Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: the evidence to date

Gajofatto, Alberto

doi:10.2147/dddt.s122249

Cited by 28 publications

(24 citation statements)

References 22 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent progress in clinical trials of ocrelizumab for PP‐MS and siponimod (BA312) for SP‐MS strongly implicate the involvement of the immune component of acquired immunity, such as T cells and B cells.…”

Section: Proposed Pathogenic Mechanism Of Secondary Progressive Msmentioning

confidence: 99%

“…Although a limited efficacy of immunomodulatory drugs could be interpreted by an active involvement of innate immunity rather than acquired immunity, recent progress in the clinical trials of ocrelizumab for PP‐MS and siponimod (BA312) for SP‐MS strongly implicate the involvement of immune components of acquired immunity, such as T cells and B cells. Furthermore, pathological studies emphasized the presence of ectopic lymphoid follicles, which is strongly associated with SP‐MS .…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…27,28 SP-MS by definition is a progressive form of disease preceded by repetition of relapse/remission with massive inflammation through activation of acquired immunity. Although numbers of infiltrated immune cells at the progressive stage of MS are relatively low, it does not necessarily exclude the possibility that those immune cells are involved in the pathogenesis of SP-MS. Actually, siponimod (BAF312), a novel selective sphingosine-1-phosphate receptor modulator, has been shown to delay disability progression in patients with SP-MS in a recent clinical trial, 29 and ocrelizumab, a humanized anti-CD20 monoclonal antibody, was shown to reach the primary disability end-point in PP-MS patients, 30 suggesting the possible involvement of immune components, such as T cells and B cells, in the pathogenesis of inflammatory CNS diseases with neurodegenerative symptoms. There is a great deal of evidence that implies the involvement of immune components, as discussed below.…”

Section: Immune-mediated Neuronal Damage Associated With Neurodegenermentioning

confidence: 99%

“…71 Importantly, this late disease is detectable only in the absence of NR4A2 in mice, because prolonged early disease conceals the concomitantly established late disease in B6 mice, suggesting that EAE in NR4A2cKO mice provide a novel tool for analyzing the pathogenesis of late EAE and SP-MS. Although a limited efficacy of immunomodulatory drugs could be interpreted by an active involvement of innate immunity rather than acquired immunity, 28 recent progress in the clinical trials of ocrelizumab for PP-MS 29 and siponimod (BA312) for SP-MS 30 strongly implicate the involvement of immune components of acquired immunity, such as T cells and B cells. Furthermore, pathological studies emphasized the presence of ectopic lymphoid follicles, which is strongly associated with SP-MS. 47,53,72 A clear gradient neuronal loss is observed in grey matter lesions and normal-appearing grey matter in the motor cortex of follicle-positive SP-MS cases, suggesting that cytotoxic molecules diffusing from the meninges participate in grey matter pathology and the following worsening of clinical disability.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

See 3 more Smart Citations

Novel mechanism and biomarker of chronic progressive multiple sclerosis

Oki

2018

Clinical & Exp Neuroim

View full text Add to dashboard Cite

Recent progress in understanding the pathogenicity of multiple sclerosis (MS) has enabled us to develop new drug entities available in the clinic. However, we still have not succeeded in preventing conversion from relapsing–remitting MS to secondary progressive MS (SP‐MS), and in curing this intractable form of MS. Furthermore, diagnosis is usually retrospective, relying on gradual worsening of neurological signs/symptoms. This is due to the lack of understanding of the pathogenicity driving disease progression in MS and of reliable biomarkers reflecting the disease status. Two relevant components are involved in the brain pathology of SP‐MS: neurodegeneration and inflammation. Neurodegeneration can occur spontaneously in a neuron‐intrinsic manner under chronic inflammation, such as glutamate excitotoxicity, mitochondrial/oxidative injury with iron deposit in the brain and loss of trophic support. Meanwhile, inflammatory and/or immune cells stimulated after repeated relapses, including T cells, B cells, and myeloid cells of peripheral and central nervous system origin, could mediate the processes of neurodegeneration. Among them, a higher frequency of leptomeningeal follicle‐like structures observed in SP‐MS patients suggests that immune cells sheltered behind a blood–brain barrier are still active under smoldering central nervous system inflammation. Accordingly, our recent comparative analysis between MS and its animal model, experimental autoimmune encephalomyelitis, raises a new possibility that ectopic expression of eomesodermin in helper T cells constitutes a previously unappreciated subset of helper T cells with cytotoxic potential against neuronal cells. In the present review article, the mechanisms proposed in the pathogenesis of SP‐MS are summarized, and a new pathogenic mechanism for neurodegeneration mediated by unique cytotoxic helper T cells is proposed.

show abstract

Section: Proposed Pathogenic Mechanism Of Secondary Progressive Msmentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Section: Immune-mediated Neuronal Damage Associated With Neurodegenermentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

See 2 more Smart Citations

Novel mechanism and biomarker of chronic progressive multiple sclerosis

Oki

2018

Clinical & Exp Neuroim

View full text Add to dashboard Cite

show abstract

“…Despite the lack of efficacy for fingolimod in progressive MS (16), the potential neuroprotective effects due to the blockade of S1P-S1P receptor axis in CNS prompted the development of novel S1P receptor modulators which work as active drugs. The recent phase-3 EXPAND trial demonstrated that oral administration of siponimod (BAF312), which targets S1P1 and S1P5 (17), attenuates the risk of disability progression in SP-MS, with a major effect in those patients with inflammatory disease (18). For this reason the European Medicines Agency recommended BAF312 as first oral treatment for active SP-MS in November 2019 1 .…”

Section: Introductionmentioning

confidence: 99%

Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration

Colombo¹,

Bassani²,

Angelis³

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) with heterogeneous pathophysiology. In its progressive course oligodendrocyte and neuroaxonal damage is sustained by compartmentalized inflammation due to glial dysregulation. Siponimod (BAF312), a modulator of two sphingosine-1-phosphate (S1P) receptors (S1P1 and S1P5) is the first oral treatment specifically approved for active secondary progressive MS. To address potential direct effects of BAF312 on glial function and glia-neuron interaction, we set up a series of in vitro functional assays with astrocytes generated from human fibroblasts. These cells displayed the typical morphology and markers of astroglia, and were susceptible to the action of inflammatory mediators and BAF312, because expressing receptors for IL1, IL17, and S1P (namely S1P1 and S1P3). Targeting of S1P signaling by BAF312 inhibited NFκB translocation evoked by inflammatory cytokines, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Further, while glia cells exposed to IL1 or IL17 downregulated protein expression of glutamate transporters, BAF312-treated astrocytes maintained high levels of GLAST and GLT1 regardless of the presence of inflammatory mediators. Interestingly, despite potential glial susceptibility to S1P signaling via S1P3, which is not targeted by BAF312, NFκB translocation and downregulation of glutamate transporters in response to S1P were inhibited at similar levels by BAF312 and FTY720, another S1P signaling modulator targeting also S1P3. Accordingly, specific inhibition of S1P1 via NIBR-0213 blocked S1P-evoked NFκB translocation, demonstrating that modulation of S1P1 is sufficient to dampen signaling via other S1P receptors. Considering that NFκB-dependent responses are regulated by Nrf2, we measured activation of this critical transcription factor for anti-oxidant reactions, and observed that BAF312 rapidly induced nuclear translocation of Nrf2, but this effect was attenuated in the presence of an inflammatory milieu. Finally, in vitro experiments with spinal neurons exposed to astrocyte-conditioned media showed that modulation of

show abstract

Multiple Sclerosis

Pitts

Dyckman

2021

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

Several new medicines have been approved or entered development for the treatment of Multiple Sclerosis (MS) in the past few years. The sphingosine‐1‐phosphate (S1P) modulator fingolimod was the first FDA approved oral disease modifying therapy for MS, and it has inspired a number of additional agents directed at this clinically validated target. Fumarates (e.g. dimethyl fumarate), dihydroorotate dehydrogenase inhibitors (e.g. teriflunomide) and other agents which decrease lymphocyte proliferation (e.g. cladribine) represent additional clinically validated therapeutic approaches. While the mechanisms of action for these new agents may not be fully defined, they have demonstrated a good degree of efficacy in the treatment of relapsing forms of MS. It is of interest to note that biologic agents which target CD20 on B cells have also shown significant efficacy in the treatment of MS. This, in turn, has spurred MS clinical trials with Bruton's Tyrosine Kinase (BTK) inhibitors, which also act on B cell pathways. The introduction of each of these newer agents still requires careful consideration of the risk–benefit for individual patients, but has also set a higher bar in the treatment of MS for subsequent agents, as evidenced by the discontinuation of several agents in late stage clinical trials. This higher bar has also pushed some historic agents to second or third line agents. This speaks to an overall advancement in the treatment of MS, and provides hope for further advances in therapeutic options.

show abstract

Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: the evidence to date

Cited by 28 publications

References 22 publications

Novel mechanism and biomarker of chronic progressive multiple sclerosis

Novel mechanism and biomarker of chronic progressive multiple sclerosis

Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration

Multiple Sclerosis

Contact Info

Product

Resources

About