Eledon Pharmaceuticals, Irvine, California, United States of America.
Departments of Neurology and Translational Neuroscience, St. Joseph's Hospital and Medical Center and Barrow Neurological Institute, Phoenix, Arizona, United States of America.
PLoS Med. 2024 Oct 31;21(10):e1004469. doi: 10.1371/journal.pmed.1004469. eCollection 2024 Oct.
The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).
In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.
Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.
Clintrials.gov ID:NCT04322149.
CD40L 与其受体 CD40 在激活的 T 细胞和 B 细胞上的相互作用分别控制着自身免疫和移植排斥的病理生理学中的促炎激活。先前的研究表明，涉及 CD40L（可互换地称为 CD154）的信号通路，以及适应性和先天免疫细胞的激活，在神经退行性疾病中的神经炎症诱导中发挥作用。本研究旨在评估抗 CD40L 抗体 tegoprubart 在肌萎缩侧索硬化（ALS）患者中的安全性、耐受性和对促炎生物标志物谱的影响。
在这项多中心剂量递增开放标签 2A 期研究中，54 名确诊为 ALS 的参与者每 2 周静脉内接受 6 次 tegoprubart 输注。该研究包括 4 个剂量队列：1mg/kg、2mg/kg、4mg/kg 和 8mg/kg。该研究的主要终点是安全性和耐受性。探索性终点评估了 tegoprubart 的药代动力学以及抗药物抗体（ADA）反应、利用修订后的 ALS 功能评定量表（ALSFRS-R）评估疾病进展的变化、CD154 靶点结合、促炎生物标志物的变化和神经丝轻链（NFL）。共筛选了 70 名受试者，54 名受试者入组本研究。54 名受试者中有 49 名（90.7%）完成了研究，接受了全部 6 次 tegoprubart 输注并完成了最后一次随访。总体而言（>10%）最常见的治疗后不良事件（TEAE）是疲劳（25.9%）、跌倒（22.2%）、头痛（20.4%）和肌肉痉挛（11.1%）。平均 tegoprubart 血浆浓度随剂量呈比例增加，半衰期约为 24 天。ADA 滴度较低，所有队列的循环 tegoprubart 水平均与预测值一致。Tegoprubart 表现出与剂量相关的靶标结合，并降低了循环中的 18 种促炎生物标志物。
Tegoprubart 似乎在 ALS 成人中安全且耐受良好，表现出与 ALS 相关的促炎趋化因子和细胞因子的剂量依赖性降低。这些结果需要进一步进行具有足够效力和持续时间的临床研究，以评估其作为成人 ALS 潜在治疗方法的临床结局。
Clintrials.gov ID:NCT04322149。
