Meier Andreas, Papapetropoulos Spyros, Marsh Andrew, Neelon Kelly, Stiles David, O'Mara Ryan, Thackaberry Evan A, Colonna Marco, Rajagovindan Raj
Formerly Vigil Neuroscience, Inc., Watertown, Massachusetts, USA.
Vigil Neuroscience, Inc., Watertown, Massachusetts, USA.
Ann Clin Transl Neurol. 2025 May;12(5):1065-1076. doi: 10.1002/acn3.70033. Epub 2025 Apr 1.
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.
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.
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.
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.
评估全人源单克隆抗体TREM2（髓样细胞表达的触发受体2）激动剂iluzanebart在单剂量（SAD）和多剂量递增给药（MAD）后的安全性、耐受性、药代动力学和药效学。
健康成年志愿者（N = 136）接受静脉注射安慰剂或1-60 mg/kg的iluzanebart（SAD）或10-60 mg/kg（MAD），随后进行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。通过非房室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），用于收集脑脊液（CSF）以进行探索性药效学生物标志物分析。
单剂量和多剂量高达60 mg/kg的iluzanebart均安全且耐受性良好。大多数AE为轻度且可自发缓解。最常报告的AE是瘙痒。未报告严重AE或与研究产品相关的生命体征、心电图或实验室评估中有临床意义的变化。Iluzanebart的血清暴露与剂量相关，半衰期为29天，支持每月给药一次，并证实了中枢神经系统（CNS）暴露（脑脊液与血清比率约为0.15%）。观察到可溶性TREM2显著降低，脑脊液中可溶性集落刺激因子1受体（CSF1R）和骨桥蛋白/分泌性磷蛋白1（SPP1）水平升高，证明了持久且剂量依赖性的靶点结合，表明iluzanebart在单次和重复给药后会改变小胶质细胞活性。
Iluzanebart在中枢神经系统中显示出良好的安全性、耐受性、药代动力学和药理活性，支持其用于成人起病的轴突球状体和色素性神经胶质白质脑病的进一步临床开发。
