Department of Neurology With Institute of Translational Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
Neurotherapeutics. 2022 Apr;19(3):785-807. doi: 10.1007/s13311-022-01246-3. Epub 2022 Jul 6.
In the past two decades, monoclonal antibodies (mAbs) have revolutionized the treatment of multiple sclerosis (MS). However, a remarkable number of mAbs failed due to negative study results were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons. While trials with positive outcomes are usually published in prestigious journals, negative trials are merely published as abstracts or not at all. This review summarizes MS mAbs that have either failed in phase II-III trials, have been interrupted for various reasons, or withdrawn from the market since 2015. The main conclusions that can be drawn from these 'negative' experiences are as follows. mAbs that have been proven to be safe in other autoimmune conditions, will not have the same safety profile in MS due to immunopathogenetic differences in these diseases (e.g., daclizumab). Identification of SAEs in clinical trials is difficult highlighting the importance of phase IV studies. Memory B cells are central players in MS immunopathogenesis (e.g., tabalumab). The pathophysiological mechanisms of disease progression are independent of leukocyte 'outside-in' traffic which drives relapses in MS. Therefore, therapies for progressive MS must be able to sufficiently cross the blood-brain barrier. Sufficiently long trial duration and multicomponent outcome measures are important for clinical studies in progressive MS. The success of trials on remyelination-promoting therapies mainly depends on the sufficient high dose of mAb, the optimal readout for 'proof of concept', time of treatment initiation, and appropriate selection of patients. Failed strategies are highly important to better understand assumed immunopathophysiological mechanisms and optimizing future trial designs.
在过去的二十年中，单克隆抗体 (mAb) 彻底改变了多发性硬化症 (MS) 的治疗方法。然而，由于意外的严重不良事件 (SAE) 或由于其他原因研究被停止，大量因阴性研究结果而失败的 mAb 已被撤回。虽然阳性结果的试验通常发表在著名期刊上，但阴性试验仅作为摘要发表或根本不发表。本综述总结了自 2015 年以来，在 II-III 期临床试验中失败、因各种原因中断或从市场撤出的 MS mAb。从这些“负面”经验中可以得出以下主要结论。由于这些疾病的免疫发病机制差异（例如，达利珠单抗），在其他自身免疫性疾病中已被证明安全的 mAb 在 MS 中可能不会具有相同的安全性。在临床试验中识别 SAE 很困难，这凸显了 IV 期研究的重要性。记忆 B 细胞是 MS 免疫发病机制的核心参与者（例如，tabalumab）。疾病进展的病理生理机制独立于白细胞“外向”运输，该运输驱动 MS 的复发。因此，用于进行性 MS 的疗法必须能够充分穿透血脑屏障。足够长的试验持续时间和多成分结局测量对进行性 MS 的临床研究很重要。促髓鞘再生治疗的试验成功主要取决于 mAb 的足够高剂量、“概念验证”的最佳读出、治疗开始时间以及患者的适当选择。失败的策略对于更好地了解假定的免疫发病机制以及优化未来的试验设计非常重要。
