Oral disease-modifying therapies (DMTs) have ushered in a new era in MS treatment. Phase 3 trials for the first 3 approved oral medications, fingolimod, dimethyl fumarate (DMF), and teriflunomide, showed good efficacy at reducing relapse rate, improving MRI measures, and slowing disability progression. All have efficacy comparable or superior to first-line injectable drugs. Slowing of disability progression appears to be superior for fingolimod compared with DMF and teriflunomide, both of which have modest effects on slowing disability progression. The side-effect profile of fingolimod, however, is more extensive, with potential cardiovascular and skin cancer risks and rare but serious lymphopenia-related complications, including opportunistic infections and progressive multifocal leukoencephalopathy (PML). Although the safety profile of DMF is more favorable than fingolimod, profound lymphopenia, in some cases, and the recent reports of PML are concerning. The long-term safety and risk-benefit ratio of these medications need to be continually evaluated. Teriflunomide appears to have a relatively safer serious side-effect profile, but liver toxicity and teratogenicity are major concerns.

In this review, we focus on the 3 oral MS medications that can be considered first line among oral DMT: fingolimod, DMF, and teriflunomide. The 2 new oral medications approved for MS in 2019, cladribine and siponimod, are discussed briefly.


Mechanism of Action

Fingolimod is an immunomodulator that acts on sphingosine-1-phosphate receptors (S1PR) to alter cell signaling and trafficking. Experimental evidence supports a potential neuroprotective effect of fingolimod; however, it is not clear if this is mediated by peripheral anti-inflammatory effects or by a modulatory effect on oligodendrocytes and astrocytes and direct effects on neurons.1-3 The S1PRs are expressed on glia and neurons and influence cell proliferation, morphology, and migration, promoting neuron growth and function.1 The active form of fingolimod modulates S1PR1, S1PR3, S1PR4, and S1PR5 receptor subtypes and causes internalization of S1PR on naive and central memory T cells and B cells, rendering them insensitive to the chemotactic signal necessary for exit from the lymph nodes. This limits inflammation by reducing trafficking of pathogenic lymphocytes into the central nervous system (CNS).2 Fingolimod reversibly sequesters a proportion of CD4+ and CD8+ T cells and B cells from blood and spleen into lymph nodes and Peyer patches without affecting many functional properties of these cells.6 Peripheral lymphocyte counts decrease to 20% to 30% of baseline within 1 week of fingolimod administration and typically rebound 4 to 8 weeks after discontinuation. Fingolimod affects T cells more than B cells and CD4+ more than CD8+ T cells. Fingolimod crosses the blood-brain barrier and accumulates in the CNS. Interaction with S1PRs on glial and neurons may contribute to the mechanism of action through neuroprotective effects.2,3 Modulation of S1PRs on human oligodendrocyte progenitor cells in vitro showed consequent functional responses, suggesting fingolimod may have a direct effect on the remyelination process.4

Clinical Efficacy

In phase 3 clinical trials, the annualized relapse rate (ARR) was significantly reduced on intention-to-treat analysis and fingolimod treatment reduced both the risk of sustained disability progression and new and enlarging T2 and T1 gadolinium (Gd)-enhancing lesions on brain MRI (Table 1).5-8 When compared with IFNβ-1a, fingolimod treatment resulted in significantly lower ARR, and MRI measures favored fingolimod. No significant differences in disability progression were seen between fingolimod and IFNβ-1a, however. In an open-label extension trial, ARR was lower (P <.0001), brain volume loss was reduced (P < .05), and proportionately more patients were free from 3-month clinical disability progression (P < 0.05) than in those switched from placebo to fingolimod. Fingolimod is not effective for reducing disability progression at 3 months in people with primary progressive MS (PPMS).9

Subgroup analyses of phase 3 and extension studies show fingolimod treatment reduces the rate of brain atrophy, independently of the degree of inflammatory activity seen on baseline or subsequent brain MRI for people with relapsing MS.10

Safety and Contraindications

In clinical trials, fingolimod treatment resulted in more adverse events (AEs). There were 2 deaths related to viral infections in individuals given the higher dose of fingolimod vs no deaths in the IFN β-1a group.6 There were 12 cases of skin or breast cancer in people treated with fingolimod vs 1 in those treated with placebo. Fingolimod treatment resulted in 19 cases of dose-related bradycardia or atrioventricular block. Other AEs occurring at higher rates with fingolimod vs placebo included lymphopenia, increased alanine aminotransferase (ALT) levels, herpes zoster infection, hypertension, first-dose bradycardia, and first-degree atrioventricular block.6,11 Serious AEs of fingolimod included basal-cell carcinoma (BCC), macular edema, infections, and neoplasms.6,11 Seemingly dose-dependent macular edema occurred predominantly during the first 3 to 4 months of therapy, more frequently in people with diabetes or prior uveitis.11 Herpes virus infections, disseminated cryptococcal infection, Kaposi’s sarcoma, cutaneous Mycobacterium leprae infection, cutaneous anaplastic large cell lymphoma and BCC were seen in the postmarketing period.11

Lymphopenia (~20%-30% decrease from baseline) can be observed 4 to 6 hours after iniating fingolimod, reaches steady-state levels within 2 weeks, and is stable with chronic treatment.1,5 Naive and central memory T cells are affected and effector memory cells are relatively unaffected. The CD19+ B cells and CD4+ T cells are preferentially affected, and reduction of up to 80% can be seen.12 Lymphocyte recovery to a normal range occurs 1 to 2 months after discontinuation.7,11

In the postmarketing period, cases of sudden unexpected cardiac death occurred within 24 hours of a first dose of fingolimod, prompting review of clinical trial and post-marketing data by regulatory agencies.13 Although fingolimod could not be directly linked to any of the deaths, it was labeled as contraindicated in those with pre-existing cardiovascular conditions myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, class III/IV heart failure, history or presence of Mobitz type II 2nd degree heart block, 3rd degree atrioventricular (AV) block, or sick sinus syndrome (unless a pacemaker was implanted). Fingolimod is contraindicated in people taking class Ia or class III anti-arrhythmic drugs or other drugs that slow heart rate or AV conduction, or people with baseline-corrected QT (QTc) interval of 500 ms or more.11

New proposed guidelines by the Food and Drug Administration (FDA) recommend an electrocardiogram (ECG) prior to dosing, hourly pulse and blood pressure monitoring for at least 6 hours after the first dose, and at the end of the observation period, extended cardiovascular monitoring beyond 6 hours (including continuous ECG monitoring overnight) in individuals defined as high risk (eg, having severe bradycardia after a first dose, conditions that decrease tolerability for bradycardia, therapy with other drugs with cardiovascular side effects, or the presence of QT interval prolongation).11

Cases of PML have occurred in people previously treated with immunosuppresants and people naïve to immunosuppressants.14 The estimated risk of PML with fingolimod treatment is 0.082 per 1,000 patients (not attributed to previous natalizumab treatment).14 Duration of fingolimod exposure and prior immunosuppressive therapy appear to be risk factors for PML. Most people with probable or definite PML received fingolimod for more than 2 years and were more than age 50; no association with grade 4 lymphopenia (absolute lymphocyte count (ALC) <200 cells/mm3) has been seen.14

Paradoxic worsening of disease activity has occurred during fingolimod treatment, including severe relapse or development of tumefactive demyelinating lesions (TDLs), some after pretreatment with natalizumab. Development of TDL is hypothesized to be caused by fingolimod-induced redistribution of immune cells that could shift MS immunopathology.

Clinical Use

Safety issues and contraindications limit fingolimod use in treatment-naive people with MS. Current use is preferred for those with MS who have an inadequate response or intolerable side effects with first-line injectable therapies. The first dose of fingolimod should be given in a setting where appropriate cardiac monitoring can be done and bradycardia treated if it occurs.11 If fingolimod treatment is interrupted for more than 2 weeks for any reason, cardiac monitoring should be done upon the next dose.11 Common side effects, recommended baseline testing, first dose, and subsequent monitoring are summarized in Table 2. Fingolimod is pregnancy class C and should be stopped 2 months before planned conception.


Mechanism of Action

Teriflunomide reversibly inhibits dihydro-orotate-dehydrogenase (DHODH), a key mitochondrial enzyme involved in pyrimidine synthesis in rapidly proliferating cells, thus reducing activation and proliferation of T cells and B cells and overall inflammatory response.15,16 Because pyrimidines are involved in cellular function; lipid glycosylation, phospholipid synthesis, DNA/RNA synthesis, and DNA repair, downstream immunomodulatory effects also occur. Of note, teriflunomide is cytostatic (ie, does not affect the replication of slowly dividing cells that use pyrimidine generated through the salvage pathway) and therefore not affected by DHODH inhibition.16

Clinical Efficacy

In clinical trials and open-label extension studies, oral teriflunomide was well tolerated and effective at reducing MS lesions and ARR and MRI measures of MS disease activity. Decreases in risk of disability progression were seen only with the higher doses given (Table 1).17,18 Teriflunomide efficacy is comparable to high-dose subcutaneous IFNβ-1a with a higher treatment satisfaction.19 Teriflunomide reduced risk of relapses defining clinically definite MS in patients with clinically isolated syndrome and showed sustained effect on disease activity with reduction in ARR and gadolinium-enhancing T1 lesions in long-term extension studies.15,20,21

Safety and Contraindications

Teriflunomide is generally well tolerated, with predominately mild-to-moderate AEs (nausea, diarrhea, hair thinning in first 6 months, and elevated ALT levels) and only rare serious AEs. 17,18,22,23 In clinical trials, mild-to-moderate and usually reversible liver-enzyme elevation was observed during the first 6 months.17,22,23 Small reductions in neutrophil and lymphocyte counts were typically observed within 3 months that stabilized with continued treatment.20,22,23

During clinical trials, a case of immune-mediated thrombocytopenia occurred. Small increases in blood pressure were reported in those treated with teriflunomide. No increase in infections was seen with teriflunomide vs placebo and no relationship between neutrophil count decrease and infection was seen. Serious opportunistic infections occurred in 2 people treated with placebo and 2 treated with the higher dose of teriflunomide. Of over 2,000 people treated in the phase 3 trials, 3 developed tuberculosis.22 A single case of PML was reported after 3 months exposure to teriflunomide in a person previously treated with natalizumab.24 There was no increase in the rate of malignancies in patients receiving teriflunomide.22

Although animal data suggest teriflunomide may cause major birth defects if used in pregnancy, this has not been demonstrated in humans. In 65 reported unplanned pregnancies during clinical trials no structural or functional deficits were seen.25 However, because the compound from which teriflunomide is metabolized (leflunomide) is teratogenic in animals, teriflunomide is contraindicated in women of childbearing potential who are not using reliable contraception.23,26 Men taking teriflunomide are advised not to father a child during treatment. Because teriflunomide has a long elimination half-life (~8 months to reach a safe plasma concentration of < 0.02 mg/L), women who become or want to become pregnant within months of taking teriflunomide should undergo accelerated elimination with cholestyramine (8 g every 8 hours for 11 days) or activated charcoal (50 g oral activated charcoal powder every 12 hours for 11 days).26,27 The accelerated elimination process can also be used in cases of possible overdose, significant hepatotoxicity, or discontinuation for other reasons.

Clinical Use

The convenience of oral administration and favorable long-term safety data make teriflunomide an attractive potential first-line oral treatment option for people with relapsing MS. In contrast to fingolimod and DMF, teriflunomide has not been associated with PML. However, continued postmarketing surveillance will be crucial to more definitively characterize the long-term safety and efficacy of teriflunomide. The existing experience with leflunomide in rheumatoid arthritis supports acceptable risk profile and further suggests safety for teriflunomide. There have been rare serious AEs with leflunomide including hepatotoxicity, hypertension, pneumonitis, cytopenia, and rare cases of PML in people previously treated with other forms of immunosuppression, emphasizing the importance of continued close monitoring (Table 2).

Dimethyl Fumarate

Delayed-release dimethyl fumarate (DMF) was developed after improvement of MS was seen in 2 people with MS treated with fumaric acid for coexisting psoriasis. This finding led to an open-label trial that showed significant reduction in MS lesions.28 A subsequent placebo-controlled phase 2 trial with an enteric-coated microtablet preparation (to improve gastrointestinal [GI] tolerability) showed dose-dependent effect on clinical and MRI disease activity.29

Mechanism of Action

The mechanism of action of DMF is thought to involve anti-inflammatory and cytoprotective effects of activating and upregulating antioxidative pathways.30 Immunomodulatory effects of DMF may include shifting dendritic cell differentiation and inhibiting proinflammatory pathways.31

Clinical Efficacy

Dimethyl fumarate significantly reduces ARR and the number of MRI lesions and may reduce disability progression.32,33 Effects of DMF on relapse rate and disability progression have been sustained and strong in long-term extension studies.34

Safety and Contraindications

The most common AEs are relatively mild, including skin flushing, redness, itching or rash, and GI symptoms such as diarrhea, nausea, and abdominal pain. Mild elevation of hepatic transaminases was observed during clinical trials and post-marketing use.32,33,35,36 In an open-label study, over 50% of people taking DMF reported GI symptoms, although these were less severe if the drug was taken with food and also with the use of symptomatic therapies such as acid secretion inhibitors, antidiarrheal agents, and bismuth subsalicylate.37 In post hoc analysis of clinical trial data, approximately one-third of GI AEs and flushing occurred in the first 3 months. Most GI and flushing events were of mild or moderate severity and resolved during the study.38 In a retrospective survey of 30 investigators involved in clinical trials, administration of DMF with food and education about the side effects were identified as proposed prophylactic measures.39 For those who needed symptomatic treatment, metoclopramide, domperidone, loperamide, proton pump inhibitors, and H2-receptor antagonists were used for GI AEs and aspirin for flushing.39

Lymphocyte count reduction was observed in clinical trials with a mean decrease of approximately 30% during the first year and stabilization thereafter.32,33,36 The risk of infections (including serious and opportunistic infections) was not increased in patients with lymphopenia in controlled trials, although a single patient developed PML in the extension study in the setting of prolonged lymphopenia (ALC <0.5x109 for 3.5 years).36 Approximately 2% of patients were reported to experience persistent grade 3 lymphopenia (ALC <0.5x109) during DMF treatment in controlled and uncontrolled trials.32,33,36 The CD8+ T cells are most profoundly affected; however, reduction in CD4+ population, particularly within the proinflammatory T-helper Th1 and Th17 subsets, also occurs.40

Profound lymphopenia can increase the risk of PML in people taking DMF and 6 confirmed cases of PML have been reported with use of DMF in people with MS, all in the setting of moderate to severe lymphopenia (<600/µL in 4). All but 1 of these cases had no exposure to prior immunosuppressive therapy or natalizumab.41 Additional cases of PML have been reported with the use of fumaric acid ester in people with psoriasis and multiple sclerosis; the majority had low CD4+ and CD8+ cell counts when diagnosed with PML.42 Prolonged, profound lymphocytopenia has been proposed as a potential risk factor for PML in patients exposed to DMF; however, the duration and degree of lymphopenia conferring the risk remain to be defined as some of the cases have occurred in the absence of severe lymphopenia. This may be due to a more profound reduction in CD4+ and CD8+ cell count than the total lymphocyte count in some cases.42

Clinical Use

Compared to glatiramer acetate, DMF has good clinical efficacy and an acceptable side effect profile (Table 3). The approved dose of DMF is 240 mg twice daily; however, the dose is slowly uptitrated in 7 days from the starting dose of 120 mg twice daily to minimize GI side effects and flushing. Tolerability issues can also be managed by administering DMF with food, pretreatment with nonenteric coated aspirin, and in some cases, temporary dose reduction and other symptomatic treatments. Whether limiting adverse effects and twice daily dosing of DMF will affect treatment adherence and use compared with other once-daily administered oral therapies (teriflunomide and fingolimod) or newer formulations of injectable MS therapies remains to be seen. Although 20 years of experience with fumaric acid esters for psoriasis and an acceptable safety profile of DMF in MS clinical trials make it an attractive treatment option, the risk of lymphopenia and rare PML cases may limit its use as first-line therapy. As with fingolimod, DMF is likely to be considered for individuals with MS who have suboptimal responses to, or intolerant side effects with, injectable and other oral MS therapies. A new formulation of fumaric acid, diroximel fumarate, which has fewer GI side effects was approved for treatment of MS by the FDA in October 2019.


Oral cladribine (2-chlorodeoxyadenosine) is an oral synthetic deoxyadenosine analogue that causes selective depletion of peripheral T and B cells but is relatively sparing of neutrophils and monocytes. Oral cladribine was FDA approved in 2019 for the treatment of relapsing forms of MS, including relapsing-remitting disease and active secondary progressive disease.

Mechanism of Action

Oral cladribine is a prodrug of cladribine triphosphate, which disrupts cellular metabolism causing DNA damage and subsequent apoptosis.43 Oral cladribine preferentially targets T cells and B cells, producing rapid and sustained reduction in CD4+ and CD8+cells and rapid but transient reduction in CD19+ B cells; innate immune cells are spared, however.43,44

Clinical Efficacy

In clinical trials, cladribine reduced ARR and lowered the risk of 3-month sustained disability progression (hazard ratio [HR] 0.67 for 3.5-mg group, 0.69 for 5.25-mg group). There were also significant reductions in number of brain lesions on MRI.45,46 In an extension trial, individuals who received cladribine were rerandomly assigned 2 to 1 to receive cladribine or placebo and those who had placebo initially were given cladribine but blinded to treatment.46 Sustained efficacy of cladribine was seen with similar ARR and relapse-freedom in both groups, suggesting oral cladribine treatment for 2 years followed by 2 years of placebo produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent after further treatment with cladribine after the initial 2-year treatment period in this trial setting.

Safety and Contraindications

Adverse effects seen more commonly with cladribine vs placebo in clinical trials were lymphopenia and herpes zoster infection.44-46 Although lymphopenia is expected because of the mechanism of action of cladribine, the risk of severe lymphopenia can be minimized by close lymphocyte monitoring to ensure the absolute lymphocyte count returns to normal before retreatment.44 Although there was a higher incidence of reported neoplasms (benign and malignant) in 1 clinical trial, reanalysis did not raise any safety concerns for long-term increased cancer risk.44-46 Meta-analysis of phase 3 trials for multiple MS therapies including cladribine, DMF, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate, did not support an increased cancer risk from cladribine in the doses used in clinical trials.48 A recent network meta-analysis reported similar risk profile of cladribine tablets compared with alternative DMTs, including: alemtuzumab, natalizumab, and ocrelizumab, in people with active relapsing MS.49 However, the approved prescribing information for cladribine’s use in MS patients carries a box warning of increased risk of malignancy, contraindication in patients with current malignancy, and the need to follow standard cancer screening guidelines in treated patients.50

Because there is evidence of teratogenicity in animal studies, women of childbearing age and men who wish to father a child should be counseled about the need for effective contraception before initiating, during, and for 6 months after treatment initiation. Pregnancy in women should be excluded before each dose. The approved prescribing information for MS patients carries a box warning of teratogenicity and the need to exclude pregnancy before starting the medication.

Clinical Use

Oral cladribine is a fixed-regimen of 2 short treatment courses (1.75 mg/kg per course), each course divided into 2 treatment cycles given over 8 to 10 days over 2 years to treat relapsing MS with highly active disease as defined by clinical or imaging features..50 Longer-term follow-up is required to assess the safety profile of cladribine, especially about risk of infection, malignancy, and teratogenicity. Given the concerns of the safety profile, oral cladribine is a DMT consideration for MS patients who have failed first- or second-line therapies.


Siponimod, like fingolimod, is an oral S1PR modulator with immunomodulating effects similarly mediated by sequestration of B and T lymphocytes through S1PR1 binding. It may also have neuroprotective effects.51 Siponimod was approved by the FDA in early 2019 for the treatment of multiple relapsing subtypes of MS, including clinically-isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Mechanism of Action

Siponimod is a synthetic molecule differing from fingolimod in that siponimod has selective affinity for the S1PR1 and S1PR5 subtypes, and not the S1PR3 subtype. The S1PR1 and S1PR5 receptors are expressed on neurons and neuroglia (astrocytes and oligodendrocytes), whereas S1PR1 and S1PR3 occur on myocytes. Siponimod is lipophilic and readily crosses the blood-brain barrier. Siponimod treatment may protect against demyelination and neurodegeneration as demonstrated in cell culture and murine model studies, acting largely through S1PR1 modulation.51

Clinical Efficacy

In a phase 2 dose-ranging trial assessing safety and efficacy versus placebo in people with relapsing-remitting MS, 2 mg of siponimod significantly decreased the number of new brain lesions and the ARR at 6 months compared with placebo.52 A subsequent phase 3 trial included 1,645 participants with at least 6 months progressing disability independent of relapse who were randomly assigned to receive siponimod or placebo on a 2:1 basis.53 Siponimod treatment was associated with a 21% reduction in the risk of confirmed disease progression at 3 months, as well as a beneficial effect on secondary efficacy outcomes including ARR (55% relative reduction), MRI lesion burden, and brain volume change.

Safety and Contraindications

In phase 3 study, frequently observed AEs (in at least 5% treated with siponimod) included elevated liver transaminases, hypertension, headache, falls, and bradycardia at initiation of treatment.54 Less frequent AEs in those treated with siponimod included herpes zoster infection, lymphopenia (<200 x 106/μL), seizure, tremor, macular edema, AV block (1st and 2nd degree), asthenia, and decreased pulmonary function tests.54 Neither death nor malignancies were increased among participants treated with siponimod, but malignant melanoma in situ and seminoma were reported.53,54 Siponimod induced a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose and reaching a nadir of approximately 20% to 30% of baseline that continues with chronic daily dosing. The lymphocyte counts returned to normal ranges in 90% of patients within 10 days of drug cessation, but remained low for 3 to 4 weeks in approximately 10%.54

No cases of PML have been reported in people taking siponimod. However, occurrence of PML in the context of fingolimod treatment and other DMTs raises concern for PML risk in people with MS treated with siponimod, especially those with prior exposure to immunomodulatory agents.

In clinical studies, asymptomatic bradycardia associated with initiation of siponimod was observed within 1 hour that peaked approximately 3 to 4 hours after the first dose, with an average 5 to 6 bpm decline. When the medication is uptitrated from 0.25 mg to 2 mg maintenance dose over 6 days as prescribed, further bradycardia with maximal decrease reached by day 5 to 6 may occur and stabilization can be expected within 10 days of initiation. Transient AV conduction delays (first or second-degree block) may follow a similar time course during dose titration. The first dose of siponimod should be given in a health care setting capable of managing symptomatic bradycardia with hourly pulse and blood pressure monitoring for 6 hours after the first dose, followed by an ECG. Additional monitoring may be needed if arrhythmias are present after 6 hours or if ECG shows new onset second degree or higher atrioventricular block or prolonged QTc. If daily siponimod dosing is interrupted for 4 or more consecutive daily doses, the medication should be reinitiated with uptitration scheduled over 5 to 6 days. Because there are potential effects on heart rate or AV conduction, consultation with a cardiologist should be obtained in anyone with pre-existing cardiac conditions or those using medications that decrease heart rate. Siponimod use is contraindicated in people with recent (within 6 months) history of myocardial infarction, unstable angina, stroke, transient ischemic attack, heart failure, or certain cardiac conduction abnormalities.54

There are special safety concerns of siponimod for people with certain CYP2C9 genotypes that affect the metabolism of the drug. Siponimod is contraindicated in people who are homozygous for CYP2C9*3 (CYP2C9*3/*3 genotype), because they can experience substantially elevated siponimod plasma levels. In people with heterozygous genotypes (CYP2C9*1/*3 or *2/*3), dosage adjustment is recommended.54

The pretreatment assessment is quite similar to fingolimod including ophthalmological evaluation, complete blood count, baseline liver transaminases and bilirubin levels, varicella zoster virus antibody, and ECG. Additionally, CYP2C9 genotype determination is recommended.54

Although there are no definitive human studies, animal studies suggest there could be fetal harm from siponimod treatment. Women of childbearing potential need to use effective contraception during treatment with siponimod and for 10 days after drug cessation.

Clinical Use

Siponimod reduced disability progression and brain atrophy in people with secondary progressive MS. Although the effect on disability progression was modest, it may represent a clinical benefit for people with active secondary progression (ie, those with clinical progression in the setting of high relapse rate and/or MRI lesion activity). Siponimod is approved for use in multiple relapsing subtypes of MS, although the experience with this DMT in multiple MS subtypes is lacking. Considering the complex side effect profile of siponimod, use at this time may be limited to people with secondary progressive MS, for whom there are very few DMT options.


The positive aspects of choosing oral drugs for relapsing MS include ease of administration and comparable or superior efficacy compared with injectable therapies. However, tolerability and safety issues related to short-term AEs and potential serious side effects from long-term immunosuppression limit use as first-line agents. Despite these concerns, oral MS agents are now routinely used in patients with inadequate therapeutic response and/or intolerable side effects to injectable therapies (glatiramer acetate and β-interferons), and use of oral MS agents as first-line therapy has increased over the past few years.

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NG and AK report no disclosures.
MM is a compensated member of the advisory board to Novartis Pharmaceuticals related to MS medications and a compensated consultant to Gateway Institute for Brain Research related to neuroscience basic and clinical research