Treatment Options for Multiple Sclerosis: Current and Emerging Therapies

Kristen M. Gawronski, Pharm.D.; Michelle M. Rainka, Pharm.D.; Malti J. Patel, M.D.; Francis M. Gengo, Pharm.D., FCP


Pharmacotherapy. 2010;30(9):916-927. 

In This Article

Emerging Therapies: Immunomodulators

Many new drugs are being investigated to determine their roles in the treatment of multiple sclerosis. Among the new investigational therapies are immunomodulators—fingolimod, laquinimod, teriflunomide, dimethyl fumarate, and cladribine—as well as monoclonal antibodies—daclizumab, alemtuzumab, and rituximab. In the next few years, patients will have many more options for multiple sclerosis treatment.

There are five immunomodulators in phase III trials, and pending United States Food and Drug Administration (FDA) approval, the first oral agent may emerge on the market by 2011. Four of the five investigational drugs are available in oral formulations, three of which can be given once/day. Certainly, oral drugs are much more discreet, and this route of administration could help to further expand therapeutic options and improve compliance issues with current disease-modifying regimens. Table 1 provides an overview of comparative efficacies for emerging therapies.[5,11–19]


Cladribine is an immunomodulatory purine analog that possesses lymphocytotoxic activity. It acts by damaging DNA and thereby causes cell death selectively, preferentially affecting CD4+ cells. Oral, intravenous, and subcutaneous formulations of cladribine have been studied in patients with either the progressive types of multiple sclerosis or RRMS.[11,20]

In a phase III study, two doses of subcutaneous cladribine were evaluated in patients with either PPMS (30% of enrollees) or SPMS (70% of enrollees) and EDSS scores of 3–6.5, over an 8-month period.[11] Patients were randomly assigned to one of three treatment groups: highdose cladribine, low-dose cladribine, or placebo. Cladribine was given at a dose of 0.07 mg/kg/day for 5 consecutive days every 4 weeks, for either two or six courses. The high-dose treatment group received treatment for six courses (2.1 mg/kg total drug given), whereas the low-dose treatment group was given two courses of cladribine (0.7 mg/kg total drug given). Drug efficacy was measured in terms of disability, by using the EDSS. The investigators defined disease progression as greater than a 1-point change in EDSS score if baseline score was 3–5, and greater than a 0.5-point change if baseline score was 5.5–6.5. Gadolinium-enhancing lesions were also assessed as a secondary efficacy measure.

No statistically significant differences in disability measured by EDSS score were observed between treatment groups and placebo. However, gadolinium-enhancing lesions decreased in both cladribine-treated groups compared with placebo. Patients receiving low-dose cladribine had a 70% reduction in enhancing lesions, whereas patients receiving high-dose cladribine showed an 83% reduction in lesions, compared with an 18% placebo effect (placebo-corrected values are shown in Table 1). This effect was apparent at 6 months and was present for the duration of the 2-year treatment period.

Cladribine was generally well tolerated. Table 2 lists the commonly experienced adverse effects. Of note, herpes simplex and herpes zoster infections were observed during the study period, although not frequently, in both treatment and placebo groups. Hematologic changes, including decreases in leukocytes and lymphocytes, were observed in a dose-dependent fashion. Higher doses of cladribine were associated with lower CD4+ counts, with 60% of patients experiencing counts below 200 cells/mm3. Liver enzyme levels, renal function, and electrocardiograms were not significantly affected during the study period. Serious neurologic effects have been observed at higher doses used in the treatment of cancer.

Based on efficacy data, it appears that cladribine will be useful for patients with SPMS and PPMS, for which treatments are not currently available. The potential places in therapy for all multiple sclerosis agents are shown in Table 3. Additional phase II and phase III trials are under way, focusing on the efficacy of cladribine in a variety of multiple sclerosis populations.[21] An ongoing phase II study is assessing cladribine as an adjunctive agent to interferon β in patients with SPMS; the study is estimated to be completed by 2013. Another phase III study is comparing cladribine with interferon β therapy, focusing on the rate of clinical disease progression in patients after their first relapse. Data from this study are estimated to become available by October 2012.


Fingolimod, known as FTY720, is an orally administered immunomodulator that acts on the sphingosine-1-phosphate (S1P) receptor. The S1P receptor is responsible for lymphocyte release from lymphoid organs.[4] Fingolimod is phosphorylated to its active form, FTY720-P, and binds to the S1P1 and S1P3–5 receptors on the surface of lymphocytes.[5,22] It depletes both CD4+ and CD8+ T lymphocytes in the blood stream, up to 75% below baseline.[5,23] The CD4+ cells are decreased to a greater extent than are CD8+ cells. Fingolimod also inhibits lymphocyte release from lymphatic organs, decreasing overall numbers in circulation.[4,23] It does not, however, inhibit lymphocyte recruitment or affect T or B cells in peripheral organs; therefore, it does not cause immunosuppression or lead to increased rates of infection or malignancies.[4,22,23]

A recently completed phase II study assessed the efficacy and safety of fingolimod in patients with RRMS or SPMS over a 24-month period.[5] Two daily doses, 1.25 and 5 mg, were evaluated compared with placebo. Both doses were found to significantly reduce inflammatory activity and the number of gadolinium-enhancing lesions on MR images versus placebo. Over 70% of patients given fingolimod were free from relapses during the treatment period. After a 6-month core study, patients electing to enter an extension study were given either 1.25 mg or placebo. The 5-mg dose was not given during the extension phase because, although both doses showed comparable efficacy, adverse-effect rates were higher with 5 mg (Table 2). One patient reported squamous cell and basal cell carcinoma but had a preexisting history of cancer before drug initiation. A preliminary report from a phase III trial comparing fingolimod with interferon β-1a given intramuscularly indicates that fingolimod is associated with a lower annual relapse rate.[24]

Fingolimod will likely be used in patients with both RRMS and SPMS. Multiple phase II studies have been completed in these patient populations, and phase III trials are ongoing. The Fingolimod (FTY720) in Patients with Relapsing-Remitting Multiple Sclerosis (FREEDOMS II) study is a 24-month, phase III assessment of lower daily doses of fingolimod, 0.5 and 1.25 mg, compared with placebo in patients with RRMS.[25] This trial is estimated to enroll more than 1000 participants, and data should be available by 2011.


Laquinimod is an orally administered immunomodulator being studied in patients with RRMS and SPMS.[13] Although its mechanism of action has not been fully elucidated, it is proposed that laquinimod acts by affecting the T-helper 1–T-helper 2 cytokine shift.[13,26] Multiple phase II studies have been completed, with varying results.

A study assessing efficacy and safety of laquinimod daily doses of 0.1 or 0.3 mg versus placebo in patients with RRMS and SPMS was conducted over 24 weeks, with a primary efficacy end point of reducing active MR imaging lesions.[12] Although the 0.1-mg dose did not significantly differ from placebo in any of the efficacy measures, the 0.3-mg dose decreased active MR imaging lesions by 44% compared with placebo. Laquinimod was generally well tolerated, and adverse effects occurred at rates similar to those reported in the placebo group, with the exception of elevations in the erythrocyte sedimentation rate and liver function test results. More than 10% of patients in each treatment group experienced transient increases in erythrocyte sedimentation rate and/or liver function test results at one laboratory measurement during evaluation.

Another phase II study assessing higher doses of laquinimod has also been completed. Laquinimod either 0.3 or 0.6 mg, or placebo, was given to patients with RRMS.[13] The number of gadolinium-enhancing lesions as measured on MR images was the primary efficacy variable assessed. Although this study did not find the 0.3-mg dose to significantly differ from placebo in any of the efficacy measures, the 0.6-mg dose was effective in many measures. Gadolinium-enhancing lesions were decreased by 40% compared with placebo. Seventy percent of laquinimodtreated patients were relapse-free during the study period, compared with 62% in the placebo group. Changes in disability status were not significantly different between any of the treatment groups. As with the previous study, rates of adverse events were reportedly similar between laquinimod and placebo (Table 2). Serious infections were not observed during the observation period. Budd-Chiari syndrome, a triad of abdominal pain, ascites, and hepatomegaly caused by occluded hepatic veins, was reported in one patient receiving laquinimod. It should be noted that this patient had documented preexisting hypercoagulability. One case of severe menometrorrhagia with myofibroma was observed, and exacerbation of preexisting glaucoma also occurred in one patient.

Based on these study results, it would appear that the ideal dosage of laquinimod is 0.6 mg/day and will likely be used for patients with RRMS and SPMS. The 0.6-mg dose showed significantly improved efficacy and a similar adverse-effect profile compared with the 0.3-mg dose. A phase III study comparing laquinimod 0.6 mg/day with interferon β-1a 30 μg intramuscularly once/week in patients with RRMS is under way; 1200 patients have been enrolled, and results should be available by mid-2011.[27]


Teriflunomide is an orally administered immunomodulatory agent thought to possess antiinflammatory and antiproliferative properties useful for the treatment of multiple sclerosis. Teriflunomide is the active metabolite of leflunomide, a drug commonly used to treat rheumatoid arthritis.[28] It is a dihydro-orotate dehydrogenase inhibitor and blocks pyrimidine synthesis in rapidly dividing cells such as T cells and B cells.[14,28] It has also been shown to inhibit protein tyrosine kinase and cyclooxygenase-2 activity, and decrease the ability of antigenpresenting cells to activate T cells.[28]

A phase II study examined the efficacy of teriflunomide daily doses of 7 and 14 mg compared with placebo over 36 weeks in patients with RRMS and SPMS.[14] Teriflunomide efficacy was measured by the number of active and nonactive gadolinium-enhancing lesions observed on MR images. Both groups receiving investigational teriflunomide had fewer active lesions compared with the placebo group, and a pattern was observed beginning at 6 weeks of treatment. Decreases in number of lesions reached maximum levels at 12 weeks, and this effect was maintained until the end of the study at 36 weeks. This resulted in a 61% reduction in MR imaging activity compared with placebo. Compared with clinical data in patients receiving glatiramer acetate or interferon β-1a given intramuscularly, this is approximately double the reduction in active lesions seen (30% and 35% reduction, respectively).

More significant changes were found for patients receiving teriflunomide 14 mg/day versus teriflunomide 7 mg/day or placebo. Patients receiving the 14-mg dose had a 32% decrease in annualized relapse rate compared with placebo, similar to that of glatiramer acetate and the interferons. Seventy-seven percent of patients in the 14-mg treatment group did not have a relapse during the study, compared with 62% receiving placebo. Fewer patients experienced relapses requiring treatment with corticosteroids, with 14% of the 14-mg treatment group requiring steroids versus 23% in the placebo group. Disability measured on the EDSS progressed in the nontreated group at a rate of 21.3% compared with 7.4% in the 14-mg/day group.

Occurrence of adverse events was similar between treatment groups (Table 2). Serious adverse events included elevated liver enzyme levels, hepatic dysfunction, neutropenia, rhabdomyolysis, and trigeminal neuralgia. Hematology, blood chemistries, urinalysis, and electrocardiogram results were not significantly affected during the study period.

As with other orally available drugs, teriflunomide will likely be used primarily for patients with RRMS and SPMS. Two phase III trials are under way.[29] One is comparing teriflunomide with interferon β-1a given subcutaneously, measuring time to first relapse in either treatment arm. Three hundred patients are enrolled in this trial, and results should be published by late 2011. An additional phase III trial assessing the efficacy of teriflunomide 7 and 14 mg in clinical disease progression in patients after their first relapse is ongoing as well. Approximately 800 people will be evaluated, and it is projected that this study will be completed by 2012.

Dimethyl Fumarate

Dimethyl fumarate, known as BG-12, is an orally administered immunomodulatory agent shown to induce T-helper 2–like cytokines (including interleukins 4, 5, and 10) to cause apoptosis in activated T cells. It also causes downregulation of intracellular adhesion molecules, leading to reduced migration of lymphocytes into the central nervous system. A small study investigating fumaric acid ester tablets in patients with RRMS assessed efficacy and safety by measuring effect on both the number and size of gadolinium-enhancing lesions.[15] Disability measured by EDSS, ambulation index, and 9-hole peg test (a measure of finger dexterity) was also assessed. Patients received treatment with fumaric acid esters at a dosage of 720 mg/day for 18 weeks, followed by 360 mg/day for 48 weeks, or placebo, given in three divided doses. This regimen decreased the number of gadolinium-enhancing lesions observed on MR images beginning at 18 weeks of treatment, with enhanced effects at 70 weeks of therapy. The EDSS scores and ambulation index remained stable or improved during treatment, and these effects were sustained throughout the 70-week study.

Common adverse effects included many gastrointestinal complaints. More than 85% of patients experienced severe diarrhea, nausea, and cramps. These gastrointestinal adverse effects decreased with continued drug use; however, patients did report the use of antacids to ameliorate symptoms. Additional adverse effects are listed in Table 2. This agent is also approved in Germany to treat psoriasis, and adverse effects reported for this study are consistent with those experienced in psoriasis treatment.

Based on available information, dimethyl fumarate will likely be used in patients with RRMS. Phase III trials are ongoing to evaluate the efficacy and safety of dimethyl fumarate in patients with RRMS.[30] The primary end point of one study is to assess number of relapses over a 2-year window. Secondary efficacy measures include number of lesions on MR images, as well as the safety and tolerability of dimethyl fumarate. The drug is being studied at a dosage of 240 mg 3 times/day over a 2-year period. Final results should be available by the end of 2010. Phase III trials are actively recruiting patients, including an active comparator trial assessing dimethyl fumarate versus glatiramer acetate. More than 1200 participants will be enrolled, and data from this evaluative study should be published by mid-2011.


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