Janssen Pharmaceutical KK, 5-2 Nishi-kanda 3-chome, Chiyoda-ku, Tokyo, 101-0065, Japan.
Janssen Research & Development, LLC, Spring House, PA, USA.
Clin Drug Investig. 2024 Aug;44(8):587-599. doi: 10.1007/s40261-024-01380-0. Epub 2024 Jul 29.
Nipocalimab is a high-affinity, fully human, effectorless immunoglobulin G1 monoclonal antibody targeting the neonatal Fc receptor and is currently under evaluation for the treatment of rare and prevalent immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases. This phase I, randomized, double-blind, placebo-controlled, single-dose escalation study in healthy Japanese volunteers (N = 24) assessed the safety, pharmacokinetics, and effect on the serum immunoglobulin G level of single doses of nipocalimab.
Volunteers were grouped into three cohorts and received intravenous nipocalimab at 10, 30, or 60 mg/kg or placebo. To complement the study, genetic variation in the Fcγ receptor and transporter subunit of the neonatal Fc receptor was analyzed in Japanese and diverse populations.
Nipocalimab was generally safe and well tolerated at all dose levels, with three (12.5% [3/24]) volunteers experiencing treatment-emergent adverse events across all nipocalimab doses. Mean serum immunoglobulin G levels decreased in a dose-dependent manner from baseline with nipocalimab treatment compared with placebo. Maximum serum nipocalimab concentrations demonstrated proportional increases with dose, while the area under the concentration-time curve was dose dependent and demonstrated non-linear increases with dose. Mean observed half-life was longer as the dose increased. Analysis of genetic variation in Fcγ receptor and transporter identified no unique Japanese variants or variants that alter amino acid sequences in or near the neonatal Fc receptor immunoglobulin G binding site targeted by nipocalimab.
The comparable pharmacokinetic/pharmacodynamic profiles and highly conserved neonatal Fc receptor structure among diverse populations further support the clinical development of nipocalimab for the treatment of various immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases across global sites and populations, including the Japanese population.
Nipocalimab 是一种高亲和力、全人源、无效应功能的 IgG1 单克隆抗体，靶向新生 Fc 受体，目前正在评估用于治疗罕见和常见的 IgG 自身抗体介导和同种抗体介导的疾病。这项在健康日本志愿者（N=24）中进行的 I 期、随机、双盲、安慰剂对照、单次递增剂量研究评估了 nipocalimab 单次剂量的安全性、药代动力学和对血清 IgG 水平的影响。
志愿者分为三组，静脉注射 10、30 或 60mg/kg nipocalimab 或安慰剂。为了补充研究，分析了日本和不同人群中 Fcγ 受体和新生儿 Fc 受体转运体亚基的遗传变异。
nipocalimab 在所有剂量水平均通常安全且耐受良好，所有 nipocalimab 剂量组有 3 名（12.5%[3/24]）志愿者出现治疗后不良事件。与安慰剂相比，nipocalimab 治疗使血清 IgG 水平从基线呈剂量依赖性下降。最大血清 nipocalimab 浓度与剂量呈比例增加，而 AUC 与剂量相关，并呈剂量依赖性非线性增加。观察到的平均半衰期随剂量增加而延长。Fcγ 受体和转运体遗传变异分析未发现日本特有的或改变 nipocalimab 靶向的 IgG 结合位点的氨基酸序列的变异。
不同人群中相似的药代动力学/药效学特征和高度保守的新生儿 Fc 受体结构进一步支持 nipocalimab 在包括日本人群在内的全球各地和人群中用于治疗各种 IgG 自身抗体介导和同种抗体介导的疾病的临床开发。
