Expert Opinion on Investigational Drugs
Siponimod in the treatment of multiple sclerosis

Andrew Goodman, Nidhiben Anadani & Lee Gerwitz


Introduction: Multiple sclerosis (MS) causes focal lesions of immune-mediated demyelinating events followed by slow progressive accumulation of disability. Over the past 2 decades, multiple medications have been studied and approved for use in MS. Most of these agents work by modulating or suppressing the peripheral immune system. Siponimod is a newer-generation sphingosine 1 phosphate (S1P) receptor modulator which internalizes S1P1 receptors thereby inhibiting efflux of lymphocytes from lymph nodes and thymus. There are promising data suggesting that it may also have a direct neuroprotective property independent of peripheral lymphocytopenia.
Areas covered: We reviewed the pharmacology and the clinical and radiological effects of siponimod.

Expert opinion: The selective effect of siponimod on the S1P1 and S1P5 receptors offers a favorable side-effect profile and transient bradycardia can be avoided by dose titration. A phase- II study showed that siponomod has dose-dependent beneficial effects in patients with relapsing remitting disease. The results of a phase-III study suggest that siponimod may be beneficial in secondary progressive MS, at least in patients with disease activity.


BAF-312, multiple sclerosis, progressive multiple sclerosis, siponimod, sphingosine 1 phosphate receptor

Article Highlights

• Siponimod is recently approved as a next generation S1P receptor modulator for MS
• Siponimod has an oral formulation with blood-brain-barrier penetration
• The agent is designed for increased S1P receptor specificity which may limit toxicity, particularly cardiac arrhythmia concerns
• There are reported findings of efficacy in a randomized clinical trial in secondary progressive MS patients
• Controversy exists regarding the efficacy of siponimod and other drugs in progressive forms of MS

1. Introduction

Multiple sclerosis (MS) is an immune-mediated disorder affecting the central nervous system (CNS). Inflammatory demyelination and axonal loss produce a range of neurologic symptoms. A typical early disease course is characterized by clinical relapses followed by symptomatic improvement or remissions with an indolent accumulation of symptoms later in life, likely in part due to a component of neurodegeneration as well as ongoing chronic inflammation. The clinical course can largely be divided into relapsing and the progressive forms (primary and secondary)[1].

Traditionally, MS was considered an immune-mediated or possibly an autoimmune disease driven by CD4 Th-1 cells[2], but growing research over the years has indicated an important role of B-cell involvement in MS pathogenesis[3]. This, in turn, has changed the treatment paradigm to include the use of B-cell depleting monoclonal antibodies such as ocrelizumab[4] in the therapeutic armamentarium. The pathogenesis of progressive MS is not clearly understood but several factors are considered to play a role, including oxidative stress, mitochondrial injury, axonal ionic channel disturbance, iron accumulation in extracellular space causing free radical damage, diffuse microglial activation, astrocyte gliosis, and diffuse axonal loss in normal appearing white matter[5]. Synaptic imbalance in glutamatergic and GABAergic transmission has been considered a factor in neurodegeneration in experimental autoimmune encephalitis (EAE) and MS brain[6]; this is a growing area of interest in terms of therapeutic development in MS. Ultimately, chronic inflammation and neurodegeneration are associated with gradual worsening of central nervous system function in progressive MS[5].

2. Overview of the Market

With the growing understanding of the pathogenesis of MS over the years, there are now 14 medications that have regulatory approval for marketing in various jurisdictions around the world. These include interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod, natalizumab, alemtuzumab, ocrelizumab, and mitoxantrone. Most of the medications are targeted towards decreasing the number of relapses and new lesions. Ocrelizumb[7] and mitoxantrone[8] have been approved for use in progressive forms of MS, but the latter is seldom used now due to the associated risk of significant cardiotoxicity and leukemia. Multiple medications have been studied for progressive forms of MS. Intravenous immunoglobulin[9], interferon Beta 1b[10] and natalizumab[11] have been studied for secondary progressive MS (SPMS) and did not show statistically significant results in terms of Expanded Disability Status Scale (EDSS) score changes, though natalizumab did show improvement in upper limb functional testing. Interferon Beta 1b[12], rituximab[13], glatiramer acetate[14] and fingolimod[15] all have been studied in primary progressive MS (PPMS) and failed to slow the disease progression. Oral cladribine[16], studied for primary and secondary progressive MS, and low dose methotrexate[17], in chronic progressive MS, showed non-significant effects on EDSS progression. Smaller studies did show slowing of disease progression with treosulfan, a chemotherapeutic agent used in gynecological cancer, in patients with active secondary progressive disease, though the results cannot be generalized given the small sample size[18].

3. Introduction to the compound

3.1 Chemistry

Siponimod is a member of a class of organic compounds known as trifluoromethylbenzenes. These are organofluorine compounds which contain a benzene ring substituted with one more trifluoromethyl groups. It was also known as BAF-312[19].

3.2 Pharmacodynamics

Siponimod is a new-generation sphingosine-1 phosphate (S1P) receptor modulator. S1P binds with G-protein-coupled receptors (S1P1-S1P5) to modulate a wide range of physiological systems. S1P receptors (S1PR) are abundant on lymphocytes, oligodendrocytes, astrocytes, erythrocytes, and in eyes and spleen. They regulate cellular trafficking, heart rate, endothelial barrier function, and smooth muscle tone. There are five known subtypes of S1PR, labeled S1PR1 through S1PR5. S1PRs are expressed differentially on different cell types. Myocytes express S1PR1 and S1PR3, lymphocytes express only S1PR1, while astrocytes and oligodendrocytes express S1PR1 and S1PR5. S1P receptor modulators bind to S1PR and cause internalization and degradation of the receptors [20].

Fingolimod was the first drug in this class to be studied for relapsing multiple sclerosis (RRMS) and showed a statistically significant reduction in relapse rate and radiological activity[21]. The proposed mechanism of action of fingolimod is through its effect on S1P1R causing lymphocyte sequestration, but it causes a transient and dose-dependent decrease in heart rate, thus requiring a monitoring period of at least 6 hours with the first dose administration [22]. Fingolimod- associated bradycardia in humans is thought to be due to its transient agonistic action on S1P1R on atrial myocytes with ultimate antagonistic action due to down-regulation of S1P1R, though in mouse bradycardia is due to its effect on S1P3R[23]. In addition to S1P1, fingolimod binds to S1P3-5 with high affinity[24]. The favorable effects of fingolimod in MS led to further studies of newer more specific S1PR modulators with potentially fewer side effects due to selective action on S1PR while preserving the broad tissue distribution and efficacy of fingolimod.

Siponimod, which was developed by Novartis Pharmaceuticals, is a selective S1PR1 and S1PR5 modulator which causes long-lasting internalization of the S1P receptor upon binding[25].
Siponimod can cause transient and dose-dependent bradycardia which peaks at 2 hours. There is minimal or no reduction in heart rate seen after the second dose suggesting that siponimod causes rapid receptor desensitization[25]. In a Phase-I study, Gergely et al reported that siponimod has species-specific effects on heart rate. Bradycardia in mice is due to its effect on S1PR3 and in humans due to activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels in atrial myocytes[25]. Bradycardia can be avoided by a dose titration such that there is down-regulation of S1PR at low doses and therefore minimal effects on heart rate once the full dose is achieved[26]. Siponimod has high affinity for S1P5 receptors which are present on oligodendrocytes in all stages of development; it plays an important role in oligodendrocyte differentiation and survival thereby affecting myelination in experimental systems[27].

Other S1PR modulators which are under investigation include ozanimod, a selective S1P1R/S1P5R modulator, and ponesimod, a S1P1 modulator which causes a decrease in the circulating lymphocyte count and has a short half-life and fast wash-out[28]. Ozanimod, in a phase-III study for RRMS, showed significant reduction in relapse rate and enhancing lesions as compared to interferon beta 1a without significant bradycardia, macular edema, or infectious adverse events[29]. Similarly, ponesimod[30] in phase-II studies did show significant reduction in enhancing lesions as compared to placebo with a phase-III study on the way comparing ponesimod to teriflunomide in RRMS patients with a similar adverse event (AE) and serious AE profile as compared to siponimod and fingolimod [31].. Oral fingolimod has failed to show benefit for progressive MS even with its effect on S1P5 receptor. To date there have been no clinical studies to evaluate the effect of ponesimod or ozanimod on progressive disease.

3.3 Pharmacokinetics and metabolism

Glaenzal et al. performed a pharmacokinetic study of 10 mg siponimod in healthy volunteer men which showed that peak plasma concentration is reached in 4 hours; apparent elimination half- life was 56.6 hours though unchanged siponimod was detected in plasma until 480 hours[32]. Another larger healthy control trial showed that for a dose range of 3 mg-20 mg, elimination half-life was 22-28 hours (mean of 30 hours) and complete elimination of the drug (takes 5 half- lives) can take 6.3 days (~ 150 hours)[25]. Siponimod undergoes biotransformation in 2 phases. Phase 1 involves hydroxylation, mainly by CYP2C9, and phase 2 involves sulfation and glucuronidation. The majority of the metabolites (M3, M5) are excreted through the feces[32]. Jin et al further established the role of CYP2C9 in siponimod metabolism by in vitro and in vivo studies with concomitant use of fluconazole which is a moderate CYP2C9 inhibitor. They also reported significant changes in siponimod metabolism depending on genotypic variation in CYP2C9 enzyme, which could help in personalizing the medication dose for individual patients according to the individual CYP2C9 genotype [33]. Gardin et al administered one dose of siponimod 0.25 mg to healthy participants. Individuals with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes experienced a two- to four-fold increase in the area under the curve (AUC) compared to individuals with the CYP2C9*1/*1 genotype. The authors also noted that the half-lives of siponimod in participants with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes were prolonged (50.9 and 126 hours, respectively) compared to that in participants with the CYP2C9*1/*1 genotype (28.1 hours). These data indicate a lower dosage requirement in individuals with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes.[34]. These findings also illustrate the potential effects of medication interaction with other CYP2C9 inhibitors. Varying degrees of hepatic impairment did not affect pharmacokinetics[36]. In patients with severe renal impairment, pharmacokinetics were marginally affected including decrease in maximum plasma concentration (Cmax) of siponimod and its metabolite, though this finding was not clinically significant[37].

3.4 Siponimod and Neuroinflammation

Both S1P1 and S1P5 receptors are present on neurons, astrocytes, microglia, and oligodendrocyte and oligodendrocyte precursor cells[38]. Siponimod is lipophilic and is known to cross the blood-brain barrier, which could be an important factor for the potential of neuroprotection[39]. Ginatile et al reported that siponimod’s effect on myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35-55) induced experimental autoimmune encephalitis (EAE), a model of the progressive type of MS, is independent of peripheral lymphocytopenia. They showed a dose-dependent effect of direct injection of siponimod in CSF on disease severity. The highest dose used in the study (4.5 microgram/day) completely inhibited EAE development. A lower dose of 0.45 microgram/day ameliorated disease severity, while the lowest dose of 0.225 mcg/day had no effect; this effect was independent of minimal peripheral lymphocytopenia produced with both lower doses (0.45 mcg/day and 0.225 mcg/day). They also noted substantial reduction in astrogliosis and glial fibrillary acidic protein (GFAP) and increase in gamma aminobutyric acid (GABA) frequency signal in striatum of siponimod treated mice[40]. O’Sullivan et al. reported that human and mouse astrocyte cell cultures treated with siponimod showed attenuation in demyelination induced by lipopolysaccharide (LPS) by decreasing IL-6. Siponimod also activates pancreatic endoplasmic reticulum kinase (pERK), pAKT, and calcium signaling in astrocyte cell culture[41]. pERK activation is shown to inhibit EAE in a mouse model[42].. Further, data from studies involving cuprizone mice show that siponimod decreases oligodendocyte and axonal loss, suggesting that it might be able to protect axons during both the acute and the chronic demyelinating phases of MS. There was no significant effect on remyelination[43].

4. Efficacy of Siponimod in Multiple Sclerosis

4.1 Models of MS

Siponimod has been studied in a chronic EAE rat model. Once daily oral administration of siponimod starting at peak time of disease manifestation in immunized animals significantly suppressed already established neurological deficits, especially with higher doses (3mg/kg and 0.3mg/kg), with borderline effects with low dose (0.03 mg/kg)[25].

4.2 Siponimod in Immunomodulation in MS

Siponimod causes a dose-depended decrease in absolute lymphocyte count (ALC) within 4-6 hours[25]. This effect is due to long-lasting internalization of S1P1 receptors, which are important for egress of B and T lymphocytes from thymus and lymph nodes[44]. Siponimod affects both peripheral B and T cells with pronounced effect on CD4 T cells than CD8 T cells and preferential decline in CD4 naive cells and CD4 central memory T cells (TCM, CCR7+) with less effect on CD4 peripheral effector memory T cells (TPEM, CCR7-). This effect is similar to
what has been reported with fingolimod [45] but due to siponimod’s shorter half-life, the ALC returns to baseline after 3 weeks of discontinuation.

4.3 Siponimod and Multiple Sclerosis Clinical Trials

With promising safety data in animal studies and phase-I studies, a phase-II study was initiated to evaluate the efficacy, safety, and tolerability in patients with RRMS. This study, published in 2013 by Selmaj, et al., was a multicenter, double-blinded, randomized, adaptive, dose-ranging, trial. Included in the trial were adults aged 18-55 with RRMS. Two patient cohorts were tested sequentially. Participants in cohort 1 were randomized (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, 0.5 mg, or placebo for 6 months. Participants in cohort 2 were randomized (4:4:1) to siponimod 1.25 mg, 0.25 mg, or placebo once daily for 3 months[46]. Patients who had experienced a relapse or received corticosteroid treatment in the 30 days before randomization were excluded from the trial. Patients with active infection, macular edema, diabetes mellitus, immunosuppression, cancer, heart disease, lung disease, or liver disease were also excluded. A total of 188 participants were recruited into cohort 1 and 109 patients into cohort 2 among 73 medical centers in Europe and North America. The primary endpoint was assessed by percentage reduction in monthly number of combined unique active brain MRI lesions (CUAL’s) at 3 months. Secondary efficacy endpoints included the effect of siponimod on the number of monthly CUAL’s, number of monthly new and all gadolinium-enhancing T1 brain lesions, number of monthly new gadolinium-enhancing T1 lesions in patients with high disease activity, number of monthly new or newly enlarged T2 lesions, the proportion of patients without any new MRI activity (CUALs), annualized relapse rates, and proportion of patients who were free of relapses.

The results of this study showed a dose-response relation (p=0.0001) across the five doses of siponimod. The reduction in CUAL’s at 3 months compared with placebo was 35% for siponimod 0.25 mg, 50% for siponimod 0.5 mg, 66% for siponimod 1.25 mg, 72% for siponimod 2 mg, and 82% for siponimod 10 mg. Efficacy was much the same with the 2 mg and 10 mg doses for secondary MRI outcomes, whereas the 0.5 mg dose showed submaximal reductions versus placebo. Taken together, the data suggest that the siponimod 10 mg dose does not offer efficacy advantages compared with the 2 mg dose, and the 0.5 mg dose might not be beneficial in terms of clinical and MRI outcomes. These findings demonstrated that an S1P receptor modulator with selectivity for subtypes 1 and 5 might be effective in RRMS.
Cohen et al did find that fingolimod had a superior effect compared to an active comparator in patients with RRMS in terms of relapse rate and MRI measures, though no difference was found in terms of confirmed disability progression between two groups[47].

4.4 Safety and Tolerability

As previously discussed, Selmaj et al studied the safety of 5 different siponimod doses for up to 6 months in patients with RRMS. Participants had a dose-dependent decrease in heart rate on treatment initiation when a dose titration was not used[46]. In a dose-blinded extension of this study, Kappos et al studied the safety of the 5 siponimod doses up to 24 months[48]. A total of 184 participants were included in the study and received siponimod at doses of either 10, 2, 1.25, 0.5, or 0.25 mg daily. The most common adverse events were nasopharyngitis, headache, lymphopenia, upper respiratory tract infection, increased alanine aminotransferase, pharyngitis, and insomnia. Frequencies of lymphopenia and decreased lymphocyte count were highest in the siponimod 10 mg group. There were no cases of macular edema. Dose titration during the first 10 days of treatment reduced the negative chronotropic effect of siponimod at all doses. There were no severe or systemic opportunistic infections in any treatment group. Importantly, there are no reported cases of progressive multifocal leucoencephalopathy (PML) with siponimod; however, the incidence of PML with fingolimod is low and therefore the limited sample size and duration of observation may be insufficient to adequately assess the risk for siponimod. , so long- term monitoring will be important. Previous immunotherapy, degree of lymphocytopenia, and duration of therapy can be considered as possible prognostic factors for PML risk. At this point there are no clear risk factors for PML development in patients treated with fingolimod, so clinical and radiological monitoring is advisable with siponimod. There are no reported cases of malignancies with siponimod, and again long-term clinical monitoring will be needed.

4.5 Assessment of Siponimod in Progressive Multiple Sclerosis

In 2018, Kappos et al. carried out a multicenter, double-blinded, placebo-controlled, phase-III trial to assess the effectiveness and safety of siponimod in patients with secondary progressive multiple sclerosis (SPMS)[49]. Included in the study were adults age 18-60 years who carried a diagnosis of SPMS with documented moderate-to-advanced disability indicated by an EDSS score of 3.0-6.5 at screening, a history of RRMS, documented EDSS progression in the 2 years before the study, and no evidence of relapse in the 3 months before randomization. Participants were randomly assigned (2:1) to receive once daily oral siponimod 2 mg or matching placebo. Exclusion criteria included substantial immunological, cardiac, or pulmonary conditions, ongoing macular edema, uncontrolled diabetes, CYP2C9*3/*3 genotype, and negative varicella zoster virus antibody status. A total of 1,651 participants were randomized in 31 countries, and 1645 participants were included in the analyses. A full neurological examination, including an assessment of walking range and EDSS score, was obtained every 3 months. MRI scans were obtained at baseline, 12 months, 24 months, and 36 months and at the end of the controlled treatment phase. The primary endpoint was time to 3-month confirmed disease “progression” (CDP). CDP was defined as a 1-point increased 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. CDP has been used previously in studies assessing the effects of interferon beta- 1b[50] and rituximab [13] on progressive MS. Secondary endpoints included time to 3-month confirmed worsening of at least 20% from baseline in the timed 25-foot walk (25FW) test and change from baseline in T2 lesion volume. Additional secondary endpoints were: time to 6- month CDP; ARR; time to first relapse; proportion of relapse-free patients; change in score on the patient-reported 12-item Multiple Sclerosis Walking Scale; number of new or enlarging T2 lesions; number of T1 gadolinium-enhancing lesions; and percentage change in brain volume from baseline.

The results of this study showed that siponimod reduced the risk of disability “progression” in participants with SPMS. In a time-to-event analysis, 26% of patients in the siponimod group and 32% in the placebo group had 3-month CDP. The risk of 6-month CDP was also reduced by siponimod (risk reduction 26%), and the annualized relapse rate was lower with siponimod than with placebo (risk reduction 46%). (Figure 1)[49] Furthermore, increase in T2 lesion volume from baseline was lower with siponimod than with placebo, and brain volume decreased at a lower rate with siponimod than with placebo. (Figure 2)[49] No significant difference was observed in the time to 3-month confirmed worsening of at least 20% in T25FW for the overall population or for patients with a baseline EDSS score of 5.5 or lower. Overall, these results suggest that siponimod may have a role in the treatment of patients with SPMS. Such an effect of siponimod in SPMS is thought to be due to anti-inflammatory and neuroprotective properties. Of note, fingolimod was not shown to have a statistically significant effect on EDSS or brain volume loss in patients with PPMS [15]. Important possible factors for such differential effects include 1) difference in study population between two studies, 2) lower affinity of fingolimod to S1PR5, and 3) differences in pathogenesis between SPMS and PPMS. Patients included in the fingolimod study were older, had less evidence of inflammatory activity on MRI, and had a primary progressive disease phenotype whereas patients in the siponimod study tended to be younger, had more evidence of inflammatory activity on MRI, and had a secondary progressive disease phenotype.

5. Expert Opinion

In this review we discuss the evidence for siponimod use in MS. It was recently approved by the United States Food and Drug Administration (FDA) as a next generation S1P receptor modulator for use in RRMS and SPMS “with activity”. Due to its selective effect on S1P1 and S1P5 receptors, it is hoped that its safety profile will prove favorable. Transient bradycardia can occur, but this could be avoided by dose titration. Indeed, siponimod’s approved dosing instructions include two options for titration and maintenance based on CYP2C9 genotype, and a first-dose observation period is not required. While this has obviated the need for cardiac monitoring, genetic testing adds a different logistical complexity to drug initiation. The personalized dosing of siponimod may enhance its long-term safety profile by preventing complications related to cardiac conduction abnormalities. Since CYP2C9 genotype was not taken into consideration during the clinical trials, it is unclear if this dosing scheme will have an effect on drug efficacy. Given the similar mechanisms of action of siponimod and fingolimod (see table 1), we predict that the respective risks of severe infections such as PML will be comparable. Furthermore, it would be reasonable to assume that, as with fingolimod, previous exposure to immunosuppressants, such as natalizumab, could increase the risk of PML in patients subsequently treated with siponimod. Due to the relatively short half-life of siponimod, its pharmacodynamic effects appear to be reversible within one week.

Siponimod crosses the blood-brain barrier and has proposed neuroprotective effects independent of its effects on peripheral lymphocyte trafficking. In a phase-II study, siponimod showed dose- dependent beneficial effects on radiological outcomes at 3 months in relapsing remitting patients. In phase-III investigation for secondary progressive MS, siponimod decreased ARR, delayed confirmed disability worsening as measured by EDSS at 6 months, and slowed brain volume loss compared to placebo. Fingolimod, a first generation S1PR modulator, was also studied in RRMS and showed favorable clinical and radiological outcomes without change in disability progression compared to active comparator. Fingolimod did not meet the primary endpoint in terms of disability progression in patients with PPMS. This discrepancy is likely due to differences in the patient populations in the studies in that the PPMS cohort in the fingolimod study was less likely to have had recent disease activity. Because of these suggested differences, some in the field[49] have questioned whether the efficacy truly represents a neuroprotective effect on the gradually progressive aspects of MS clinical worsening or simply the impact, albeit important, on the relapsing focal inflammatory processes seen in relapsing MS. The lack of compelling data in support of the former possibility likely contributed to the FDA’s decision not to approve siponimod for use in secondary progressive multiple sclerosis “without activity.” In order to gain more insight about this controversy, we will need more data and perhaps additional clinical trials to understand whether siponimod impacts beneficially on the gradual worsening that is characteristic of progressive MS. In our experience, fingolimod does not have a clinically meaningful effect on slowing the gradual disease worsening seen in secondary progressive MS, and we are not optimistic that siponimod, which has a similar mechanism of action, will be the answer that everyone in the field has been seeking.

This paper was not funded.

Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

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