Siponimod is a second-generation oral sphingosine 1-phosphate (S1P) receptor modulator that was approved by the US Food and Drug Administration (FDA) in March 2019 for the treatment of relapsing types of multiple sclerosis (MS), including “active” secondary progressive MS (SPMS).1 The phenotypic subtypes of MS are defined by their clinical course.2 Most patients initially exhibit a relapsing-remitting course (RRMS), characterized by acute bouts of inflammation associated with clinical relapses, typically with corresponding accrual of lesions on magnetic resonance imaging (MRI), without worsening in neurologic function outside of relapses.

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S1P Modulation

A proportion of patients with RRMS will ultimately begin to develop a gradual worsening of neurologic disability outside of any clinical relapses or MRI lesion accrual, termed secondary progressive MS (SPMS). Importantly, patients with SPMS may still experience superimposed relapses, albeit typically at a reduced rate compared with patients who have RRMS, which is referred to as “active” SPMS. While there are many disease-modifying therapies indicated for RRMS, effective treatments for SPMS have been elusive.2

The S1P cell-surface receptor family is made up of 5 subtypes — S1P1, S1P2, S1P3, S1P4, and S1P5 — that are present and play a role in various organ systems, including the immune, cardiovascular, and respiratory systems, as well as in the central nervous system (CNS).3 Efficacy of treatment for MS is thought to be primarily mediated by S1P1 binding on lymphocytes, which leads to internalization of the cell-surface receptor. Functional antagonism of this receptor, which is necessary for lymphocyte egress from lymphoid tissue, leads to sequestration of lymphocytes in lymph nodes, thereby preventing CNS infiltration. Additionally, as S1P receptors are present on neurons, astrocytes, oligodendrocytes, and microglia, S1P modulators may exhibit neuroprotective effects.3 In preclinical studies of experimental autoimmune encephalitis, the mouse model of MS, S1P modulators have been shown to help prevent synaptic neurodegeneration4 and exhibit pro-remyelination effects.5 While the nonselective S1P modulator fingolimod has been used in the treatment of RRMS for almost a decade,6 siponimod selectively modulates S1P1 and S1P5, thereby potentially reducing adverse effects while still retaining effects on lymphocyte trafficking and the CNS.1 Additionally, siponimod has a shorter half-life, leading to washout in 7 to10 days and reversal of effects within several weeks.1

Clinical Trials

Siponimod was studied in a dose-finding, placebo-controlled, phase 2 study (Safety, Tolerability, Efficacy and Optimal Dose Finding Study of BAF312 in Patients With Relapsing Remitting-Multiple Sclerosis [BOLD]; ClinicalTrials.gov Identifier: NCT00879658)7 in patients with RRMS; a 2-mg daily dose was associated with a decrease in annualized relapse rate (ARR) of 65% and a decrease in active lesion count of 70% compared with placebo. Siponimod was subsequently studied in a randomized, double-blind, placebo-controlled, event-driven phase 3 study (Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis [EXPAND]; ClinicalTrials.gov Identifier: NCT0101665144)8 in patients with SPMS. Recruitment criteria comprised being aged between 18 and 60 years, a diagnosis of SPMS, an expanded disability status scale (EDSS) score of 3.0 to 6.5 at baseline (range 0-10, higher scores indicating increased disability, with 6.5 being the highest possible score for an ambulatory patient), documented EDSS worsening over the 2 years prior to the study, and absence of relapses in the 3 months prior to randomization.8 Those with substantial immunologic, cardiac, or pulmonary conditions, or those with macular edema or uncontrolled diabetes were excluded from the study. In a 2:1 ratio, 1651 patients were randomly assigned to receive once-daily oral siponimod 2 mg or placebo. The medication was titrated from 0.25 mg to 2 mg over 6 days to limit unwanted cardiovascular effects. The primary end point was time to 3-month confirmed disability progression (CDP), which refers to disability worsening that was maintained for at least a 3-month period. This was defined as a 1-point increase in EDSS from a baseline score of 3.0 to 5.0, or a 0.5-point increase if the baseline score was 5.5 to 6.5. The major secondary end points included time to 3-month confirmed 20% slowing of walking speed measured on the timed 25-foot walk test and overall accrual of T2 lesion volume from baseline. The study was continued until a total of 374 “3-month CDP events” occurred, with a median time on study of 21 months and a median exposure to the study drug of 18 months. Overall, 26% of patients on siponimod and 32% of patients on placebo had 3-month CDP, with a modest but significant 21% risk reduction.8 Of note, planned subgroup analysis demonstrated that patients with superimposed relapses in the 2 years before enrollment had a 33% reduction in 3-month CDP, whereas the reduction in those without a recent relapse was 13% and was not statistically significant. Furthermore, siponimod did not have an effect on walking speed. Additional secondary end points showed an 80% reduction in T2 lesion accrual, a 55% reduction in ARR, and a significant reduction in brain atrophy.8

Indication and Initiation

Based on outcomes of the EXPAND study demonstrating a statistically significant effect on CDP only in patients with SPMS with superimposed relapses over the prior 2 years, the FDA approved siponimod for the treatment of “active SPMS” but not for “inactive SPMS.”1 Additionally, based on results from the BOLD, EXPAND, and prior fingolimod studies demonstrating a class effect, siponimod has also been approved for clinically isolated syndrome (CIS) and RRMS. However, while siponimod holds some benefits over fingolimod with regard to monitoring requirements, insurance approvals and step-edits may currently prevent replacement of fingolimod with siponimod in patients with RRMS and CIS.

Siponimod is metabolized primarily by the cytochrome P450 family 2 subfamily C member 9 gene (CYP2C9) and cytochrome P450 family 3 subfamily A member 4 gene (CYP3A4), and genotype testing is required prior to treatment initiation to determine the optimal dose of the medication.1 The majority of patients will have CYP2C9 genotypes *1/*1, *1/*2, or *2/*2 and will require a maintenance dosage of 2 mg daily starting on day 6 of treatment after a short up-titration (0.25 mg on days 1 and 2, 0.5 mg on day 3, 0.75 mg on day 4, and 1.25 mg on day 5). In patients with a CYP2C9*1/*3 or *2/*3 genotype who metabolize the medication more slowly, the recommended maintenance dosage is 1 mg daily starting on day 5 of treatment after the first 4 days of up-titration. Siponimod is contraindicated in patients in whom genetic tests show that they are homozygous for CYP2C9*3, which makes up approximately 0.4% to 0.5% of whites and an even lower proportion of other populations.

Safety, Tolerability, and Monitoring Requirements

As with fingolimod, the safety and tolerability profile of siponimod is driven by its effects on S1P receptors. The most common adverse reactions were headache (15% compared with 14% on placebo), hypertension (13% compared with 9% on placebo), and transaminitis (11% compared with 3% on placebo).1 Hence, caution should be exercised when using siponimod in patients with hypertension or history of liver disease. Treatment with siponimod was discontinued in patients in the EXPAND trial who developed hepatic enzyme elevations more than 3 times the upper limit of normal8; therefore, it is prudent to monitor blood work regularly and discontinue siponimod if a substantial transaminitis is noted.

Initiation of siponimod results in a typically asymptomatic transient heart rate decrease and atrioventricular (AV) conduction delay, and performing electrocardiography in all patients prior to initiation is recommended. While fingolimod requires a first dose observation (FDO) for cardiac effects,6 siponimod limits the cardiac risk by using a slow up-titration protocol, which depends on CYP2C9 genotype. Although the lack of a general FDO requirement is advantageous, if a patient misses 1 of the titration doses, he or she should re-initiate the up-titration from the beginning. Additionally, given the short half-life of siponimod, if more than 4 consecutive maintenance doses are missed, the up-titration needs to be repeated. In patients with mild sinus bradycardia, first or second-degree AV block, or remote history of myocardial infarction (MI), cardiology consultation and FDO is recommended. In patients with a history of cardiac arrest, recent MI, or uncontrolled hypertension, alternatives to siponimod should be considered. In patients taking stable doses of medications that decrease heart rate, such as β-blockers or calcium channel blockers, or medications that can prolong QT, it is possible to temporarily suspend these treatments during initiation of siponimod to avoid additive effects. Consideration of treatment suspension should always be done with the help of a cardiologist, and the potential benefit of siponimod should be weighed against the risk of holding such medications.

As siponimod is metabolized by cytochrome P450, the potential for complex drug interactions is high. Concomitant use of medications that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition (such as fluconazole) is not recommended due to resultant increased siponimod drug levels. Conversely, a significant decrease in siponimod drug levels has been seen with the concomitant use of medications that cause moderate CYP2C9 and strong CYP3A4 induction (such as rifampin or tegretol); therefore, concomitant use of these medications is not recommended. Concomitant use with medications that are moderate or strong CYP3A4 inducers is not recommended in patients with the CYP2C9*1/*3 and*2/*3 genotypes; this restriction includes modafinil, which is commonly used as a treatment for MS-related fatigue.

Consistent with its lymphocyte-sequestering mechanism of action, siponimod causes a dose-dependent reduction in peripheral lymphocyte counts to 20% to 30% of baseline values,1,8 which increases the risk for typical and opportunistic infections. In the EXPAND study, the overall rate of infections was similar in both the drug and placebo groups (49% vs 49.1%), but herpes zoster, herpes, bronchitis, sinusitis, upper respiratory infections, and fungal skin infections occurred more frequently in patients taking siponimod.1 Serious infections occurred at a mildly elevated rate (2.9% with siponimod compared with 2.5% on placebo).1 Rare cases of cryptococcal meningitis have been reported with siponimod; therefore, vigilance is indicated.1 Patients should be tested for antibodies to varicella-zoster virus (VZV) prior to initiation of siponimod as reactivation of VZV infection leading to meningitis has been reported.1 Patients without a sufficient VZV titer should be vaccinated 1 month prior to initiation with siponimod.  Progressive multifocal encephalopathy — an opportunistic, potentially life-threatening brain infection — has not been reported with siponimod, but rare cases have occurred with fingolimod, and the incidence appears to be higher with increased patient age.6 Given the similarity in mechanism of action, vigilance for JC virus is indicated for patients on siponimod therapy.1 Additionally, as the target population of SPMS patients tends to be older, there is potential for JC virus risk with siponimod to be higher than what has been reported with fingolimod, which was indicated for RRMS only. However, further postmarketing experience is necessary to elucidate this further.

Due to the risk for infection, patients beginning siponimod should be evaluated with a complete blood count, and those with active infection should not initiate siponimod until there has been resolution of the infection. In the case of a serious infection occurring during treatment, siponimod should be held and proper treatment initiated. Although siponimod has a short half-life with washout in 7 days, residual pharmacodynamic effects may persist for up to 3 to 4 weeks after discontinuation.

Evaluation for macular edema is indicated with siponimod. Macular edema was reported in 1.8% of patients receiving siponimod compared with only 0.2% of patients receiving placebo.8 Caution should be used when considering siponimod for patients with diabetes or prior history of uveitis, as these comorbidities significantly increase the risk for macular edema.1 The FDA recommends that all patients undergo ophthalmologic evaluation prior to initiation of siponimod. Additionally, as routine ophthalmologic examinations may detect macular edema in patients without visual symptoms, it seems prudent to refer patients for ophthalmologic examinations 3 to 4 months after initiation of siponimod, when the risk is at its peak, as was recommended with fingolimod.6

Similar to fingolimod, siponimod is potentially teratogenic, and women of childbearing age should be counseled on the need for adequate contraception during treatment. While fingolimod should be discontinued no less than 2 months prior to attempts at conception, the half-life of siponimod is short and the drug is completely washed out after 10 days.10 Therefore, siponimod may be more advantageous than fingolimod with regard to family planning.

Conclusion

Siponimod is certainly beneficial in the treatment of relapsing MS and has a modest effect on disability worsening in active SPMS. Therefore, it is reasonable to consider siponimod in the treatment of patients with early SPMS or those with RRMS who may be slowly transitioning to SPMS. While it is clear that siponimod is a potent anti-inflammatory agent and has a substantial effect on relapse rate, its role as a neuroprotective agent is less well elucidated, although preclinical studies suggest such a role is possible. As siponimod’s main clinical benefit on disability progression was seen in patients with “active SPMS,” it seems that the majority of its efficacy in SPMS may be by reduction of relapses. The EXPAND study results are similar to results from studies on ocrelizumab, which showed a potent effect on relapse rate but only a modest effect on disability worsening in primary progressive MS.9 The notion that significant relapse reduction can prevent disability in progressive MS is very much in line with evidence that relapses drive disability in early progressive MS.10 On the other hand, recent EXPAND subgroup analysis demonstrates a potential cognitive benefit of siponimod. A higher proportion of patients receiving siponimod had cognitive improvement at the end of the study than did participant taking a placebo.11 As cognitive function affects many patients with MS in general and especially those with SPMS, this is certainly of interest. An effect on the pathophysiologic substrate of “progression,” which remains poorly understood, is possible, and further research is necessary.

References

1. Novartis Pharmaceuticals Corporation. Mayzent (siponimod) [package insert]. US Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf Revised March 2019. Accessed July 31, 2019.

2. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72(suppl 1):1-5.

3. Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci. 2013;328(1-2):9-18.

4. Gentile A, Musella A, Bullitta S, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation. 2016;13(1):207.

5. Jackson SJ, Giovannoni G, Baker D. Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation. 2011;8:76.

6. Novartis Pharmaceuticals Corporation. Gilenya (fingolimod) [package insert]. US Food and Drug Administration Website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008lbl.pdf. Revised May 2012. Accessed July 31, 2019.

7. Selmaj K, Li DK, Hartung H-P, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12(8):756-767.

8. Kappos L, Bar-Or A, Cree BAC, et al; for the EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273.

9. Montalban X, Hauser SL, Kappos L, et al; for the ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220.

10. Paz Soldán MM, Novotna M, Abou Zeid N, et al. Relapses and disability accumulation in progressive multiple sclerosis. Neurology. 2015;84(1):81-88.

11. Benedict R, Fox R, Tomic D, et al. Effect of siponimod on cognition in patients with secondary progressive multiple sclerosis (SPMS): phase 3 expand study subgroup analysis. Presented at: American Academy of Neurology Annual Meeting, May 4-10, 2019; Philadelphia, PA.