Department of Neurology, Huashan Hospital, Fudan University and Institute of Neurology, Fudan University, Shanghai, China.
National Center for Neurological Disorders, Shanghai, China.
CNS Neurosci Ther. 2024 Nov;30(11):e70126. doi: 10.1111/cns.70126.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the central nervous system (CNS). This is the first-in-human dose-escalation Phase I clinical study of BAT4406F, an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced fully humanized anti-CD20 monoclonal antibody, in Chinese NMOSD patients.
Using a "3 + 3" design and based on the planned algorithm of dose escalation, the enrolled NMOSD patients were sequentially assigned to one of the five dose-escalation cohorts of BAT4406F with a single intravenous dose, and were then followed for a 6-month observation period. The maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of BAT4406F were investigated, and the efficacy of BAT4406F in NMOSD was also preliminarily explored.
Fifteen Chinese NMOSD patients were enrolled to receive BAT4406F of escalated doses ranging from 20 to 750 mg. No subjects experienced DLT at the studied doses. BAT4406F injection exhibited favorable safety, with most of the adverse events (AE) of CTCAE Grade 1 or 2 in severity, and no Grade ≥ 3 adverse drug reactions (ADR) or serious adverse reactions occurred in any subjects. With the dose increase of BAT4406F, the maximum plasma concentration (C), area under concentration-time curve from 0 to the last measurable timepoint (AUC) and area under concentration-time curve from 0 to infinity (AUC) showed an increasing trend, whereas the mean clearance (CL), terminal elimination rate (λ), and apparent volume of distribution (V) decreased. The mean elimination half-life (T) was ranged from 9.0-16.4 days. PK profile of BAT4406F was generally nonlinear. BAT4406F led to a rapid and significant B-cell depletion in all dose groups. Single administration of 500 mg or 750 mg maintains the CD19 B lymphocyte count below 10/μL within the whole 6-month observation period. Three subjects were antidrug antibody (ADA) positive and all of them were neutralizing antibody (NAb)-negative. On day 99/180 postdose, several groups had decreased expanded disability status scale (EDSS) scores compared to baseline. During the observation period, NMOSD relapse occurred in two patients (13.3%) and the other 13 (86.7%) subjects remained relapse free.
BAT4406F was well tolerated at doses up to 750 mg and showed an expected pharmacodynamic effect of significant and long-term depletion of CD19 B lymphocytes. It has also shown preliminary evidence of activity in NMOSD maintenance treatment, warranting further investigations.
ClinicalTrials.gov identifier: NCT04146285.
视神经脊髓炎谱系障碍（NMOSD）是一种罕见的中枢神经系统（CNS）自身免疫性疾病，会使人致残。这是首例在中国 NMOSD 患者中进行的 BAT4406F 的剂量递增、I 期临床研究。BAT4406F 是一种增强抗体依赖性细胞介导的细胞毒性（ADCC）的全人源化抗 CD20 单克隆抗体。
采用“3+3”设计，并根据既定的剂量递增算法，将入组的 NMOSD 患者按 BAT4406F 的五个递增剂量组顺序分配，接受单次静脉注射，然后进行为期 6 个月的观察期。研究目的是评估 BAT4406F 的最大耐受剂量（MTD）和剂量限制毒性（DLT）、安全性、药代动力学（PK）、药效学和免疫原性，并初步探索 BAT4406F 在 NMOSD 中的疗效。
共纳入 15 例中国 NMOSD 患者，接受了递增剂量的 BAT4406F，范围为 20 至 750mg。在研究剂量下，无受试者发生 DLT。BAT4406F 注射具有良好的安全性，大多数不良事件（AE）的严重程度为 CTCAE 1 级或 2 级，无任何受试者发生任何≥3 级药物不良反应（ADR）或严重不良反应。随着 BAT4406F 剂量的增加，最大血浆浓度（C）、从 0 到最后可测量时间点的浓度-时间曲线下面积（AUC）和从 0 到无穷大的浓度-时间曲线下面积（AUC）呈上升趋势，而平均清除率（CL）、末端消除率（λ）和表观分布体积（V）则下降。平均消除半衰期（T）范围为 9.0-16.4 天。BAT4406F 的 PK 特征通常是非线性的。在所有剂量组中，BAT4406F 均导致 B 细胞迅速而显著的耗竭。单次给予 500mg 或 750mg，可使 CD19 B 淋巴细胞计数在整个 6 个月的观察期内保持在 10/μL 以下。3 名受试者的抗药抗体（ADA）呈阳性，且均为中和抗体（NAb）阴性。在给药后第 99/180 天，与基线相比，多个剂量组的扩展残疾状况量表（EDSS）评分降低。在观察期间，2 名患者（13.3%）发生 NMOSD 复发，其余 13 名患者（86.7%）未复发。
BAT4406F 耐受良好，最高剂量达 750mg，且具有预期的药效学作用，可显著且长期耗竭 CD19 B 淋巴细胞。它在 NMOSD 的维持治疗中也显示出初步的疗效证据，值得进一步研究。
ClinicalTrials.gov 标识符：NCT04146285。
