肌萎缩性脊髓侧索硬化症患者服用替戈鲁巴特的安全性和耐受性:2A 期临床试验。

IF 15.8 1区 医学 Q1 Medicine
PLoS Medicine Pub Date : 2024-10-31 eCollection Date: 2024-10-01 DOI:10.1371/journal.pmed.1004469
Steven Perrin, Shafeeq Ladha, Nicholas Maragakis, Michael H Rivner, Jonathan Katz, Angela Genge, Nicholas Olney, Dale Lange, Daragh Heitzman, Cynthia Bodkin, Omar Jawdat, Namita A Goyal, Jeffrey D Bornstein, Carmen Mak, Stanley H Appel, Sabrina Paganoni
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引用次数: 0

摘要

背景:CD40L 及其受体 CD40 分别与活化的 T 细胞和 B 细胞相互作用,在自身免疫和移植排斥的病理生理学过程中控制促炎性激活。以往的研究表明,涉及 CD40L(可互换称为 CD154)的信号通路以及适应性和先天性免疫细胞活化与神经退行性疾病中神经炎症的诱导有关。本研究旨在评估抗 CD40L 抗体 tegoprubart 在肌萎缩性脊髓侧索硬化症(ALS)患者中的安全性、耐受性以及对促炎生物标志物特征的影响:在这项多中心剂量递增开放标签 2A 期研究中,54 名确诊为肌萎缩性脊髓侧索硬化症(ALS)的患者接受了每两周 6 次的 tegoprubart 静脉注射。该研究由 4 个剂量组群组成:1 毫克/千克、2 毫克/千克、4 毫克/千克和 8 毫克/千克。研究的主要终点是安全性和耐受性。探索性终点评估了特戈鲁巴特的药代动力学、抗药物抗体(ADA)反应、利用修订 ALS 功能评定量表(ALSFRS-R)进行的疾病进展变化、CD154 靶点参与、促炎生物标志物变化和神经丝蛋白轻链(NFL)。研究共筛选出 70 名受试者,54 名受试者参加了研究。54 名受试者中有 49 人(90.7%)完成了研究,接受了全部 6 次泰戈鲁巴特输注,并完成了最后一次随访。总的来说,最常见的治疗突发不良事件(TEAEs)(>10%)是疲劳(25.9%)、跌倒(22.2%)、头痛(20.4%)和肌肉痉挛(11.1%)。替戈鲁巴特的平均血浆浓度随剂量增加而成正比增加,半衰期约为 24 天。ADA滴度较低,所有组群的特戈鲁巴特循环水平均符合预期。Tegoprubart表现出与剂量相关的靶点参与性,并减少了血液循环中的18种促炎生物标志物:Tegoprubart 对 ALS 成人患者似乎安全且耐受性良好,显示出与剂量相关的 ALS 促炎趋化因子和细胞因子的减少。这些结果值得进一步开展临床研究,研究应具有足够的功率和持续时间,以评估作为ALS成人患者潜在治疗方法的临床效果:试验注册:Clintrials.gov ID:NCT04322149。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.

Background: 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).

Methods and findings: 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.

Conclusions: 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.

Trial registration: Clintrials.gov ID:NCT04322149.

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来源期刊
PLoS Medicine
PLoS Medicine MEDICINE, GENERAL & INTERNAL-
CiteScore
17.60
自引率
0.60%
发文量
227
审稿时长
4-8 weeks
期刊介绍: PLOS Medicine is a prominent platform for discussing and researching global health challenges. The journal covers a wide range of topics, including biomedical, environmental, social, and political factors affecting health. It prioritizes articles that contribute to clinical practice, health policy, or a better understanding of pathophysiology, ultimately aiming to improve health outcomes across different settings. The journal is unwavering in its commitment to uphold the highest ethical standards in medical publishing. This includes actively managing and disclosing any conflicts of interest related to reporting, reviewing, and publishing. PLOS Medicine promotes transparency in the entire review and publication process. The journal also encourages data sharing and encourages the reuse of published work. Additionally, authors retain copyright for their work, and the publication is made accessible through Open Access with no restrictions on availability and dissemination. PLOS Medicine takes measures to avoid conflicts of interest associated with advertising drugs and medical devices or engaging in the exclusive sale of reprints.
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