Phase 1, First-In-Human, Single-/Multiple-Ascending Dose Study of Iluzanebart in Healthy Volunteers

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY Annals of Clinical and Translational Neurology Pub Date : 2025-04-01 DOI:10.1002/acn3.70033

Andreas Meier, Spyros Papapetropoulos, Andrew Marsh, Kelly Neelon, David Stiles, Ryan O'Mara, Evan A. Thackaberry, Marco Colonna, Raj Rajagovindan

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Abstract

Objective

To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of iluzanebart, a fully human monoclonal antibody TREM2 (triggering receptor expressed on myeloid cells 2) agonist, after single- (SAD) and multiple-ascending-dose (MAD) administration.

Methods

Healthy adult volunteers (N = 136) received intravenous placebo or iluzanebart 1–60 mg/kg (SAD) or 10–60 mg/kg (MAD) followed by serial pharmacokinetics and safety assessments. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory evaluations. Pharmacokinetics were assessed through noncompartmental analysis. The study also included open-label cohorts (3, 10, 20, 40, 60 mg/kg SAD; 10, 20, 40 mg/kg MAD) for cerebrospinal fluid (CSF) collection for exploratory pharmacodynamic biomarker analysis.

Results

Iluzanebart was safe and well tolerated following single and multiple doses of up to 60 mg/kg. Most AEs were mild and resolved spontaneously. The most frequently reported AE was pruritus. No serious AEs or investigational product–related clinically meaningful changes in vital signs, electrocardiograms, or laboratory assessments were reported. Iluzanebart serum exposure was related to dose, with a 29-day half-life that is supportive of monthly dosing and confirmed central nervous system (CNS) exposure (≈0.15% CSF-to-serum ratio). Durable and dose-dependent target engagement, evidenced by marked reductions in soluble TREM2 and increased soluble CSF1R (colony-stimulating factor 1 receptor) and osteopontin/SPP1 (secreted phosphoprotein 1) levels in CSF, was observed, indicating that iluzanebart changes microglial activity following single and repeat dosing.

Interpretation

Iluzanebart demonstrated favorable safety, tolerability, pharmacokinetics, and pharmacological activity in the CNS, supporting further clinical development for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

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i期，首次在健康志愿者身上进行的单次/多次递增剂量伊鲁扎内巴特的人体研究。

目的：评价单次（SAD）和多次（MAD）给药后伊鲁扎尼巴特（iluzanebart）的安全性、耐受性、药代动力学和药效学。伊鲁扎尼巴特是一种完全人单克隆抗体TREM2（骨髓细胞上表达的触发受体2）激动剂。方法：健康成人志愿者（N = 136）静脉注射安慰剂或伊鲁扎尼巴特1- 60mg /kg （SAD）或10- 60mg /kg (MAD)，并进行一系列药代动力学和安全性评估。安全性评估包括不良事件（ae）、生命体征、心电图和临床实验室评估。通过非区隔分析评估药代动力学。该研究还包括开放标签队列(3、10、20、40、60 mg/kg SAD；10、20、40 mg/kg MAD)采集脑脊液（CSF）进行探索性药效学生物标志物分析。结果：依鲁扎内巴特在单次和多次给药高达60mg /kg时是安全且耐受性良好的。大多数ae是轻微的，自发消退。最常见的AE是瘙痒。在生命体征、心电图或实验室评估方面，没有严重的不良事件或与研究产品相关的有临床意义的改变。伊鲁赞尼巴特血清暴露与剂量相关，29天的半衰期支持每月给药和中枢神经系统（CNS）暴露（csf -血清比≈0.15%）。观察到持久的和剂量依赖性的靶标作用，证明了脑脊液中可溶性TREM2的显著降低和可溶性CSF1R（集落刺激因子1受体）和骨桥蛋白/SPP1（分泌的磷酸化蛋白1）水平的增加，表明伊鲁zaneart在单次和重复给药后改变了小胶质细胞活性。解释：伊鲁赞内巴特在中枢神经系统中表现出良好的安全性、耐受性、药代动力学和药理活性，支持了成人发病的轴突球状和色素胶质脑白质病的进一步临床开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)

CiteScore

9.10

自引率

1.90%

发文量

218

审稿时长

8 weeks

期刊介绍： Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.