drug at all visits exceeded 35 g/ml, the minimum concentration sufficient to completely inhibit intravascular hemolysis in patients with PNH. The pharmacodynamic efficacy of the drug Elizaria was confirmed by a decrease in the concentration of the membrane-attack complex (MAC) after the first infusion of the drug was maintained at stable levels until visit 5. A persistent decrease in the level of MAC and a four-fold decrease in the average values of lactate dehydrogenase to visit 5 from 1286.4 to 280.9 U/l demonstrated a marked decrease in activity and stabilization of the hemolytic process against the background of the induction of therapy with Elizaria at a dose of 600 mg once a week and confirmed the effecacy of the study drug. Among the 9 adverse events, only 5 had a relationship with the studied drug, including one serious adverse event in the form of an allergic reaction, which, according to the researcher, had a possible cause-effect relationship with the infusion of the studied drug. In 2 patients, low-titer binding anti-drug antibodies were detected without neutralizing activity during treatment with the studied drug, which may indicate its low immunogenicity.
The study evaluated the pharmacokinetic and pharmacodynamic properties of the drug Elizaria in the regimen of induction therapy in previously untreated patients with PNH, confirming its efficacy. The study demonstrated the safety and low immunogenicity of the study drug.
目前，阵发性夜间血红蛋白尿（PNH）治疗的主要致病方法是使用重组单克隆抗体阻断补体系统的C5成分进行治疗。依库珠单抗是第一种生物技术药物，它是一种单克隆抗体，在世界临床实践中已被证明对治疗PNH患者具有临床疗效和安全性。在俄罗斯，在2013 - 2020年制药和医疗行业发展国家计划框架内，开发了原研药依库珠单抗的首个生物类似药Elizaria（JSC GENERIUM公司）。
评估Elizara药物在先前未接受治疗的PNH患者治疗诱导期的药代动力学和药效学参数，以及安全性和免疫原性参数。
该研究纳入了11例年龄在26至75岁之间、先前未接受过依库珠单抗治疗的PNH患者。每位研究参与者静脉注射研究药物Elizaria，剂量为600mg，每周一次，共4周。
在临床研究期间，注意到研究药物的浓度在输注完成时显著升高，然后在给药间隔结束时逐渐降至最低。在所有访视中，研究药物给药前5分钟依库珠单抗的平均浓度超过35μg/ml，这是完全抑制PNH患者血管内溶血所需的最低浓度。在首次输注药物后膜攻击复合物（MAC）浓度降低，且在第5次访视前一直维持在稳定水平，证实了Elizaria药物的药效学疗效。MAC水平持续下降，乳酸脱氢酶平均值从1286.4降至280.9U/l，在每周一次600mg剂量的Elizaria诱导治疗背景下，溶血过程的活性显著降低并稳定，证实了研究药物的疗效。在9例不良事件中，只有5例与研究药物有关，包括1例严重不良事件，表现为过敏反应，据研究人员称，该过敏反应与输注研究药物可能存在因果关系。在2例患者中，在使用研究药物治疗期间检测到低滴度结合抗药物抗体，但无中和活性，这可能表明其免疫原性较低。
该研究评估了Elizaria药物在先前未接受治疗的PNH患者诱导治疗方案中的药代动力学和药效学特性，证实了其疗效。该研究证明了研究药物的安全性和低免疫原性。
