Siponimod is an orally available immunomodulatory drug used to treat relapsing forms of multiple sclerosis. Siponimod is associated with transient serum enzyme elevations during therapy but has not been linked to instances of clinically apparent liver injury with jaundice, although experience with its use has been limited.

Siponimod (Mayzent^®) is an oral selective sphingosine 1-phosphate receptor subtypes 1 and 5 (S1PR_1,5) modulator being developed by Novartis Pharmaceuticals for the treatment of multiple sclerosis (MS) and intracerebral haemorrhage. In March 2019, siponimod received its first global approval in the USA, for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Siponimod is under regulatory review in the EU and Japan for secondary progressive MS. This article summarizes the milestone in the development of siponimod leading to this first global approval for MS in the USA.

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, with an unpredictable course. Current MS therapies such as disease-modifying therapies focus on treating exacerbations, preventing new exacerbations and avoiding the progression of disability. Siponimod (BAF312) is an oral treatment, a selective sphingosine-1-phosphate (S1P) receptor modulator, for the treatment of adults with relapsing forms of MS including active, secondary progressive MS with relapses.

Objectives: To assess the benefits and adverse effects of siponimod as monotherapy or combination therapy versus placebo or any active comparator for people diagnosed with MS.

Search methods: On 18 June 2020, we searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Trials Register, which contains studies from CENTRAL, MEDLINE and Embase, and the trials registry databases ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). We also handsearched relevant journals and screened the reference lists of published reviews and retrieved articles and searched reports (2004 to June 2020) from the MS societies in Europe and America.

Selection criteria: We included randomised parallel controlled clinical trials (RCTs) that evaluated siponimod, as monotherapy or combination therapy, versus placebo or any active comparator in people with MS. There were no restrictions on dose or administration frequency.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. We discussed disagreements and resolved them by consensus among the review authors. Our primary outcomes wereworsening disability , relapse and adverse events, and secondary outcomes were annualised relapse rate, gadolinium-enhancing lesions, new lesions or enlarged pre-existing lesions and mean change of brain volume. We independently evaluated the certainty of evidence using the GRADE approach. We contacted principal investigators of included studies for additional data or confirmation of data.

Main results: Two studies (1948 participants) met our selection criteria, 608 controls and 1334 treated with siponimod. The included studies compared siponimod with placebo. Overall, all studies had a high risk of bias due to selective reporting and attrition bias. Comparing siponimod administered at a dose of 2 mg to placebo, we found that siponimod may reduce the number of participants with disability progression at six months (56 fewer people per 1000; risk ratio (RR) 0.78, 95% confidence interval (CI) 0.65 to 0.94; 1 study, 1641 participants; low-certainty evidence) and annualised relapse rate (RR 0.43, 95% CI 0.34 to 0.56; 2 studies, 1739 participants; low-certainty evidence). But it might lead to little reduction in the number of participants with new relapse (166 fewer people per 1000; RR 0.38, 95% CI 0.15 to 1.00; 1 study, 94 participants; very low-certainty evidence). We observed no evidence of a difference due to adverse events for siponimod at 2 mg compared to placebo (14 more people per 1000; RR 1.52, 95% CI 0.85 to 2.71; 2 studies, 1739 participants, low-certainty evidence). In addition, due to the high risk of inaccurate magnetic resonance imaging (MRI) data in the two included studies, we could not combine data for active lesions on MRI scans. Both studies had high attrition bias resulting from the unbalanced reasons for dropouts among groups and high risk of bias due to conflicts of interest. Siponimod may reduce the number of gadolinium-enhancing T1-weighted lesions at two years of follow-up (RR 0.14, 95% CI 0.10 to 0.19; P < 0.0001; 1 study, 1641 participants; very low-certainty evidence). There may be no evidence of a difference between groups in the number of participants with at least one serious adverse event excluding relapses (113 more people per 1000; RR 1.80, 95% CI 0.37 to 8.77; 2 studies, 1739 participants; low-certainty evidence) at six months. No data were available regarding cardiac adverse events. In terms of safety profile, the most common adverse events associated with siponimod were headache, back pain, bradycardia, dizziness, fatigue, influenza, urinary tract infection, lymphopenia, nausea, alanine amino transferase increase and upper respiratory tract infection. These adverse events have dose-related effects and rarely led to discontinuation of treatment.

Authors' conclusions: Based on the findings of the RCTs included in this review, we are uncertain whether siponimod interventions are beneficial for people with MS. There was low-certainty evidence to support that siponimod at a dose of 2 mg orally once daily as monotherapy compared with placebo may reduce the annualised relapse rate and the number of participants who experienced disability worsening, at 6 months. However, the certainty of the evidence to support the benefit in reducing the number of people with a relapse is very low. The risk of withdrawals due to adverse events requires careful monitoring of participants over time. The duration of all studies was less than 24 months, so the efficacy and safety of siponimod over 24 months are still uncertain, and further exploration is needed in the future. There is no high-certainty data available to evaluate the benefit on MRI outcomes. We assessed the certainty of the body of evidence for all outcomes was low to very low, downgraded due to serious study limitations, imprecision and indirectness. We are uncertain whether siponimod is beneficial for people with MS. More new studies with robust methodology and longer follow-up are needed to evaluate the benefit of siponimod for the management of MS and to observe long-term adverse effects. Also, in addition to comparing with placebo, more new studies are needed to evaluate siponimod versus other therapeutic options.

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. To view this Bench to Bedside, open or download the PDF.

Siponimod fumarate (BAF-312) is a synthetic sphingosine 1- phosphate (S1P) receptor modulator, which exerts immunomodulating effects mediated by B- and T-cell sequestration in secondary lymphoid organs. S1P receptor modulators have consistently shown a significant benefit on relapse rate and other measures of disease activity in patients with relapsing multiple sclerosis (MS), compared with both placebo and active comparator. However, most clinical trials of S1P receptor modulators--as well as other therapies for MS--lack evidence of a significant benefit on disability progression. A phase III trial of siponimod for secondary progressive MS showed a significant effect of the active drug compared with placebo on reduction of disability progression. Siponimod exhibits selective affinity for types 1 and 5 S1P receptors, indicating a possible lower risk of bradycardia and vasoconstriction compared with modulators with type 3 S1P receptor affinity. Current evidence supporting siponimod efficacy for secondary progressive MS is reviewed in the present article.

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.

Oral siponimod (Mayzent^®), a next-generation, selective sphingosine 1-phosphate receptor (S1PR) 1 and 5 modulator, is approved in several countries for the treatment of secondary progressive multiple sclerosis (SPMS), with specific indications varying between individual countries. In the pivotal EXPAND trial (median duration double-blind treatment 18 months) in a broad spectrum of patients with SPMS, once-daily oral siponimod 2 mg (initial dose titration over 6 days) was significantly more effective than placebo in reducing clinical and MRI-defined outcomes of disease activity and disability progression, including 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), and was generally well tolerated in the core phase of the study. These beneficial effects of siponimod appeared to be sustained during up to 5 years of treatment in the ongoing open-label extension phase of EXPAND. The safety profile of siponimod is similar to that of other agents in its class, including adverse events of special interest (i.e. those known to be associated with S1PR modulators). No new safety signals were identified during up to 5 years' treatment in the open-label extension phase. Albeit further long-term efficacy and safety data from the real-world setting are required to fully define its role, given the paucity of current treatment options and its convenient dosage regimen, siponimod represents an important emerging option for the treatment of adult patients with SPMS with active disease evidenced by relapses or imaging-features of inflammatory activity.

Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE.

Minipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for 4 weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, qPCR experiments, and peripheral lymphocyte counts were performed. In addition, the effect of siponimod on activated microglia was assessed in vitro to confirm the direct effect of the drug on CNS-resident immune cells.

Siponimod administration (0.45 μg/day) induced a significant beneficial effect on EAE clinical scores with minimal effect on peripheral lymphocyte counts. Siponimod rescued defective GABAergic transmission in the striatum of EAE, without correcting the EAE-induced alterations of glutamatergic transmission. We observed a significant attenuation of astrogliosis and microgliosis together with reduced lymphocyte infiltration in the striatum of EAE mice treated with siponimod. Interestingly, siponimod reduced the release of IL-6 and RANTES from activated microglial cells in vitro, which might explain the reduced lymphocyte infiltration. Furthermore, the loss of parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was rescued by siponimod treatment, providing a plausible explanation of the selective effects of this drug on inhibitory synaptic transmission.

Altogether, our results show that siponimod has neuroprotective effects in the CNS of EAE mice, which are likely independent of its peripheral immune effect, suggesting that this drug could be effective in limiting neurodegenerative pathological processes in MS.

Multiple sclerosis (MS) is a chronic central nervous system immune-mediated disease with an important inflammatory component associated with focal demyelination and widespread neurodegeneration. In most cases, the clinical presentation is relapsing-remitting, followed by a secondary progressive phase, characterized by disability accrual unrelated to relapses. In a minority, the phenotype is progressive from the beginning. Major therapeutic achievements have been made concerning the relapsing phase but modifying the evolution of progressive MS remains an unmet need. Areas covered: This review covers siponimod (BAF312), a new sphingosine 1-phosphate receptor modulator, and its role in the treatment of secondary progressive MS. The authors reviewed PubMed English literature using the keywords 'siponimod' or 'BAF312' and 'multiple sclerosis.' They also present the pharmacological profile of siponimod, as well as clinical efficacy and safety, with emphasis on the recently published results of a Phase III trial. Phase II data in relapsing MS are also summarized. Expert opinion: Siponimod may reduce the activity of the disease and has a modest effect on the gradual disability accrual. If approved, it may become one of the few available therapy options for secondary progressive MS.

The modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes in lymph nodes. Different sphingosine 1-phosphate receptor subtypes are expressed in the brain and spinal cord, and their pharmacological effects may improve disease development and neuropathology. Siponimod (BAF312) is a novel sphingosine 1-phosphate receptor modulator that has recently been approved for the treatment of active secondary progressive multiple sclerosis (MS). In this review article, we summarize recent evidence suggesting that the active role of siponimod in patients with progressive MS may be due to direct interaction with central nervous system cells. Additionally, we tried to summarize our current understanding of the function of siponimod and discuss the effects observed in the case of MS.

Keywords: astrocytes; demyelination; fingolimod; inflammation; microglia; multiple sclerosis; neuroprotection; siponimod; sphingosine-1 phosphate.

Background: In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.

Objective: To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.

Methods: Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.

Results: Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.

Conclusion: By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.

Keywords: Multiple sclerosis; progression; progressive multiple sclerosis; relapses; secondary progressive multiple sclerosis; siponimod.

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. On the histopathological level, the disease is characterized by inflammatory demyelination and diffuse neurodegeneration. Although on the surface the development of new inflammatory CNS lesions in MS may appear consistent with a primary recruitment of peripheral immune cells, questions have been raised as to whether lymphocyte and/or monocyte invasion into the brain are really at the root of inflammatory lesion development. In this review article, we discuss a less appreciated inflammation-neurodegeneration interplay, that is: Neurodegeneration can trigger the formation of new, focal inflammatory lesions. We summarize old and recent findings suggesting that new inflammatory lesions develop at sites of focal or diffuse degenerative processes within the CNS. Such a concept is discussed in the context of the EXPAND trial, showing that siponimod exerts anti-inflammatory and neuroprotective activities in secondary progressive MS patients. The verification or rejection of such a concept is vital for the development of new therapeutic strategies for progressive MS.

Objective: To investigate the effects of siponimod on cognitive processing speed (CPS) in secondary progressive (SP) multiple sclerosis (MS) patients, by means of a pre-defined exploratory, and post-hoc analysis of the EXPAND study, a randomized controlled trial (RCT) comparing siponimod and placebo.

Methods: EXPAND was a double-blind, placebo-controlled, phase 3 trial involving 1651 SPMS patients randomized (2:1) to either siponimod 2 mg/day or placebo. Cognitive function was assessed using the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT) and Brief Visuospatial Memory Test-Revised (BVMT-R), administered at baseline, 6-month intervals, and end of treatment.

Results: Between-group differences in mean change from baseline in SDMT scores were significantly better in siponimod- vs placebo-treated patients at Month 12 (difference 1.08 [95% CI 0.23, 1.94]; p=0.0132), Month 18 (1.23 [0.25, 2.21); p=0.0135), and Month 24 (2.30 [1.11, 3.50]; p=0.0002). Siponimod-treated patients were at significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR] 0.79 [0.65, 0.96]; p=0.0157) while their chance for having a 4-point sustained increase in SDMT score was higher [HR 1.28 [1.05, 1.55]; p=0.0131). PASAT and BVMT-R scores did not differ significantly between the two treatment groups (all p>0.28).

Conclusion: Siponimod had a significant benefit on SDMT in SPMS patients. Siponimod-treated patients were at significantly lower risk for having a ≥4 point decrease in SDMT score and had a significantly higher chance for having a ≥4 point increase in SDMT score, a magnitude of change accepted as clinically meaningful.

Background and objectives: A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod.

Methods: We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020.

Results: As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients.

Discussion: Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.

Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM), New England States Consortium Systems Organization, Blue Cross Blue Shield of Massachusetts, Harvard Pilgrim Health Care, Kaiser Foundation Health Plan, and Partners HealthCare to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Synnott and Pearson are employed by ICER. Bloudek and Carlson report a research agreement between the University of Washington and ICER; Bloudek reports consulting fees from Allergan, Seattle Genetics, Dermira, Sunovion, TerSera Therapeutics, Cook Regentech, and Mallinckrodt Pharmaceuticals; and Carlson reports personal fees from Bayer, unrelated to this report. Sharaf reports consulting fees from ICER.