GeNeuro SA, Chemin des Aulx 18, CH 1228 Plan-les-Ouates, Geneva, Switzerland; Division of Clinical Pharmacology and Toxicology, Rue Perret-Gentil, University of Geneva, Geneva, Switzerland.
GeNeuro SA, Chemin des Aulx 18, CH 1228 Plan-les-Ouates, Geneva, Switzerland; Department of Pharmacology, University of Pretoria, Pretoria, South Africa.
Mult Scler Relat Disord. 2016 Sep;9:95-100. doi: 10.1016/j.msard.2016.07.002. Epub 2016 Jul 1.
GNbAC1, a humanized monoclonal antibody, is an innovative treatment currently in development for multiple sclerosis (MS) which, contrary to the immunomodulation/immunosuppressive mechanism of action of most of the MS drugs, targets specifically a protein of endogenous retroviral origin supposed to be critical in MS pathogenesis.
This trial is a randomized placebo controlled 4-arm study with the objective of demonstrating the efficacy of repeated doses of GNbAC1 on the cumulative number of T1 Gd-enhancing lesions measured from Week 12 to 24 in patients with relapsing remitting MS (RRMS). Two hundred sixty patients with RRMS are planned to be included. Three doses of GNbAC1 will be tested versus placebo: 6mg/kg, 12mg/kg and 18mg/kg, administered intravenously, with 4-week administration intervals. The design is based on the classic 24-week placebo-controlled repeated brain MRI trial design (Period 1), with an extension of 24 weeks during which placebo patients will be re-randomized to one of the three doses of GNbAC1 to assess efficacy and safety of prolonged treatment of GNbAC1 (Period 2). The primary endpoint is the cumulative number of new Gadolinium enhanced T1 lesions measured using repeated brain magnetic resonance imaging (MRI) scans from Week 12 to 24; secondary endpoints, including additional MRI and clinical endpoints, will be assessed at the end of both Periods 1 and 2. Pharmacokinetics and biomarkers will be assessed in serum in all patients at several time points and also in cerebrospinal fluid in a subgroup of patients. To alleviate potential ethical concerns regarding placebo administration in MS, an early escape from trial will be implemented for patients with a worsening clinical condition during trial.
This dose-finding study should provide the first proof-of-concept of an innovative therapeutic approach for MS. The constraints of using a placebo group in RRMS patients while optimizing the trial power to evidence a new mechanism of action is discussed.
GNbAC1 是一种人源化单克隆抗体，是一种针对多发性硬化症（MS）的创新治疗方法。与大多数 MS 药物的免疫调节/免疫抑制作用机制不同，它专门针对一种内源性逆转录病毒来源的蛋白，该蛋白被认为在 MS 发病机制中至关重要。
这是一项随机、安慰剂对照的四臂研究，旨在证明重复给予 GNbAC1 剂量对从第 12 周到 24 周测量的复发缓解型多发性硬化症（RRMS）患者 T1 Gd 增强病变累积数量的疗效。计划纳入 260 例 RRMS 患者。将测试三种剂量的 GNbAC1 与安慰剂进行比较：6mg/kg、12mg/kg 和 18mg/kg，静脉内给药，给药间隔为 4 周。该设计基于经典的 24 周安慰剂对照重复脑部 MRI 试验设计（第 1 期），并延长 24 周，在此期间，安慰剂患者将重新随机分配至三种剂量的 GNbAC1 之一，以评估 GNbAC1 延长治疗的疗效和安全性（第 2 期）。主要终点是从第 12 周到 24 周使用重复脑部磁共振成像（MRI）扫描测量的新钆增强 T1 病变的累积数量；次要终点，包括其他 MRI 和临床终点，将在第 1 期和第 2 期结束时进行评估。所有患者将在多个时间点检测血清中的药代动力学和生物标志物，部分患者还将检测脑脊液中的药代动力学和生物标志物。为了缓解在 MS 患者中使用安慰剂的潜在伦理问题，对于在试验期间病情恶化的患者，将实施早期退出试验。
这项剂量发现研究应为 MS 的一种创新治疗方法提供首个概念验证。讨论了在 RRMS 患者中使用安慰剂组的同时优化试验效力以证明新作用机制的限制。
