Sphingosine 1‐phosphate receptor modulators in multiple sclerosis treatment: A practical review

Abstract Four sphingosine 1‐phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head‐to‐head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real‐world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.


Background
Sphingosine 1-phosphate (S1P) receptor modulators are G protein-coupled receptors found throughout the body.They mediate a broad range of functions via five distinct subtypes (S1P 1-5 ). 1,2Owing to the widespread expression of these receptor subtypes across multiple organ systems, they can influence the immune system, brain, lung, liver, heart, and vasculature (Fig. S1). 1,2Considering the extensive presence of S1P receptors on cardiomyocytes and vascular endothelial cells, S1P receptor modulators are expected to have cardiovascular effects. 3These were observed in preclinical studies, particularly for S1P receptor modulators that target S1P 1 and S1P 3 . 4wing to their ability to bind with high affinity to one or more S1P receptor subtypes, S1P receptor modulators have a complex mechanism of action with both peripheral immunological and central nervous system (CNS) effects. 1,5Consequently, S1P receptor modulators represent a therapeutic option for immune-mediated diseases, including multiple sclerosis (MS). 1,2][8][9][10][11][12][13] S1P receptor modulators function by blocking the capacity of lymphocytes to egress from lymph nodes, leading to a reduction in the number of lymphocytes in peripheral blood. 14While the full mechanistic pathway by which S1P receptor modulators exert therapeutic effects is unknown, lymphocyte sequestration and reduction of lymphocyte migration into the CNS were proposed as the primary mechanism of action in MS. [6][7][8][9] Fingolimod, a nonselective S1P receptor modulator targeting S1P 1 , S1P 3 , S1P 4 , and S1P 5 , was approved in the US in 2010 and the EU in 2011 as the first oral capsule for the treatment of MS. 10,15,16 Fingolimod, the only S1P receptor modulator studied in children with MS, is indicated for patients at least 10 years of age with relapsing MS (RMS), including clinically isolated syndrome (CIS, US only), relapsing-remitting MS (RRMS), and active secondary progressive MS (SPMS). 6Fingolimod is a prodrug that requires phosphorylation to be converted to its active form, which is thought to contribute to its relatively long elimination halflife. 2Safety concerns, particularly the cardiac-related effects (e.g., bradycardia) associated with fingolimod led to the development of more selective, second-generation S1P receptor modulators: ozanimod, ponesimod, and siponimod. 17The FDA recently approved an orally disintegrating fingolimod tablet for the treatment of adult patients with RMS, which provides faster onset and improved bioavailability than the oral capsule formulation. 18he second generation of S1P receptor modulators do not require phosphorylation for activity and also have shorter half-lives, implying a shorter washout period. 15he exception is ozanimod, which has active metabolites with a longer mean elimination half-life than fingolimod (Table 1). 19Siponimod and ozanimod, which are selective for S1P 1 and S1P 5 , received FDA approval in 2019 and 2020, respectively, for the treatment of adults with RMS, including CIS, RRMS, and active SPMS. 7,9The EMA approved siponimod in 2020 for the treatment of SPMS and ozanimod in 2020 for the treatment of active RRMS. 11,12Additionally, in 2021, ozanimod was the first in this class to receive FDA approval for moderately to severely active ulcerative colitis. 7,20Ponesimod is selective for S1P 1 , and received FDA approval in 2021 for the treatment of adults with RMS, including CIS, RRMS, and active SPMS, and EMA approval in 2021 for the treatment of adults with active RMS. 8,131P receptor modulators are of particular interest in the MS treatment landscape because they may have direct CNS effects and are able to cross the blood-brain barrier, whereas several other disease-modifying therapies (DMTs) (e.g., interferons, glatiramer acetate, and monoclonal antibodies) function only in the periphery. 21,22A direct CNS effect, which is supported by preclinical evidence, may contribute to clinical benefits in MS, because S1P receptors are expressed by cells in the CNS. 17This direct mechanism of action potentially provides a benefit for S1P receptor modulators in the treatment of MS; however, clinical studies have not substantiated these findings.Notably, clinical studies clearly demonstrated reductions in brain volume loss, as is common with DMTs and particularly at early stages of disease, 23 suggesting use of these agents early in the course of MS rather than waiting until progression is clinically evident. 24onsidering the plethora of recent and ongoing research on S1P receptor modulators, this review aimed to summarize the data generated to date on the efficacy and safety of S1P receptor modulators for the treatment of MS, with an emphasis on detailing the similarities and differences of each agent.

Efficacy of S1P Receptor Modulators in Multiple Sclerosis
The efficacies of fingolimod, ozanimod, ponesimod, and siponimod were evaluated in phase 2 and phase 3 clinical trials.Efficacy data from the pivotal phase three trials for the key endpoints listed in the respective prescribing information for each drug are summarized in Table 2.The safety and efficacy of fingolimod was assessed in adults with RRMS (FREEDOMS, 25 FREEDOMS II, 30 and TRANSFORMS 31 ) and in pediatric participants with RMS (PARADIGMS 32 ); siponimod in adults with SPMS (EXPAND 29 ); ozanimod in adults with RMS (SUNBEAM 26 and RADIANCE 27 ); and ponesimod in adults with RMS (OPTIMUM). 28The safety and efficacy of fingolimod has also been assessed in adults with primary progressive MS (INFORMS). 33However, in this phase 3 trial, fingolimod did not slow disease progression compared with placebo, 33 suggesting that CNS penetration of fingolimod alone was inadequate to alter the course of progression in primary progressive MS.The results of this study are not further discussed in this review.
In the pivotal phase 3 trials, treatment with fingolimod 25 or siponimod 29 resulted in statistically significantly lower annualized relapse rates (ARR) compared with placebo, while fingolimod, 31 ozanimod, 26,27 and ponesimod 28 showed statistically significantly lower ARR compared with active comparators.The proportion of patients without relapse was higher with fingolimod compared with placebo and intramuscular interferon beta-1a (IFN b-1a), 25,31 ozanimod compared with IFN b-1a, 26,27 ponesimod compared with teriflunomide, 28 and siponimod compared with placebo. 29Treatment with fingolimod 25 and siponimod 29 resulted in a significantly lower proportion of patients with 3-month confirmed disability progression (CDP) compared with placebo.The mean numbers of gadolinium-enhancing and new/enlarging T2 lesions were significantly reduced with fingolimod compared with placebo and IFN b-1a, 25,31 ozanimod compared with IFN b-1a, 26,27 ponesimod relative to teriflunomide, 28 and siponimod compared with placebo. 29n terms of durability of efficacy, the response to S1P receptor modulator treatment appears to be sustained long term.In LONGTERMS, an open-label, phase 3b extension study, sustained efficacy was reported with fingolimod over 10 years in more than 4000 participants with MS who had participated in the core trials. 34][37] Overall, while the efficacy data between the pivotal clinical trials of fingolimod, ozanimod, ponesimod, and siponimod are generally comparable, head-to-head clinical trials were not conducted; therefore, definitive conclusions comparing the efficacy of S1P receptor modulators cannot be made. 2

Safety of S1P Receptor Modulators in Multiple Sclerosis
There are no direct comparative trials between S1P receptor modulators, and the currently available safety information for agents is from their individual trials; this should be considered when comparing event rates between agents.

Adverse events
The varying effects of S1P receptor modulators on different receptor subtypes (S1P 1 , S1P 3 , S1P 4 , and S1P 5 ) may increase the risk of certain AEs, because these receptors are expressed on cells throughout the body. 15Therefore, it is important for clinicians to consider specific events known to be associated with a particular S1P receptor modulator when considering a treatment approach.Notably, pretreatment screening and continued follow-up can minimize risks, with the overall safety profile of this drug class remaining favorable. 38The most relevant AEs encountered with S1P receptor modulators include cardiovascular AEs, lymphopenia, serious infections, malignancy (including  cutaneous malignancies), hepatotoxicity, seizures (mainly in children), and pulmonary effects (Table 3). 428][9]43 Meta-analysis of S1P receptor modulator clinical trials showed that cardiovascular AEs occurred in 10.9% in patients treated with S1P receptor modulators compared with 4.8% in those receiving the control treatment, with a significantly increased risk of arrhythmia (primarily bradyarrhythmia) and hypertension in patients treated with S1P receptor modulators compared with control treatment. 3Fingolimod and siponimod are associated with greater rates of first-degree AV block than placebo, 6,9 whereas ozanimod and ponesimod are associated with greater rates of bradycardia and firstdegree AV block than IFN b-1a or teriflunomide, respectively. 7,8Second-or third-degree AV block was reported with fingolimod and siponimod 6,9 but not with ozanimod and ponesimod. 7,8Fingolimod, ponesimod, and siponimod are associated with prolongation of QTc intervals, 6,8,9 whereas ozanimod is not. 7hile S1P receptor modulators were associated with an increased risk of macular edema, 42 there was no increase in these events with ozanimod compared with IFN b-1a in pivotal trials. 26,27Macular edema was reported in 0.3% of patients treated with ozanimod and 0.3% of patients treated with IFN b-1a. 7Fingolimod increases the risk of macular edema in a dose-dependent manner, 6 and in clinical trials, macular edema generally occurred in the first 3-4 months of treatment and partially or completely resolved after fingolimod discontinuation. 42Macular edema was reported in 1.1% and 1.8% of patients treated with ponesimod and siponimod, respectively, and in 0% and 0.2% of patients receiving teriflunomide or placebo, respectively. 8,9otably, patients with a history of uveitis, diabetes mellitus, and cataract surgery are at increased risk of macular edema during treatment with an S1P receptor modulator. 42,441P receptor modulators reduce the capacity of lymphocytes to egress from lymph nodes, thereby reducing the number of lymphocytes in peripheral blood, which in turn can lower the ability of the immune system to fight infections. 2,45Reductions in lymphocyte counts from baseline ranged from 57% with ozanimod to ~70% with fingolimod, siponimod, and ponesimod, with a nadir of ~760 cells/lL with ozanimod, 500 cells/lL with fingolimod, 560 cells/lL with siponimod, and 650 cells/lL with ponesimod (Table 3). 6,8,9,26,277][8][9] All four S1P receptor modulators are associated with a risk of serious infections.In fingolimod trials, two patients died from herpetic infections, one due to disseminated primary herpes zoster and one to herpes simplex encephalitis.Both patients received high-dose corticosteroids to treat suspected MS relapses. 6Other serious infections that occurred during S1P receptor modulator treatment include progressive multifocal leukoencephalopathy and cryptococcal meningitis (Table 3).
][8][9] Lymphoma, particularly non-Hodgkin's lymphoma, has also been associated with fingolimod use, and a recent analysis noted a small increase in the overall risk of invasive cancer with fingolimod. 6,467][8][9] For ozanimod and ponesimod, these elevations typically resolved within 2-4 weeks of continued treatment, 7,8 while for siponimod and fingolimod, these elevations returned to normal 1-2 months after treatment discontinuation. 6,9][8][9] Routine monitoring with pulmonary function tests is not recommended for any S1P receptor modulator.Spirometry and diffusion lung capacity of carbon monoxide evaluation should be performed when clinically indicated.
5][36][37] However, instances of disease rebound were reported following discontinuation of fingolimod. 6,47In most of these cases, patients did not return to the functional status they had before stopping fingolimod treatment. 6Symptoms generally occurred within 12 weeks but were reported for up to 24 weeks after discontinuation. 6One such condition, relapse with tumefactive demyelinating lesions, was observed within the initial 9 months following treatment initiation as well as 6 months after treatment discontinuation. 6,48Due to the association of fingolimod with tumefactive MS, the condition should be considered when a severe MS relapse occurs during fingolimod treatment, especially during initiation, or after discontinuation of treatment, prompting imaging evaluation and subsequent appropriate treatment initiation. 6,48To our knowledge, no cases of severe disease rebound were reported following the discontinuation of ozanimod, ponesimod, or siponimod. 8,9,49Mild to moderate relapses occurred in 2.3% of patients with RMS following ozanimod discontinuation, and 70% of those experienced a complete recovery within 30 days of onset. 50

Safety and tolerability during pregnancy
7][8][9] S1P receptor modulators and/or their metabolites were also detected in the milk of treated lactating rats. 51Dedicated human pregnancy studies were not conducted.
Pooled data from clinical trials of fingolimod reported 66 pregnancies with in utero exposure (the total number of pregnancies including exposure to fingolimod, placebo, or IFN b-1a, was 89). 52Among these, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, and 5 that were ongoing or lost to follow up at the time. 52In the postmarketing fingolimod pregnancy registry, 6.0% of reported pregnancies resulted in major congenital malformations in live births; 6.6% in major congenital malformations in live births, stillbirths, and pregnancies that were terminated due to fetal anomalies. 535][56] The ozanimod trials reported 78 pregnancies, including 42 live births, 1 report of duplex kidney, 12 spontaneous abortions, and 15 elective abortions. 57Over the course of the ponesimod clinical program (which included the 30-day period following treatment discontinuation), a total of 19 pregnancies were reported. 58Among these, six resulted in live, normal births; three were spontaneous abortions, and there were eight elective abortions.Of the 12 abortion cases, one reported benign hydatidiform mole, while fetal abnormalities were not known/ reported for the other cases. 59As of March 2022, 31 pregnancies were reported in women treated with siponimod, with no events of congenital malformation or fetal/maternal complications. 60

Safety outcomes with concomitant SARS-CoV-2 infection
Considering the reduction in lymphocyte count observed with S1P receptor modulator treatment, it was initially thought that patients with MS undergoing treatment may be more susceptible to poor outcomes from COVID-19. 61owever, severe disease and mortality in patients treated with all four S1P receptor modulators were comparable to the general population. 35,62,635][66][67][68] Fingolimod-, ponesimod-, or siponimod-treated patients were seropositive after second and third mRNA vaccinations, but with lower immunoglobulin G levels compared with untreated patients. 68Following a second mRNA vaccine, 25% of fingolimod patients had a T-cell response.Nearly all vaccinated participants with serological data in the ozanimod DAYBREAK open-label extension study mounted a serologic response after full COVID-19 vaccination. 69A literature review found that fingolimod treatment was associated with blunted antibody vaccine responses (seroconversion rate of 28%-77%) compared with untreated individuals, while seroconversion rates seen in the majority of people treated with siponimod, ozanimod, and ponesimod are higher (71%-100%). 63Differences in (COVID-19) vaccine responses between fingolimod and newer S1P receptor modulators may be due to differences in S1P receptor subtype modulation. 63ingolimod targets S1P 1 , S1P 3 , S1P 4 , and S1P 5 , while ponesimod, siponimod, and ozanimod target S1P 1 , and siponimod and ozanimod also target S1P 5 . 63The stronger antibody vaccine responses of ponesimod, siponimod, and ozanimod may be due to their limited impact on S1P 3 and S1P 4 and their effect on the formation and function of the germinal center, important in generating neoantigen antibody responses. 63While, reduced T-cell responses have been reported with fingolimod, data on the peripheral blood T-cell responses in patients treated with second generation S1P modulators have been inconsistent. 63

Clinical considerations when prescribing S1P receptor modulators to patients with multiple sclerosis
Clinical considerations for patients with MS who are candidates for S1P receptor modulator therapy are listed in Table 4.

Contraindications
Certain contraindications are unique to individual agents.For example, fingolimod is contraindicated in patients with a baseline QTc interval ≥ 500 msec and cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs 6 ; ozanimod in patients with sino-atrial block, severe untreated sleep apnea, and those taking an MAO inhibitor 7 ; ponesimod in patients with sino-atrial block 8 ; and siponimod in patients with CYP2C9*3/*3 genotype. 9Contraindications for all four S1P receptor modulators are listed in Table 1.

Additional considerations for specific drug-drug interactions
7][8][9] In addition, clinicians are advised to use caution when concomitantly prescribing beta-blockers, digoxin, calcium-channel blockers, or QT-prolonging therapies, considering the cardiovascular effects of S1P receptor modulators.Antineoplastic, immune-modulating, or corticosteroid or noncorticosteroid immunosuppressive therapies should also be used with caution owing to additive effects with S1P receptor modulators.
Some clinical considerations apply only to a particular medication in this class, owing to specific interactions.Coadministration of ozanimod with opioids, selective serotonin reuptake inhibitors (SSRI), serotoninnorepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, or tyramine is not recommended. 7Although a post hoc analysis of the DAYBREAK study did not find an excess number of adverse events, including serotonin syndrome-related TEAEs or hypertension in patients taking an SSRI or SNRI in combination with ozanimod. 70oncomitant use of beta-blockers and nondihydropyridine calcium channel blockers with ponesimod could lead to severe bradycardia and heart block; therefore, advice from a cardiologist should be sought before treatment initiation to determine the most appropriate monitoring for patients prescribed these medications. 8Administration of ponesimod is also not recommended with strong CYP3A4 and UGT1A1 inducers (e.g., rifampin, phenytoin, carbamazepine). 8Concomitant use of siponimod with modafinil plus all CYP2C9 and CYP3A4 inhibitors or inducers is not recommended due to a significant increase or decrease in siponimod exposure, respectively. 9

Pretreatment assessments
Patients initiating treatment with siponimod should be tested to determine CYP2C9 genotype. 97][8][9] The ophthalmologic evaluation should be conducted throughout the treatment period of the S1P receptor modulator in patients with a history of uveitis, macular edema, and diabetes mellitus. 71A skin examination should be performed by a dermatologist in all patients before starting siponimod. 9

First dose monitoring and dose escalation protocols
When treating patients with S1P receptor modulators, the most important clinical consideration is the effect of initial dosing on heart rate and subsequent hypertension. 728][9] First-dose monitoring is recommended depending on the specific agent and comorbidities in a setting where resources are available to appropriately manage symptomatic bradycardia as described in Table 4 for fingolimod, ponesimod, and siponimod. 6,8,9First-dose monitoring is not noted as required in the label for ozanimod.In patients with mild or moderate hepatic impairment (Child-Pugh class A or B) beginning ozanimod, the prescribing information recommends an every-other-day dosing schedule following the 7-day titration period 7 ; however, there is a lack of published data for this recommendation.

Continued monitoring during treatment
][8][9] Monitoring should focus on blood pressure, ocular examinations, possible serious infections, skin examinations, white blood cell and lymphocyte counts, and liver aminotransferase levels (Table 4).Skin examinations and screening for cutaneous malignancies should be performed annually by a dermatologist in people receiving treatment when indicated.7][8][9] Patients should be counseled about the risk for progressive multifocal leukoencephalopathy (PML).7][8][9] PML is a rare infection that predominantly occurs in cases of prolonged moderate-to-severe lymphopenia, and in older patients. 73So far, in clinical studies, PML occurred in 61 patients treated with fingolimod, 74 three patients treated with siponimod, 75 one patient treated with ozanimod, 35 and no patients treated with ponesimod. 8These data indicate that there is a risk of PML in fingolimod-treated patients, particularly in those of older age.Immune reconstitution inflammatory syndrome (IRIS) has also been reported in MS patients who developed PML, generally within a few months of S1P receptor modulator discontinuation.Patients who discontinue treatment due to PML should be monitored for the development of IRIS. 7A small number of cases of posterior reversible encephalopathy syndrome (PRES) have occurred with fingolimod use.Symptoms include sudden onset severe headache, visual disturbances, altered mental status, and seizure.If PRES is not promptly treated, it can lead to ischemic stroke or cerebral hemorrhage.Treatment should be discontinued if PRES is suspected. 6Clinicians should educate patients of childbearing potential of the requirement for effective contraception during treatment and for the prescribed duration following treatment discontinuation.Concomitant use of S1P receptor modulators is not expected to decrease the efficacy of hormonal contraceptives based on a lack of relevant pharmacokinetic interaction between these medications.7][8][9] All patients receiving S1P receptor modulators should be made aware of the risk of relapse causing severe disability following treatment discontinuation, particularly those treated with fingolimod.If this occurs, it is typically within 3 months of treatment cessation and may be associated with IRIS.Thus far, there is no evidence of rebound secondary to discontinuation when using the newer S1P receptor modulators.Importantly, a clear-cut plan to monitor and treat exacerbations should be in place.

Conclusions
S1P receptor modulators have emerged as an oral diseasemodifying treatment option for MS that has a unique mechanism of action compared with other therapies.While efficacy data across the pivotal clinical trials of fingolimod, ozanimod, ponesimod, and siponimod appear to be relatively similar in patients with MS, each agent is unique and may be better suited for specific patients.For example, siponimod was the first S1P receptor modulator to be approved for patients with active SPMS; although the other agents could potentially be effective in this disease state, their efficacy in SPMS has not been proven.Clarification is needed whether all S1P receptor modulators have rebound effects, and more data are needed regarding their impact on vaccine response and the risk for infections, including PML.

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2024 The Authors.Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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2024 The Authors.Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Table 1 .
Indications and dosing of the different S1P receptor modulators.

Table 2 .
Overview of efficacy data from adult MS registrational trials of the different S1P receptor modulators.

Table 3 .
Overview of safety data of the different S1P receptor modulators.
(Continued) 846 ª 2024 The Authors.Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.S1P Receptor Modulators for the Treatment of MS P. K. Coyle et al.
a PML is an opportunistic viral infection of the brain caused by the JC virus that typically occurs in patients who are immunocompromised and that usually leads to death or severe disability.b Mainly in children. 41ª 2024 The Authors.Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Table 4 .
Clinical considerations before initiating treatment, at first dose, and throughout treatment.
a Within 6 months or after discontinuation of prior MS therapy.b Ophthalmic evaluation is recommended for patients with diabetes mellitus or uveitis, prior to treatment initiation with follow-up.