Chamberlain Paul, Hemmer Bernhard, Höfler Josef, Wessels Hendrik, von Richter Oliver, Hornuss Cyrill, Poetzl Johann, Roth Karsten
bioLOGICA Consulting, Arthez-d'Asson, France.
Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Munich and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Front Immunol. 2024 Dec 19;15:1414304. doi: 10.3389/fimmu.2024.1414304. eCollection 2024.
Biosimilar natalizumab (biosim-NTZ) is the first biosimilar monoclonal antibody of reference natalizumab (ref-NTZ) for treatment of relapsing forms of multiple sclerosis (MS). Within the totality of evidence for demonstration of biosimilarity, immunogenicity assessments were performed in healthy subjects and patients with relapsing-remitting MS (RRMS) to confirm a matching immunogenicity profile between biosim-NTZ and ref-NTZ.
Immunogenicity of biosim-NTZ versus ref-NTZ was evaluated in two pivotal clinical studies. In a comparative efficacy and safety study, patients with RRMS (n=264) received monthly infusions of biosim-NTZ/EU-ref-NTZ over 48 weeks. The primary endpoint period was Week 0 to Week 24. In a separate, comparative pharmacokinetic/pharmacodynamic (PK/PD) study, healthy subjects (n=450) received a single dose of biosim-NTZ, US-ref-NTZ or EU-ref-NTZ prior to an 85-day follow-up. In both studies, state-of-the-art, highly sensitive and drug tolerant bioanalytical assays were used to identify the proportion of participants with anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against natalizumab over time.
In the comparative efficacy and safety study, biosim-NTZ and EU-ref-NTZ demonstrated similar incidences of overall ADA (79.4% vs 73.7%, respectively) and NAb (68.7% vs 66.2%, respectively) at Week 24. ADA titers over time were also concordant throughout the study period. Switching treatment from EU-ref-NTZ to biosim-NTZ had no impact on treatment-related ADA/NAb or clinical responses. Likewise, the single-dose PK/PD study reported matching overall incidence of ADA between treatment groups and matching ADA titer profiles over time.
The immunogenicity profile of biosim-NTZ was confirmed to match that of ref-NTZ in healthy subjects and patients with RRMS by applying highly sensitive methods.
生物类似药那他珠单抗（biosim-NTZ）是首个参照那他珠单抗（ref-NTZ）的生物类似单克隆抗体，用于治疗复发型多发性硬化症（MS）。在生物相似性证明的全部证据范围内，对健康受试者和复发缓解型MS（RRMS）患者进行了免疫原性评估，以确认biosim-NTZ和ref-NTZ之间的免疫原性特征匹配。
在两项关键临床研究中评估了biosim-NTZ与ref-NTZ的免疫原性。在一项比较疗效和安全性研究中，RRMS患者（n = 264）在48周内每月输注一次biosim-NTZ/EU-ref-NTZ。主要终点期为第0周 至第24周。在另一项单独的比较药代动力学/药效学（PK/PD）研究中，健康受试者（n = 450）在85天随访前接受单剂量的biosim-NTZ、美国ref-NTZ或欧盟ref-NTZ。在两项研究中，均使用了最先进、高度敏感且耐药物的生物分析方法来确定随着时间推移针对那他珠单抗的抗药物抗体（ADA）和中和抗体（NAb）的参与者比例。
在比较疗效和安全性研究中，biosim-NTZ和EU-ref-NTZ在第24周时总体ADA（分别为79.4%和73.7%）和NAb（分别为68.7%和66.2%）的发生率相似。在整个研究期间，ADA滴度随时间变化也一致。从EU-ref-NTZ转换为biosim-NTZ治疗对治疗相关的ADA/NAb或临床反应没有影响。同样，单剂量PK/PD研究报告了各治疗组之间ADA的总体发生率匹配以及ADA滴度随时间变化的情况匹配。
通过应用高度敏感的方法，证实了biosim-NTZ在健康受试者和RRMS患者中的免疫原性特征与ref-NTZ相匹配。
