Graphical Abstract
Progressive multiple sclerosis (PMS) causes slow accumulation of neurologic disability and has been refractory to treatment with the immunomodulatory medications that effectively control relapsing MS. Siponimod modestly slowed the rate of disability progression among PMS patients who had inflammatory disease activity, evidenced by new or gadolinium-enhancing MRI lesions.
NAME
Siponimod
APPROVED FOR
Relapsing and active secondary progressive multiple sclerosis
TYPE
Small Molecule
MOLECULAR TARGETS
Sphingosine 1-phosphate receptors 1 and 5
CELLULAR TARGETS
Lymphocytes
EFFECTS ON TARGETS
Siponimod binds S1P receptors 1 and 5 on lymphocytes, leading to receptor internalization and degradation. In the absence of these receptors, lymphocyte egress from lymphoid organs is blocked. Siponimod was engineered to eliminate binding of S1PR3, thought to mediate cardiac side effects, and to shorten the drug’s half-life. Siponimod may also have direct neuroprotective effects mediated by direct binding of S1P receptors on oligodendrocytes, astrocytes, microglia, and CNS neurons.
DEVELOPED BY
Novartis Pharmaceuticals
References
- 1.Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, Arnold DL, Arnould S, Scherz T et al. , EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018; 391: 1263–1273 [DOI] [PubMed] [Google Scholar]
- 2.Pan S, Gray NS, Gao W, Mi Y, Fan Y, Wang X, Tuntland T, Che J, Lefebvre S, Chen Y et al. Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett 2013; 4: 333–337 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Tur C, Montalban X Progressive MS trials: Lessons learned. Mult. Scler 2017; 23: 1583–1592 [DOI] [PubMed] [Google Scholar]