Eisen Andrew, Greenberg Benjamin M, Bowen James D, Arnold Douglas L, Caggiano Anthony O
Acorda Therapeutics Inc, Ardsley, NY, USA.
University of Texas SW Medical Center, Dallas, TX, USA.
Mult Scler J Exp Transl Clin. 2017 Nov 21;3(4):2055217317743097. doi: 10.1177/2055217317743097. eCollection 2017 Oct-Dec.
The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22).
Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months.
rHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of C and AUC. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort.
Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.
本文旨在评估单克隆重组人抗体IgM22（rHIgM22）在临床病情稳定的多发性硬化症（MS）患者中的安全性、耐受性、药代动力学（PK）及探索性药效学。
72例病情稳定的成年MS患者参与了一项双盲、随机、安慰剂对照、单剂量递增的1期试验，试验中rHIgM22的剂量为0.025至2.0mg/kg。评估内容包括磁共振成像（MRI）、磁共振波谱分析、血浆PK，以及三个月内临床状态、实验室检查值和不良事件的变化。最终队列还进行了额外的临床、眼科、脑脊液采集及探索性生物标志物评估。对参与者进行了为期六个月的监测。
rHIgM22耐受性良好，未出现具有临床意义的安全信号。非房室PK模型显示C和AUC均呈线性剂量比例关系。约58ml/kg的稳态表观分布容积表明主要分布于血管腔隙。脑脊液：血浆rHIgM22浓度在第2天，1.0mg/kg和2.0mg/kg剂量组均为0.003%，至第29天，1.0mg/kg和2.0mg/kg剂量组分别增至0.056%和0.586%。在扩展队列的21名参与者的探索性药效学结局指标中，未观察到与治疗相关的具有统计学意义的变化。
单剂量rHIgM22耐受性良好，呈现线性PK，且在脑脊液中检测到了抗体。
