Gajofatto Alberto
Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
Drug Des Devel Ther. 2017 Nov 2;11:3153-3157. doi: 10.2147/DDDT.S122249. eCollection 2017.
Siponimod (BAF312) is a synthetic molecule belonging to the sphingosine-1-phosphate (S1P) modulator family, which has putative neuroprotective properties and well-characterized immunomodulating effects mediated by sequestration of B and T cells in secondary lymphoid organs. Compared to fingolimod (ie, precursor of the S1P modulators commercially available for the treatment of relapsing-remitting [RR] multiple sclerosis [MS]), siponimod exhibits selective affinity for types 1 and 5 S1P receptor, leading to a lower risk of adverse events that are mainly induced by S1P3 receptor activation, such as bradycardia and vasoconstriction. In addition, S1P1 and S1P5 receptors are expressed by neurons and glia and could mediate a possible neuroprotective effect of the drug. A Phase II clinical trial of siponimod for RR MS showed a significant effect of the active drug compared to placebo on reducing gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) after 3 months of treatment. In a recently completed Phase III trial, treatment with siponimod was associated with a significant reduction in disability progression in secondary progressive (SP) MS patients compared to placebo. In this article, current evidence supporting siponimod efficacy for SP MS is reviewed.
西尼莫德（BAF312）是一种合成分子，属于1-磷酸鞘氨醇（S1P）调节剂家族，具有假定的神经保护特性，以及通过将B细胞和T细胞隔离在二级淋巴器官中而介导的特征明确的免疫调节作用。与芬戈莫德（即市售用于治疗复发缓解型[RR]多发性硬化症[MS]的S1P调节剂的前体）相比，西尼莫德对1型和5型S1P受体表现出选择性亲和力，导致主要由S1P3受体激活引起的不良事件风险较低，如心动过缓和血管收缩。此外，S1P1和S1P5受体由神经元和神经胶质细胞表达，可能介导该药物的神经保护作用。一项针对RR MS的西尼莫德II期临床试验显示，与安慰剂相比，活性药物在治疗3个月后对减少脑磁共振成像（MRI）上的钆增强病灶有显著效果。在最近完成的一项III期试验中，与安慰剂相比，西尼莫德治疗使继发进展型（SP）MS患者的残疾进展显著降低。在本文中，我们综述了支持西尼莫德对SP MS疗效的现有证据。
