Providence Multiple Sclerosis Center, Providence Brain Institute, 9135 SW Barnes Rd Suite 461, Portland, OR, 97225, USA.
University at Buffalo, State University of New York, Buffalo, NY, USA.
CNS Drugs. 2022 Jul;36(7):703-719. doi: 10.1007/s40263-022-00927-z. Epub 2022 Jun 20.
Siponimod is a selective sphingosine 1-phosphate receptor subtype 1 (S1P) and 5 (S1P) modulator approved in the United States and the European Union as an oral treatment for adults with relapsing forms of multiple sclerosis (RMS), including active secondary progressive multiple sclerosis (SPMS). Preclinical and clinical studies provide support for a dual mechanism of action of siponimod, targeting peripherally mediated inflammation and exerting direct central effects. As an S1P receptor modulator, siponimod reduces lymphocyte egress from lymph nodes, thus inhibiting their migration from the periphery to the central nervous system. As a result of its peripheral immunomodulatory effects, siponimod reduces both magnetic resonance imaging (MRI) lesion (gadolinium-enhancing and new/enlarging T2 hyperintense) and relapse activity compared with placebo. Independent of these effects, siponimod can penetrate the blood-brain barrier and, by binding to S1P and S1P receptors on a variety of brain cells, including astrocytes, oligodendrocytes, neurons, and microglia, exert effects to modulate neural inflammation and neurodegeneration. Clinical data in patients with SPMS have shown that, compared with placebo, siponimod treatment is associated with reductions in levels of neurofilament light chain (a marker of neuroaxonal damage) and thalamic and cortical gray matter atrophy, with smaller reductions in MRI magnetization transfer ratio and reduced confirmed disability progression. This review examines the preclinical and clinical data supporting the dual mechanism of action of siponimod in RMS.
西尼莫德是一种选择性鞘氨醇 1-磷酸受体亚型 1（S1P）和 5（S1P）调节剂，已获美国和欧盟批准用于治疗成人复发型多发性硬化症（RMS），包括活跃的继发进展型多发性硬化症（SPMS），作为口服治疗药物。临床前和临床研究为西尼莫德的双重作用机制提供了支持，针对外周介导的炎症，并发挥直接的中枢作用。作为一种 S1P 受体调节剂，西尼莫德可减少淋巴细胞从淋巴结中的迁出，从而抑制其从外周向中枢神经系统的迁移。由于其外周免疫调节作用，与安慰剂相比，西尼莫德可减少磁共振成像（MRI）病变（钆增强和新/扩大 T2 高信号）和复发活动。独立于这些作用，西尼莫德可以穿透血脑屏障，并通过与 S1P 和 S1P 受体结合，作用于各种脑细胞，包括星形胶质细胞、少突胶质细胞、神经元和小胶质细胞，调节神经炎症和神经退行性变。SPMS 患者的临床数据表明，与安慰剂相比，西尼莫德治疗与神经丝轻链（神经轴突损伤的标志物）水平降低、丘脑和皮质灰质萎缩有关，MRI 磁化传递率降低，证实残疾进展减少。这篇综述检查了支持西尼莫德在 RMS 中双重作用机制的临床前和临床数据。
