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Kipp, M. Mechanism of Siponimod. Encyclopedia. Available online: https://encyclopedia.pub/entry/16500 (accessed on 27 July 2024).
Kipp M. Mechanism of Siponimod. Encyclopedia. Available at: https://encyclopedia.pub/entry/16500. Accessed July 27, 2024.
Kipp, Markus. "Mechanism of Siponimod" Encyclopedia, https://encyclopedia.pub/entry/16500 (accessed July 27, 2024).
Kipp, M. (2021, November 29). Mechanism of Siponimod. In Encyclopedia. https://encyclopedia.pub/entry/16500
Kipp, Markus. "Mechanism of Siponimod." Encyclopedia. Web. 29 November, 2021.
Mechanism of Siponimod
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This entry is adapted from the peer-reviewed paper 10.3390/cells8010024

Multiple sclerosis (MS) is a neuroinflammatory disorder of the central nervous system (CNS), and represents one of the main causes of disability in young adults. The Sphingosine 1-phosphate receptor modulator, siponimod, does not just ameliorate the inflammatory aspect but also the degenerative aspect of secondary progressive MS. 

Siponimod Multiple sclerosis (MS) Brain Cell

1. A Historical Perspective of Siponimod Development

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates a variety of physiological processes including lymphocyte recirculation and cardiac function. Most S1P effects are mediated via five G-protein-coupled S1P receptor subtypes referred to as S1P1–5 (originally termed EDG-1, 3, 5, 6, and 8) [1]. These receptors are differentially expressed on various cell types, including lymphocytes [2][3], cardiomyocytes [4][5] and brain cells. In 2000, Kuppermann showed that S1P receptors regulate cell migration during vertebrate heart development [6], and two years later a similar pro-migratory effect of S1P receptors was demonstrated for CD4+ T cells [7]. Two years after, in 2004, Matloubian for the first time showed that the egress of lymphocytes from the thymus and the peripheral lymphoid organs is dependent on S1P1 [8]. Due to these observations, the anti-inflammatory potency of S1P-receptor modulators have been intensively investigated.
The S1P-receptor modulator fingolimod, also called FTY720, induces a rapid and drastic deletion of T cells from the peripheral blood by inhibiting the egress of T cells from the thymus [9] and lymph nodes. By this mechanism, fingolimod prevents the entry of lymphocytes into the blood, and thus T cell infiltration into the CNS [10][11][12]. It has additionally been demonstrated that fingolimod can trigger lymphocyte apoptosis [10][13][14]. Consequently, preclinical studies show that fingolimod ameliorates pathology in several models of autoimmune diseases, including type 1 diabetes [15], adjuvant-induced arthritis [16], systemic lupus erythematosus [17] and, most importantly in the context of MS research, in different models of experimental autoimmune encephalomyelitis (EAE) [18][19]. In a number of clinical trials, it has been shown that fingolimod is well tolerated and associated with low relapse rates and lesion activity in relapsing-remitting MS patients [20][21][22][23]. Consequently, fingolimod was the first oral disease-modifying therapeutic agent to be approved for the treatment of MS. This pro-drug is rapidly converted in vivo into the active S-fingolimod-phosphate (FTY720-P) which is a potent agonist on S1P1, S1P3, S1P4 and S1P5 receptors. Since S1P-receptors are ubiquitinated and subsequently degraded when exposed to FTY720-P [24], the experimental and clinical efficacy of FTY720-P is thought to involve functional antagonism by persistent internalization and enhanced degradation of the S1P-receptor. Of note, its efficacy in MS and related animal models may in part be due to additional, direct effects within the brain. For example, a strong increase in S1P1 and S1P3 expression on reactive astrocytes was detected in active and chronic inactive MS lesions [25], whereas another study has suggested S1P5 expression in oligodendrocytes [26][27].
In general, fingolimod has a favorable benefit-risk profile [28]. However, a critical challenge of fingolimod therapy still remains in the initiation phases due to the risk of cardiac events. The first dose of fingolimod is associated with a decrease in heart rate and slowing of atrioventricular conduction [22][23][29]. The discovery of the S1P3 receptor mediating bradycardia in mice [30] prompted the search for S1P-receptor modulators devoid of S1P3 signaling. This effort led to the discovery of siponimod (also called BAF312), which is a selective modulator of S1P1 and S1P5 receptors. Siponimod was furthermore designed to have a relatively short elimination half-life that provides a rapid recovery of blood lymphocyte counts on stopping treatment, but would allow once-daily oral dosing [31].

2. Results of the EXPAND Study

In 2013, Selmaj reported the results of a phase 2 dose-finding study in patients with relapsing-remitting MS (RRMS). Siponimod reduced active brain lesion counts and the annualized relapse rate by approximately two-thirds, in a dose-dependent manner [32]. Due to the eminent medical need for having treatment options during progressive MS, a phase 3, randomized, parallel-group, double-blind, placebo-controlled, event-driven, and exposure-driven trial (EXploring the efficacy and safety of siponimod in PAtients with secoNDary progressive multiple sclerosis [EXPAND]) was conducted to investigate the efficacy and safety of siponimod in patients with secondary progressive MS (SPMS) [33]. Key inclusion criteria for subjects was being aged 18–60 years, having a history of RRMS following the 2010 revisions to the McDonald criteria [34], having a confirmed diagnosis of SPMS, having a moderate-to-advanced disability indicated by an Expanded Disability Status Scale (EDSS) score of 3–6 at screening, having documented EDSS progression in the 2 years before the study, and having no evidence of a relapse in the 3 months before randomization. The primary endpoint of the EXPAND study was the time to 3-month confirmed disability progression, which was defined as a 1-point increase in EDSS if the baseline score was 3.0–5.0, or a 0.5-point increase if the baseline score was 5.5–6.5, confirmed at a scheduled visit at least 3 months later. From February 2013 to June 2015, 1105 patients were randomly assigned to the siponimod group, and 546 to the placebo group, respectively. As one main result of this study, there was a significant reduction in the 3-month confirmed disability progression, with 26% of patients in the siponimod group and 32% in the placebo group having a 3-month confirmed disability progression, which equaled a relative risk reduction of 21% compared with placebo.
A number of secondary endpoints are relevant for this review article: First, the increase in T2 lesion volume from baseline was lower with siponimod than with placebo. Second, a higher number of patients receiving siponimod than placebo were free from gadolinium-enhancing lesions, and third, more patients receiving siponimod than placebo were free from new or enlarging T2 lesions. All these findings suggest a potent anti-inflammatory activity of siponimod in SPMS patients. Furthermore, brain volume decreased at a lower rate with siponimod (0.28%) than with placebo (0.46%). The only key secondary outcome that did not favor siponimod was time to 3-month confirmed worsening of at least 20% in the timed 25-foot walk (T25FW). In summary, siponimod attenuated the inflammatory activity in SPMS patients and at the same time ameliorated the degenerative aspect of the disease (i.e., disease progression). Notably, a subgroup analyses of the EXPAND study data suggested that the treatment effect of siponimod is most pronounced in patients with ongoing inflammatory activity. This finding is similar to what was seen with ocrelizumab in the ORATORIO trial in primary progressive MS, where greater benefit was detected in patients with gadolinium-enhancing lesions at baseline [35].

3. Possible Siponimod Mode of Action

As pointed out in the previous chapter, siponimod reduced the inflammatory activity (i.e., less gadolinium-enhancing lesions and new or enlarging T2 lesions) as well as the extent/progression of neurodegeneration (i.e., reduced disability progression and brain atrophy). It is an intriguing question how the two aspects of the disease, inflammation and neurodegeneration, influence each other. On the one hand, it is well known that the recruitment of peripheral immune cells can activate signaling cascades leading to neurodegeneration. In EAE, various aspects of neurodegeneration can be found, including synaptic degeneration, dendritic spine loss [36][37], alterations of synaptic plasticity [38], or the loss of lower motor neurons [39]. Siffrin nicely demonstrated that in EAE, the direct interaction of myelin oligodendrocyte glycoprotein (MOG)-specific Th17 and neuronal cells in demyelinating lesions is associated with extensive axonal damage [40]. Thus, the anti-inflammatory activity of sipinimod might results in less severe neurodegeneration and in consequence, amelioration of brain atrophy and disease progression.
On the other hand, it has been shown that siponimod readily crosses the blood brain barrier and therefore potentially exerts beneficial effects by a direct interaction with brain cells. For example, findings from preclinical studies suggest that siponimod prevents synaptic neurodegeneration [41] and has the potential to promote remyelination in the CNS [42]. Additionally, siponimod was shown to modulate biological pathways involved in cell survival with subsequent attenuation of demyelination, in a mouse model [43]. It is therefore also possible that siponimod prevents brain atrophy and disease progression by directly interfering with brain cells, such as astrocytes, microglia, oligodendrocytes or neurons. Both aspects have recently been addressed in a commentary [44]. A third aspect, however, has not been discussed so far: The observed anti-inflammatory effects of siponimod in the EXPAND trial might be due to a primary CNS protective effect.

4. Siponimod Ameliorates Degenerative Brain Events

As already pointed out above, siponimod readily crosses the blood brain barrier, and the receptors of siponimod, S1P1 and S1P5, are expressed by neural cells such as astrocytes [25], oligodendrocytes [26][27], microglia or neurons [45][46]. In order to assess whether siponimod has direct neuronal effects, in one elegant study, the drug was delivered directly into the brain by means of continuous intracerebroventricular infusion. While such a siponimod treatment strategy ameliorated the EAE disease score, it did not affect peripheral CD3+ cell counts [41]. Of note, astrocytosis and microgliosis as well as neuronal loss were less severe in siponimod-treated mice, and IL6 secretion was ameliorated in cultured microglia by siponimod. From these results it was concluded that siponimod is neuroprotective (i.e., it prevents the loss of neurons [41], probably by the modulation of microglia cell function). Furthermore, it has been shown using an organotypic slice culture model, that siponimod attenuates lysophosphatidylcholine-induced demyelination, suggesting that siponimod ameliorates as well oligodendroglia-degeneration. This assumption is in line with a recent report showing that siponimod decreases oligodendrocyte loss and demyelination in the cuprizone model [47].

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