Glatiramer acetate (GA), a short polypeptide copolymer that is antigenically similar to myelin basic protein (MBP), is another commonly used injectable DMT. Its function in MS is thought to be mediated by its ability to bind to HLA-DR2 and compete with various myelin antigens for their presentation to T cells. GA causes anergy of MBP-reactive T cells and induction of anti-inflammatory T helper type 2 cells [11]. It is administered SC at a dose of 20 mg daily or at the more recently approved dosing of 40 mg three times a week.

The efficacy and safety of GA was evaluated in several placebo-controlled trials. The copolymer 1 MS Study Group trial showed that SC administration of 20 mg GA daily over 2 years led to a 29 % reduction in ARR [24], with an extension trial demonstrating sustained ARR reduction of 32 % over up to 35 months [25]. In addition, more patients in the placebo group had progression in disability as assessed by a standardized version of the neurological examination. Subsequently, a European/Canadian multicenter placebo-controlled study corroborated the beneficial effect of GA, showing a 33 % ARR reduction in GA-treated patients [26]. This study also demonstrated a statistically significant benefit with regard to MRI markers of disease activity, such as lesion volume and number of new T2 and enhancing lesions. More recently, a new dosing regimen of GA (40 mg SC three times a week) showed a comparable 34 % reduction in ARR compared to placebo [27] and was shown to reduce injection-related AEs when compared to the old regimen [28]. Finally, three trials have directly compared the efficacy of GA to that of IFN β-1a (REGARD) and IFN β-1b (BECOME, BEYOND), and found no statistically significant differences in ARR [29–31].

GA has the most favorable safety profile of all the DMTs. In clinical trials, the most common AEs were mild injection site reactions, consisting of pain and erythema, occurring in 90 % of patients. Focal lipoatrophy at injection sites occurs commonly after prolonged medication use but likely occurs less frequently with the new dosing schedule available [28]. The most notable AE in trials was a transient immediate post-injection reaction that was experienced at least once by 16 % of patients, occurring within minutes after an injection, and consisting of flushing, chest pressure, palpitations, shortness of breath, and anxiety. This reaction is of unknown etiology but is benign and resolves spontaneously within 30 min [32]. Finally, unique among all the DMTs, patients on GA are not required to undergo regular monitoring of laboratory values. No hematologic abnormalities have been encountered and drug-induced liver injury has only been reported in isolated cases as an idiosyncratic drug reaction and is exceedingly rare [33].

Natalizumab is a humanized monoclonal antibody against α4 integrin, a glycoprotein expressed on the surface of lymphocytes that allows for adhesion to the endothelial vessel wall. By blocking adhesion and subsequent transmigration of lymphocytes into the central nervous system (CNS), natalizumab prevents CNS inflammation. It is administered as a 300 mg IV infusion every 28 days.

Natalizumab was approved for relapsing MS in 2004 on the basis of two Phase III trials. The randomized placebo-controlled AFFIRM study demonstrated a 68 % reduction in ARR and a 42 % reduction of SAD at 2 years in the treatment arm compared to placebo. It also showed a remarkable 83 % reduction in new/enlarging T2 lesions and a 92 % reduction in contrast-enhancing lesions [34]. An additional study, SENTINEL, enrolled patients who, despite treatment with weekly IFN β-1a, had experienced at least one relapse in the prior year. The study found that natalizumab added to INF β-1a 30 μg IM weekly was significantly more effective than IFN β-1a alone, with a 54 % reduction in ARR at 1 year and a 24 % decrease in the risk of SAD [35].

However, natalizumab was temporarily withdrawn from the market in 2005 after discovery of three cases of progressive multifocal leukoencephalopathy (PML), a potentially lethal opportunistic infection of CNS oligodendrocytes caused by reactivation of the John Cunningham polyomavirus (JCV). Natalizumab was reintroduced to the market in 2006 with the stipulation that it be only used as monotherapy and with the implementation of an extensive risk evaluation and monitoring program, Tysabri Outreach: Unified Commitment to Health (TOUCH). A better understanding of the risk factors for developing PML has emerged since re-introduction, and the drug is now FDA-approved as monotherapy for any patient with relapsing MS. The major risk factors include the presence of JCV antibodies (Ab) in the serum (which indicates prior exposure, essentially a prerequisite for developing PML), use of prior immunosuppressive therapy, and cumulative duration of therapy [36]. The estimated probabilities of developing PML after accounting for known risk factors are detailed in Table 4.2. It is recommended to check JCV Ab prior to initiating therapy and at 6-month intervals during treatment because there is a seroconversion rate of 1–2 % per year [37]. Consideration of PML risk factors is useful for informing appropriate patient selection, and many practitioners feel comfortable prescribing natalizumab in Ab-negative patients. However, in the seropositive population, most clinicians will limit duration of exposure to the drug, or will restrict use of the drug to those who have failed other therapies or have especially active disease.

Another concern with natalizumab is that cessation of the medication has, in several studies, been associated with rebound inflammation [38]. However, other studies have failed to show that post-natalizumab inflammatory activity is higher than activity prior to treatment [39], arguing against a true rebound effect. Given the possibility of rebound inflammation after stopping natalizumab, long “washout periods” after discontinuation of the drug have fallen out of favor. Although there is no consensus regarding the optimal timing for starting a DMT after natalizumab cessation, MS subspecialists increasingly recommend initiating alternative therapy by around 2 months after discontinuation of natalizumab.

Aside from PML, natalizumab is well tolerated and generally safe. In trials, there was no increased risk for other infections with natalizumab. However, the current prescribing information indicates an increased risk of encephalitis and meningitis caused by herpes simplex or varicella zoster virus. Allergic reactions occurred in 1–4 % of patients and were generally mild, and fatigue occurred more often than with placebo. A small number of patients (6 %) developed neutralizing Abs to natalizumab, which were associated with an increase in infusion-related AEs as well as a loss of efficacy [34].

The first oral agent for relapsing forms of MS was approved by the FDA in 2010 [40]. Fingolimod is a nonselective sphingosine-1-phosphate (S1P) receptor modulator that is metabolized by sphingosine kinase to the active metabolite fingolimod-phosphate. The S1P₁ receptor on lymphocytes is responsible for T lymphocyte circulation, exit from lymph nodes, and differentiation. Fingolimod-phosphate causes internalization and degradation of this receptor, leading to sequestration of T cells in secondary lymphatic tissues, in turn bringing about a reduction of MS-related inflammation [41]. Fingolimod is administered as a once daily 0.5 mg capsule.

Several large Phase III trials have studied the efficacy and safety of fingolimod. The first trial, FREEDOMS, was a 24-month study that compared two doses of fingolimod (0.5 mg and 1.25 mg daily) with placebo. Patients receiving fingolimod showed a significantly decreased ARR compared to placebo (0.16 on 1.25 mg, 0.18 on 0.5 mg, 0.40 on placebo), and fingolimod use led to a reduction of the number of new/enlarged T2 lesions, T1-enhancing lesions, and brain-volume loss on MRI. In this study, fingolimod significantly reduced SAD [42], and an extension of the trial showed sustained effect after 4 years [43]. The second trial, TRANSFORMS, was a 12-month long study comparing the same two doses of fingolimod (0.5 mg and 1.25 mg daily) to weekly intramuscular IFN β-1a (30 mcg). The two groups receiving fingolimod exhibited a lower ARR (0.20 on 1.25 mg, 0.16 on 0.5 mg, 0.33 on IFN) and had fewer new/enlarged T2 lesions and T1 enhancing lesions. Disability progression was infrequent in all three groups, and, unlike in FREEDOMS, there was no statistical difference in SAD [44]. The 1.25 mg dose of fingolimod failed to provide additional benefit compared to the 0.5 mg dose in both studies, leading to approval of only the 0.5 mg dose.

In both trials, AEs occurred at similar rates in all arms and were generally mild to moderate. The most common serious AEs were bradycardia and atrioventricular block after the initial dose, as well as macular edema. There were two deaths in the TRANSFORMS study, both in the group receiving 1.25 mg of fingolimod. One was due to disseminated primary zoster infection in a patient without history of chicken pox, while the other was secondary to herpes simplex encephalitis. However, infections as a whole occurred with similar rates in all arms. Cardiovascular side effects, such as hypertension, bradycardia, and AV block, were largely asymptomatic and are thought to be related to the presence of S1P₁ and S1P₂ receptors in the heart [45]. Hypertension occurred in 3 %–6 % of patients and was mild. Bradycardia was seen in 2–3 % of patients and was temporary, occurring within 1 h of initial fingolimod administration, and beginning to resolve within 6 h of administration. Heart block was infrequent, transient, and largely asymptomatic, occurring in 0.5 % of patients after initial administration. No further effects on heart rate or conduction were observed with continued administration of the drug during the clinical trials. Consistent with the drug’s mechanism of action, peripheral lymphocyte counts decreased by 73–77 % over the first month of treatment with fingolimod in both Phase III studies, and remained stable thereafter. Given an increased risk of skin cancers in the Phase II study of fingolimod [46], patients underwent close dermatological monitoring in Phase III trials. Five cases of basal cell carcinoma and three of melanoma occurred in the TRANSFORMS fingolimod treatment arms, and only one in the IFN group. FREEDOMS, on the other hand, showed a higher rate of malignancies in the placebo group. In a more recent Phase III trial, FREEDOMS II, there was a slight increase in incidence of basal cell carcinoma (3 % with 0.5 mg fingolimod vs. 1 % in placebo) [47]. Finally, while trials did not show any risk of PML in patients taking fingolimod, to date, there have been rare cases of PML in the absence of prior exposure to natalizumab among the >125,000 patients treated with fingolimod [48]. No PML risk stratification has been established for patients taking fingolimod, but currently the overall risk seems to be quite low.

Based on FDA recommendations, all patients should undergo evaluation with baseline ECG, blood pressure, complete blood count (CBC), liver function tests (LFTs), and ophthalmological and dermatological exams prior to starting fingolimod and regularly during treatment [49]. Varicella antibody should be tested in patients without a history of chicken pox or varicella immunization; those who are seronegative should be vaccinated before initiation of fingolimod, and treatment should be postponed for at least 30 days. Fingolimod is contraindicated in those with recent myocardial infarction, severe heart failure, unstable angina, prolonged QTc >500 ms, or history of Mobitz Type II 2nd or 3rd degree atrioventricular block or sick sinus syndrome unless a pacemaker is present. Patients should undergo observation and cardiac monitoring for at least 6 h after receiving the first dose of fingolimod, with a repeat electrocardiogram (ECG) at the end of observation. Those at higher risk of cardiac complications should be observed overnight. If treatment is interrupted for over 2 weeks, the observation and cardiac monitoring period has to be repeated upon restarting fingolimod [49].

The second oral agent for MS, teriflunomide, was approved by the FDA in the USA in 2012. Teriflunomide reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), leading to a decrease in de novo pyrimidine synthesis, a crucial step in DNA/RNA synthesis. In this manner, teriflunomide exerts a cytostatic effect on B and T cells [50]. The drug is administered as a once daily 7 mg or 14 mg dose.

Teriflunomide has been studied in several Phase III clinical trials in RRMS. TEMSO and TOWER both evaluated the efficacy and safety of the drug compared to placebo [51, 52]. Both trials included two treatment arms (7 mg and 14 mg doses) and used ARR as the primary outcome and SAD as a secondary outcome. In TEMSO, ARR was significantly reduced in both treatment arms when compared to placebo (ARR 0.37 for teriflunomide at either 7 mg or 14 mg vs. 0.54 for placebo). In TOWER, there was also reduction in ARR in both treatment arms (0.39 and 0.32 for teriflunomide at 7 mg and 14 mg, respectively, vs. 0.50 for placebo). The higher treatment dose in both trials reduced the risk of SAD (29.8 % reduction in TEMSO and 31.5 % in TOWER). MRI endpoints were also met. Based on these data, both the 7 and 14 mg doses were approved by the FDA; however, in practice, the 7 mg dose is rarely used and is not licensed in most countries outside of the USA. Finally, in another recent Phase III study, TENERE, teriflunomide was noninferior, but failed to show superiority, over three times weekly IFN β-1a in reducing risk of treatment failure [53].

In the Phase III trials, the most common AEs associated with teriflunomide were diarrhea, nausea, hair thinning, and transaminitis, each occurring in more than 10 % of patients. However, these were generally mild and rarely led to the discontinuation of the drug. Teriflunomide was not associated with an overall higher risk of infections; however, one case of intestinal tuberculosis occurred in the 14 mg treatment arm in the TOWER trial. Mean reductions in neutrophil and lymphocyte counts were generally mild and mostly occurred within 12 weeks of treatment. A small percentage of patients in the teriflunomide arms developed serious neutropenia, which was asymptomatic, and which resolved during continued treatment with the drug or after discontinuation [51, 52].

Based on FDA guidelines [54], patients should be evaluated with baseline CBC, LFTs, and TB testing prior to initiation of teriflunomide. LFTs should be monitored monthly for the first 6 months after starting the drug, and a CBC should be repeated regularly during treatment. Based on animal studies suggesting that use of teriflunomide can cause significant fetal malformations, it has been classified as pregnancy category X under the current FDA rating system. Women of childbearing age should be using reliable contraception and pregnancy should be ruled out prior to beginning treatment. In addition, since teriflunomide is present in low levels in semen, the FDA recommends that a man should not father a child while taking the drug, though this is not part of the European prescribing information. As teriflunomide is cleared slowly from plasma (an average of 8 months is necessary to achieve negligible drug levels), an accelerated elimination protocol consisting of either activated charcoal or cholestyramine followed by laboratory testing to ensure drug clearance should be implemented if reproduction is planned or if drug removal is necessary for another reason.

Dimethyl fumarate (DMF), the third oral agent for MS, was approved by the FDA in 2013 but related fumaric acid esters have been used in Europe since 1994 for treatment of psoriasis. Administered as a twice-daily 240 mg capsule, DMF is thought to function by reducing inflammation and neurodegeneration via activation of the nuclear factor-like 2 (Nrf2) antioxidant pathway.