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Keywords:

  • multiple sclerosis;
  • therapeutics

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease-modifying therapies introduced in the 1990s, the beta-interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha-4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long-term postmarketing efficacy and safety data in a general MS population. Because of this lack of long-term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit-to-risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e.g. fingolimod or natalizumab if JC virus antibody-negative). The aim of this review is to discuss the clinical benefits, mechanisms of action, safety profiles and monitoring strategies of current MS disease-modifying therapies in clinical practice and of those expected to enter the market in the near future.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Multiple sclerosis (MS) is a common, presumed autoimmune disease of the central nervous system (CNS) estimated to affect over 2.1 million people worldwide [1]. MS is the second most common cause of disability in young adults, after trauma.

Amongst neurological diseases, MS holds the positive distinction of having effective treatments that favourably alter clinical outcomes and the disease course. Beta-interferon (beta-IFN) 1b was approved in the USA by the Food and Drug Administration (FDA) in 1993 and the European Medicines Agency (EMA) (in the European Union in 1995 for relapsing–remitting MS (RRMS). Subsequently, nine other disease-modifying treatments (DMTs) have been approved in the USA [beta-IFN 1a (two formulations), beta-IFN 1b, glatiramer acetate (GA), mitoxantrone, natalizumab, fingolimod, teriflunomide and dimethyl fumarate]. Several other medications, mostly with distinctive mechanisms of action (MOAs), are awaiting approval in the near future. The success of these several and varied medications with differing MOAs has not only been fortunate for patients living with MS, but has also enhanced our understanding of the disease. Whilst more medication options are an advantage, challenges arise in education, monitoring and treatment goals. Treatment decisions must balance the benefits of individual medications with their risks and side effects. For newer medications, such as the oral MS DMTs, long-term safety and efficacy are not yet known. Moreover, the monetary burden of these expensive medications can be considerable. As costs of medical care increase, the cost of medications is likely to gain importance as a factor in the choice of the DMT.

In this review, we will discuss the older medications, all of which are administered parenterally (the beta-IFNs, GA, natalizumab and mitoxantrone), as well as the newer oral medications (fingolimod, teriflunomide and dimethyl fumarate), medications in the pipeline (alemtuzumab, laquinimod, ocrelizumab and daclizumab) and therapies on the horizon that may repair the CNS. The latter includes two antibody therapies [anti-LINGO-1 and anti-oligodendrocyte immunoglobulin (Ig)M] that may enhance remyelination and mesenchymal stem cell (MSC) therapies for MS.

Injectable disease-modifying therapies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

The beta-IFNs and GA are established, effective treatments for which we have clinical experience over two decades (Table 1). Major advantages of the injectable DMTs include a known and favourable safety profile, long-term efficacy and established patient support services. In addition, they are generally well tolerated despite the route of administration. Injectable therapies continue to have a major role in MS treatment (Fig. 1). Approval of long-acting pegylated beta-IFN that requires less frequent administration is anticipated. Whilst a generic or ‘biosimilar’ version of these injectable therapies is not presently available, a future generic option with supporting clinical studies is expected to provide similar benefits at lower costs.

Table 1. Injectable and infused disease modifying therapies in MS
TherapyRelapse rate reduction vs. placebo, %Disability reduction, %T2w lesion reduction, %Gadolinium enhancement reduction, %Side effectsMonitoring
  1. a

    Approved Sept 2013 by European Commission for adult RRMS patients with active disease defined by clinical or imaging features, and December 2013 by Health Canada for adult RRMS patients with active disease by clinical and imaging features, with inadequate response to beta-IFN or other disease-modifying therapies. Alemtuzumab has not been approved for use in MS in the United States.

Beta-IFN 1b SQ QOD [64]33NS7583Flu-like symptoms, injection site reactions, depression, hepatic dysfunction, rare: anemia, lymphopenia, thrombocytopeniaWhite blood counts and hepatic enzymes at baseline and every 3–6 months
Beta-IFN 1a IM Weekly [70]1837NS50  
Beta-IFN 1a SQ TIW [65]27 for 22ug TIW, 33 for 44ug TIW~307888  
PEG beta-IFN 1a SQ QOW [66]36386786  
Glatiramer acetate SQ QD [67, 68]29NA3035Injection site reactions, heart palpitations, allergic reaction, lipoatrophyNA
Glatiramer acetate SQ TIW [69]34NS34.744.8 NA
Natalizumab [6, 7]68428392Infusion reactions, Progressive multifocal leukoencephalopathyAnti-JC virus antibodies, white blood counts, hepatic enzymes
Alemtuzumaba [37, 38]49–54 vs. beta-IFN 1a28–42 s. beta-IFN 1aReported as proportion of patients with new/enlarging T2w lesions and gadolinium-enhancing lesions. significantly reduced compared with beta-IFN 1aInfusion reactions, infections, secondary autoimmunity, cancerComplete blood counts including platelets, hepatic, kidney and thyroid function tests
image

Figure 1. Immunopathogenesis of multiple sclerosis and sites of therapeutic action for available disease-modifying therapies.

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Beta-IFN 1a is administered either three times weekly as a subcutaneous (SQ) injection, or weekly as an intramuscular (IM) injection. Beta-IFN 1b is administered as a SQ injection every other day. There are a number of potential MOAs by which beta-IFNs may inhibit several aspects of the pathophysiology of MS (Fig. 2). These mechanisms include decreased IFN-gamma production and inhibition of antigen presentation leading to reduced activation of T lymphocytes, and reduction of T-cell adhesion and proteases important for T-cell entry across the blood–brain barrier (BBB) [2].

image

Figure 2. Proposed treatment algorithm after determining disease severity by magnetic resonance imaging (MRI) and clinical measures. MS, multiple sclerosis; beta-IFN, beta-interferon. T, T cell; B, B cell; M, macrophage; ODC, oligodendrocyte; NO, nitric oxide, BDNF, brain-derived neurotrophic factor; NK, natural killer cell; CNS, central nervous system

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The MOA of GA is entirely different from those of the beta-IFNs. GA is composed of a synthetic four-amino acid copolymer designed to simulate myelin basic protein. Currently, GA is administered as a daily SQ dose of 20 mg, but may become available for three times weekly dosing. GA results in a shift from Th1 towards Th2 cytokines (e.g. IL-4, IL-10 and transforming growth factor-beta), which may contribute to disease amelioration [3].

Natalizumab

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Natalizumab was the first monoclonal antibody approved as a DMT for relapsing MS. Natalizumab targets the alpha-4 subunit of the VLA-4 receptor that is expressed on activated T cells and other mononuclear white blood cells. Normally, VLA-4 interacts with vascular cell adhesion molecule 1 on endothelium and fibronectin in tissue, allowing cell adherence to the vessel wall and trafficking within tissues. Blocking VLA-4 prevents inflammatory cell migration from the vasculature and within the CNS [4, 5].

Two Phase 3 clinical trials, AFFIRM and SENTINEL, were pivotal in the approval process for natalizumab. In AFFIRM, natalizumab 300 mg intravenously (IV) infused every 4 weeks was compared to placebo in over 900 patients with relapsing MS with a mean age of 36 years and mild disease [mean baseline Expanded Disability Status Scale (EDSS) 2.3] [6]. Natalizumab reduced the annualized relapse rate (ARR) by 68% and sustained disability progression by 42% compared to placebo. New or enlarging T2-weighted lesions were reduced by 83% and new gadolinium-enhancing lesions by 92%.

SENTINEL evaluated the combination of natalizumab and weekly beta-IFN 1a, in comparison with weekly beta-IFN 1a alone. Patients were required to have had a relapse whilst receiving beta-IFN 1a and were randomly assigned to the addition of placebo or natalizumab to ongoing beta-IFN. Over 1100 patients with relapsing MS with a mean age of 39 years and mild disease (mean baseline EDSS 2.4) were enrolled in this 2-year study [7]. Combination therapy reduced sustained disability progression by 24% and reduced ARR by 54% compared to beta-IFN 1a alone. New or enlarging T2-weighted lesions were reduced by 83% and gadolinium-enhancing lesions by 89% with combination therapy.

Natalizumab can be associated with mild infusion reactions (e.g. headache and fevers) but discontinuation is recommended if a hypersensitivity reaction develops (e.g. urticaria, dermatitis and bronchospasm), due to the risk of anaphylaxis with subsequent infusions. Significant liver injury is possible but rare. Natalizumab is contraindicated during pregnancy and breastfeeding. Treatment may increase the risk of common or opportunistic infections. Withdrawal of natalizumab has been associated with return of disease activity after 3–4 months [8].

Natalizumab has been associated with the activation of latent JC virus infection to cause progressive multifocal leukoencephalopathy (PML). Based upon the data from a dedicated postmarketing surveillance programme, the overall incidence of PML in natalizumab-treated patients is 2.96 per 1000. The risk can be further stratified based upon the presence of serum JC virus antibody, length of natalizumab treatment and prior use of immunosuppressive medication. The stratified JC virus serum antibody assay has proven to be especially important for assessing the risk of PML, because JC virus antibody seropositivity is essentially a prerequisite for PML development [9, 10]. In the general population, 50–55% of adults are seropositive for JC virus antibodies. For seropositive patients taking natalizumab, the risk of PML after 2 years of treatment ranges from 2 to 11 per 1000 and is higher for those with prior use of immunosuppressive medication. The risk of PML is approximately 1 per 10 000 for those who are JC virus serum antibody-negative. In JC virus antibody seronegative patients, testing for serum antibodies against the virus is recommended every 6 months, as the incidence of seroconversion is 2–3% per year. If the patient experiences new neurological symptoms whilst on natalizumab, PML should be considered. When warranted, evaluation should include brain imaging and cerebrospinal fluid assessment for JC virus by polymerase chain reaction. If PML is confirmed or highly suspected, natalizumab should be discontinued and plasma exchange initiated to remove any residual drug [11].

Mitoxantrone

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Mitoxantrone is an anthracenedione chemotherapeutic agent that inhibits T-cell activation and reduces proliferation of B- and T cells. The risk of dose-related cardiotoxicity limits its lifetime use to 140 mg m−2. The effect of mitoxantrone at 12 mg m−2, administered every 3 months over 24 months compared to placebo, was investigated in 194 patients [12]. Mean patient age was 40 years, EDSS was 4.5, and 48% of the patients had secondary progressive MS. ARR was reduced by 65% over 2 years in the 12 mg m−2 mitoxantrone group, and time to sustained disability progression was reduced from 22% to 8% in the placebo group.

The use of mitoxantrone has decreased in recent years due to a combination of factors. The introduction of natalizumab has provided an alternative high-efficacy option for patients who are not optimally treated with injectable DMTs. The duration of treatment with mitoxantrone is limited due to cardiotoxicity. Importantly, mitoxantrone is associated with a 0.9% risk of acute myeloid leukaemia, which carries a fatality rate of more than 37% [13]. Some practitioners use low-dose mitoxantrone as a 6-month induction agent for patients with aggressive MS [14].

The oral disease-modifying medications

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Fingolimod was the first oral DMT for relapsing MS to be approved by the FDA (2010) and European Medicines Agency (EMA) (2011) (Table 2). It has a novel MOA, acting as an antagonist of normal endogenous sphingosine-1-phosphate (S-1-P). Lymphocytes normally exit lymph nodes along an S-1-P concentration gradient, which directs them back into the blood. Fingolimod binds to S-1-P receptors on naïve and activated lymphocytes, leaving them temporarily unable to respond to the S-1-P signal. Thus, in MS, fingolimod is believed to act by retaining autoreactive lymphocytes in lymph nodes, away from the CNS where they incite inflammation and tissue damage [15, 16]. In addition, fingolimod may have beneficial effects by acting directly on neurons and glial cells within the CNS [17, 18]. For example, animal studies have shown enhanced production of brain-derived neurotrophic factor (BDNF) by the interaction of fingolimod with S-1-P receptors on neurons [19]. If similar effects occur in MS, this would be likely to support neuronal maintenance.

Table 2. Oral disease modifying therapies in MS
TherapyRelapse rate reduction vs. placebo, %Disability reduction, %T2w lesion reduction, %Gadolinium enhancement reduction, %Side effectsMonitoring
  1. T2W, T2 weighted; T1W, T1 weighted; GI, gastrointestinal;TIW, three times weekly; beta-IFN, Interferon-Beta; SQ, subcutaneous; QOD, every other day; IM, intramuscular; PEG, pegylated; QOW, every other week; QD, every day; NA, not applicable; NS; not significant.

Fingolimod53307482First dose bradycardia, increased blood pressure, macular edema, increased liver enzymes, infectionsBaseline anti-varicella zoster IgG, pregnancy test, blood pressure, EKG. Baseline and Ongoing: blood counts, liver enzymes, ophthalmology exam baseline and 3 months
Teriflunomide31–3630–316780GI, hair thinning, leukopenia, elevated liver enzymes, increased blood pressure Pregnancy category X within US.Baseline blood counts, liver enzymes, Tuberculosis test, pregnancy test, blood pressure. Monthly liver enzymes for first 6 months. Biannual blood counts and liver enzymes.
Dimethyl fumarate44–533871–8574–90Flushing, diarrhea, abdominal pain, vomiting, lymphopenia, elevated hepatic enzymes.Baseline blood counts, liver enzymes with periodic retesting as indicated.

The FREEDOMS I, FREEDOMS II and TRANSFORMS clinical trials assessed the use of fingolimod in relapsing MS. In FREEDOMS I, two doses of fingolimod were compared to placebo treatment in over 1000 patients with relapsing MS of mean age 36–37 years with mild disease (mean baseline EDSS 2.4) [20]. The primary end-point was ARR. Both doses of fingolimod led to a reduction of over 50% in ARR, compared to placebo. The higher dose did not demonstrate a clear-cut efficacy advantage, but was associated with more toxicities. Disability progression was reduced by 30% for those on the lower 0.5-mg dose of fingolimod versus placebo, and the rate of decline in brain volume was also reduced by 30%. FREEDOMS II was a 2-year study of oral fingolimod versus placebo. Patients in this study were older (mean age 40–41 years) than those in FREEDOMS I. ARR was reduced by 48% versus placebo for the 0.5-mg daily dose [21].

TRANSFORMS was a 1-year clinical trial that enrolled over 1000 patients with mild relapsing MS with a mean age of around 35 years [22, 23]. Two-thirds of enrolled subjects received fingolimod at one of two doses (0.5 mg or 1.25 mg day−1) and one-third received an active comparator drug, weekly beta-IFN 1a (30 μg IM). Patients in the two fingolimod groups fared better, with more than a 50% reduction in ARR compared to the beta-IFN group. No significant effect upon disability progression was seen compared to beta-IFN 1a in this short 1-year study. Also, there was no apparent dose effect, but there were more side effects in the higher dose group. Two deaths from herpetic infections occurred in this study, both in subjects who received fingolimod at the higher 1.25 mg daily dose. One death occurred due to disseminated varicella zoster in a person without immunity to the virus. Thus, it is currently recommended that the presence of antibodies against varicella zoster should be checked before initiating treatment with fingolimod, with immunization if negative. Only the 0.5-mg dose is approved by the FDA (2010) and the EMA (2011). The EMA approved fingolimod for patients failing beta-IFN, or first line for those with ‘rapidly evolving severe relapsing-remitting MS’.

Notable contraindications for using fingolimod include a recent myocardial infarction, unstable angina, stroke or transient ischaemic attacks, heart failure within 6 months, the presence of Mobitz type II second- or third-degree heart block or sick sinus syndrome unless the patient has a functioning pacemaker, a history of symptomatic bradycardia or a prolonged QT interval on electrocardiogram (ECG), or has been treated with class Ia or III anti-arrhythmic agents. An ECG prior to and after the first dose, and several hours of medical monitoring of heart rate and blood pressure are required when the initial dose of fingolimod is given. Patients receiving fingolimod should be evaluated for the presence of macular oedema at baseline and at month 3–4 after treatment initiation. Pulmonary function testing should be performed in patients with a history of pulmonary disease; an abnormal result might preclude the use of fingolimod. As with all MS DMTs, female patients should avoid becoming pregnant whilst taking fingolimod.

Teriflunomide

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Teriflunomide is approved in the USA as a single tablet at either 7 or 14 mg day−1. Final European approval is pending at this time, but the Committee for Medicinal Products for Human Use provided a positive recommendation on the 14-mg dose. Teriflunomide is the active metabolite of leflunomide, which has been approved in the USA since 1998 to treat rheumatoid arthritis. Teriflunomide interferes with lymphocyte proliferation by inhibiting the enzyme dihydroorotate dehydrogenase. This enzyme is essential for de novo pyrimidine synthesis, and thus, teriflunomide blocks high levels of lymphocyte proliferation. Teriflunomide does not kill resting lymphocytes, which are able to divide and proliferate at low level using pyrimidines from the ‘salvage’ pathway [24]. Thus, previously acquired cellular immunity is not lost with teriflunomide treatment. This may account for the lack of increased risk of infections reported in the clinical trials.

Two Phase 3 clinical trials, TEMSO and TOWER, were pivotal in the approval process for teriflunomide. In TEMSO, two doses of teriflunomide (7 and 14 mg) were compared to placebo treatment in over 1000 patients with relapsing MS with a mean age of 38 years and mild disease (mean baseline EDSS 2.7) [25]. Both teriflunomide doses reduced ARR by 31% compared to placebo. Disability progression was reduced by 30% with the 14-mg dose versus placebo, whereas a nonsignificant reduction of 24% was seen with the 7-mg dose (= 0.08). Total new lesion volume was reduced by 33% and 69% with 7 and 14 mg, respectively, and gadolinium-enhancing lesions were reduced by 57% and 80% with the two doses, respectively.

TOWER similarly evaluated the 7- and 14-mg daily doses of teriflunomide against placebo for 1 year in over 1100 patients with relapsing MS at a mean time of 8 years from first MS symptoms and with mild disease (baseline EDSS 2.7). ARR was reduced by 36% with 14 mg day−1 and 22.3% with 7 mg day−1, compared to placebo. Similar to TEMSO, a 31% reduction in sustained disability progression was seen with the 14-mg dose, without significant reduction with the 7-mg daily dose [26].

Teriflunomide is designated as pregnancy category X by the FDA and should only be used together with a reliable form of birth control in women of childbearing potential. FDA-recommended testing prior to drug initiation includes pregnancy testing when appropriate, lymphocyte counts, hepatic function tests, tuberculosis testing and baseline blood pressure. Hepatic enzymes should be monitored monthly for the first 6 months. Lymphocyte counts might also be monitored every few months.

Potential side effects include elevated hepatic enzymes, hair thinning, nausea, diarrhoea, peripheral neuropathy and blood pressure elevation. Teriflunomide has a long half-life (>6 months); however, rapid elimination can be achieved in 7–14 days using either cholestyramine or activated charcoal.

Dimethyl fumarate (BG-12)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

This oral medication is given at a dose of 240 mg twice daily. It was approved in March 2013 by the FDA for relapsing forms of MS and by the EMA for adult patients with RRMS. It is likely that the MOA involves enhancing endogenous mechanisms to counteract oxidative stress, via activation of the nuclear factor erythroid 2-related factor 2 transcriptional pathway [27]. For over a decade, dimethyl fumarate has been used in Europe as a component of the drug Fumaderm™ for psoriasis [28].

The DEFINE clinical trial compared 240 mg dimethyl fumarate twice or three times per day versus oral placebo for 2 years in over 1200 patients with relapsing MS. The primary end-point, the proportion of subjects experiencing a relapse, was reduced by more than 40% for both doses compared to placebo [29, 30]. Secondary end-points in DEFINE showed significant benefits of dimethyl fumarate on ARR, with a decrease of about 50% compared to placebo, and on disability progression, which was reduced by more than 30%. No clear benefit of three times versus twice daily was observed in DEFINE [29]. The CONFIRM study also examined dimethyl fumarate at 240 mg twice or three times per day versus placebo; results were similar to those of the DEFINE study [31]. In CONFIRM, the ARR for twice daily dosing was reduced by 44% versus placebo.

In these pivotal clinical trials, the adverse effects with an incidence ≥5% higher with the active drug versus placebo included flushing, gastrointestinal effects (diarrhoea, nausea and upper abdominal pain), rash and lymphopenia. No increased risks of serious or opportunistic infections or malignancies were seen. Laboratory abnormalities observed included a decrease in the mean lymphocyte count by around 30% during the initial year, followed by stabilization. Increased liver transaminase levels were also noted in some cases.

Laquinimod

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Laquinimod is a synthetic oral medication, which is still under study in Phase 3 trials. Its synthesis was based on the structure of linomide, which was studied in clinical trials for MS in the 1990s. Linomide was effective in MS, but studies were halted due to unexpected cardiopulmonary toxicity [32]. Such toxicities have not been encountered with laquinimod. The MOA of laquinimod in MS is not completely clear. Laquinimod has anti-inflammatory activity that is probably due, at least partly, to its ability to suppress signalling through the NF-kappa B pathway. Laquinimod decreased major histocompatibility complex class II molecules on human cells in culture, suggesting that it might inhibit antigen presentation to T cells. Furthermore, laquinimod penetrates the intact BBB and so may act directly in the CNS [33]. It has potential neuroprotective properties by enhancing the production of BDNF [34]. In the ALLEGRO Phase 3 clinical trial of laquinimod, which enrolled over 1000 patients with MS, the drug was given at 0.6 mg day−1 versus placebo for 2 years. The primary end-point, ARR, was reduced by 23% compared to placebo [35]. Laquinimod-treated subjects showed a 36% reduction in the secondary end-point of disability progression sustained for 3 months versus placebo [35].

In the BRAVO trial, which enrolled over 1000 patients with relapsing MS, laquinimod was compared to placebo, with a third group treated with the active comparator of beta-IFN 1a (30 μg IM weekly). Laquinimod at 0.6 mg day−1 reduced relapse rate by 21.3% compared to placebo; this study achieved statistical significance for its primary end-point only after accounting for a baseline imbalance in two MRI characteristics. A prespecified statistical analysis plan allowed correction of this imbalance. Adverse effects reported with laquinimod have included transient elevations in liver transaminase levels in a small percentage of patients, abdominal pain, back pain, cough and arthralgia [35].

Another Phase 3 trial, CONCERTO, will investigate a higher daily dose of oral laquinimod (1.2 mg day−1) versus a lower dose (0.6 mg day−1, i.e. the dose used in ALLEGRO and BRAVO) and placebo. The primary end-point for this 2-year study will be disability progression. This study is expected to be completed in 2018.

Monoclonal antibodies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Alemtuzumab

Alemtuzumab is a humanized IgG1 monoclonal antibody directed against CD52, a small glycoprotein expressed on the surface of many types of white blood cells including T and B lymphocytes, natural killer (NK) cells, monocytes and some subsets of dendritic cells [36]. Alemtuzumab lyses cells expressing CD52 by antibody-dependent cellular cytolysis. The function of the CD52 molecule is not known, but it may be involved in cell activation as its cross-linking leads to T-cell activation.

In the CARE-MS I study, alemtuzumab was administered I.V. to patients with RRMS who were naïve to DMTs and had little disability. Notably, alemtuzumab was not compared to placebo, but instead to 44 μg beta-IFN 1a given SQ three times per week. In this study, there were two co-primary end-points, reduction in ARR and in disability progression sustained for 6 months. Compared to beta-IFN-treated subjects, those treated with alemtuzumab had a relative reduction of 54% in ARR and a nonsignificant 28% reduction in disability progression [37].

In the CARE-MS II study, alemtuzumab treatment was again compared to beta-IFN 1a (44 μg SQ three times per week) [38]. Subjects enrolled in CARE-MS II were not naïve to MS treatment, but had experienced a relapse whilst on prior DMT (predominantly either beta-IFN or GA). Patients enrolled in this study were older and more disabled than those in CARE-MS I. In the CARE-MS II study, compared to those treated with beta-IFN, alemtuzumab-treated patients fared better, with a reduction in ARR of 49% and in disability progression of 42% [38].

Adverse effects were similar in the two studies. Infusion reactions were seen in 90% of patients, but most were not considered serious. More infections, mainly of mild-to-moderate severity, were seen in the alemtuzumab arm in each study. Secondary autoimmune diseases developed in a sizeable proportion of alemtuzumab-treated subjects in both studies as well as in the earlier Phase 2 CAMMS223 study [39]. A separate analysis of 248 alemtuzumab-treated patients with MS showed that secondary autoimmunity developed in over 22% during a 34-month median follow-up [40]. Most cases were autoimmune thyroid disease, with Grave's disease being most common. Immune thrombocytopenia has been reported after alemtuzumab, resulting in at least one death. Thus, frequent assessment of the platelet count is indicated in patients who have received this drug. In CARE-MS I, two cases of thyroid papillary carcinoma, of unknown significance, were encountered in patients who received alemtuzumab.

Following treatment with alemtuzumab, very prolonged effects on circulating white blood cells are seen, especially on CD4+ T lymphocytes. A follow-up of the first 37 patients with MS who received alemtuzumab in the period from 1991 to 1997 demonstrated that the median time to recover to the lower limit of normal was almost 3 years for CD4+ T cells, 20 months for CD8+ T cells and 7.1 months for B cells [41]. Remarkably, even after more than a decade, CD8+ T-cell counts had returned to baseline in only 30% of patients and CD4+ T-cell counts had reached baseline in only 21%.

Daclizumab

Daclizumab is another monoclonal antibody DMT in late-stage development for MS. It is a humanized monoclonal antibody directed against the alpha subunit of the IL-2 receptor [42]. Daclizumab was formerly FDA-approved as a drug to limit rejection of kidney transplants, but was removed from the market in 2009 by its manufacturer, apparently due to diminishing market demand and not because of any safety issues.

Despite the knowledge that daclizumab is a monoclonal antibody with a singular target, its MOA in MS is not fully understood. Effectiveness in MS appears to be related to the ability of daclizumab to increase CD56bright NK cells, which have a regulatory effect on the immune system [43]. These NK cells achieve their regulatory effect at least in part by lysing activated T cells in a perforin-dependent manner. However, it is not clear whether this is the only MOA of daclizumab.

The CHOICE study was a 24-week Phase 2 add-on trial of daclizumab in 230 patients with relapsing MS. Placebo was compared to daclizumab dosed SQ every 2 or every 4 weeks (low dose), added to beta-IFN. Patients had to be receiving the beta-IFN for at least 6 months and have had either a relapse or a gadolinium-enhancing lesion on MRI [44]. A statistically significant benefit on mean new or enlarging gadolinium-enhancing lesions was seen with the addition of the high dose of daclizumab versus placebo. MRI outcomes were better in those subjects who responded with higher numbers of CD56bright NK cells [44]. The SELECT Phase 2 trial compared two doses of daclizumab and placebo in approximately 600 patients with RRMS. Daclizumab (150 or 300 mg) or placebo was administered SQ every 4 weeks for 52 weeks. Daclizumab reduced the ARR by 54% in the 150-mg group and by 50% in the 300-mg group compared to the placebo group at 1 year. Daclizumab also reduced the risk of sustained disability progression at 1 year by 57% and 43% in the 150- and 300-mg dose groups, respectively [45]. In the SELECTION extension phase of this trial, there was a death due to autoimmune hepatitis at the higher daclizumab dose and autoimmune complications in two other subjects.

Ocrelizumab

Ocrelizumab is a fully humanized monoclonal antibody against the CD20 molecule, which is found exclusively on B lymphocytes. Similar to the chimeric monoclonal antibody rituximab, ocrelizumab depletes B lymphocytes by cell lysis. Compared to rituximab, ocrelizumab may be better tolerated due to its MOA of lysing B cells via noncomplement-dependent cytolysis. A Phase 2 study in relapsing MS compared ocrelizumab with placebo or beta-IFN 1a IM weekly for 24 weeks; the primary end-point was total number of gadolinium-enhancing MS lesions [46]. Two doses of ocrelizumab were tested, 600 mg and 2000 mg, given as two IV infusions 2 weeks apart; no major differences between the doses were observed. Both doses almost eliminated gadolinium-enhancing lesions at 24 weeks, with 89% and 96% reductions, respectively, compared to placebo or the beta-IFN. Phase 3 trials of ocrelizumab in MS are ongoing and will help to determine whether this drug will achieve agency approvals. Information about these trials can be found online at http://clinicaltrials.gov/show/NCT01247324 (OPERA 1), http://clinicaltrials.gov/show/NCT01412333 (OPERA 2) and http://clinicaltrials.gov/show/NCT01194570 (ORATORIO).

Clinical studies of ocrelizumab in rheumatoid arthritis and systemic lupus erythematosus were discontinued after serious and opportunistic infections (including some deaths) were seen in the ocrelizumab-treated arms. The increased number of infections in these trials occurred mainly with the higher 2000-mg dose, which is not being used in the MS Phase 3 trials [47] Side effects seen in MS clinical trials have been mild-to-moderate infusion reactions during the initial infusion.

Ofatumumab

Ofatumumab is a monoclonal antibody that also targets the CD20 molecule, which is expressed exclusively on B cells. Ofatumumab binds to a different region of CD20 than ocrelizumab and rituximab, and has a slower rate of dissociation. In a small Phase 2 study in patients with active RRMS randomly assigned to escalating doses ofatumumab or placebo, ofatumumab reduced the number of new gadolinium-enhancing lesions by >99% after 24 weeks [48].

Remyelinating antibodies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

The ‘holy grail’ of MS therapy is regeneration. However, currently available therapies all target the inflammatory aspects of MS pathogenesis, partly in the hope that this will also slow the progression of the disease, and the ensuing disability. Remyelination can occur naturally in MS, although the new myelin is thinner and internodes are shorter [49]. A treatment that could enhance remyelination would provide a new and much needed type of therapy that would not only restore saltatory conduction, but also protect and provide trophic support to axons [50]. Encouraging experimental results suggest that treatments to enhance remyelination are feasible. Thus, the regeneration of myelin is now a major goal for the near future.

Anti-LINGO-1

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

The protein LINGO-1 has been shown to inhibit oligodendrocyte differentiation and myelination, neuron survival and axonal regeneration [51]. Antagonism of LINGO-1 was shown to enhance remyelination in animal models [52]. LINGO-1 is only expressed in the CNS, by oligodendrocytes and neurons. Its expression is increased in oligodendrocyte progenitor cells found in MS post-mortem lesion samples [53]. Therefore, targeted inhibition of LINGO-1 is a promising potential therapeutic approach for the treatment for MS and perhaps other CNS diseases. A small Phase 1 trial of intravenous anti-LINGO-1 has reportedly been completed [NCT01244139; http://www.clinicaltrials.gov/ct2/show/study/NCT01244139].

rHIgM22

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

A natural IgM antibody present in animals and humans has been shown to promote remyelination in animal models [54]. It is directed against a surface antigen on oligodendroglial cells. In mice, one relatively small dose is sufficient to induce remyelination. The monoclonal antibody, rHIgM22, is being developed for a Phase I clinical trial in MS [55]. It is possible that a combination of rHIgM22 plus anti-LINGO-1 might be particularly effective as they appear to act in different ways to promote remyelination.

Mesenchymal stem cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

Bone marrow contains stromal cells, which can differentiate into cells of endodermal and neuroectodermal lineage. Using animal models, these mesenchymal stem cells (MSCs) have been shown to modulate the immune response [56, 57]. Whether such a strategy can result in effective and functional neurogenesis to aid in CNS repair remains controversial. Pilot studies involving a small number of patients with MS have not raised safety concerns when using MSCs [58, 59].

Autologous haematopoietic stem cell transplantation (HSCT) has been used in a number of clinical studies to dramatically alter the immune system in patients with either aggressive relapsing or progressive MS. Trials have varied greatly in terms of selection criteria, outcome measures, follow-up period, conditioning regimens and dosing [60-63]. HSCT remains an investigative technique, as clinical trials still need to be conducted to define the optimal candidate, and compare the benefits and risks of HSCT with an approved DMT. Nonetheless, patients with aggressive, fulminant, highly inflammatory and early MS appear to have a positive response to this treatment. However, some patients do continue to relapse after HSCT, and it appears to have little effect on the progressive component for those with primary and secondary progressive MS.

Summary

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

The past two decades have witnessed the arrival of several different types of agents that beneficially modify the course of MS. This new era began in the early 1990s, when beta-IFN 1b was shown to reduce relapse rate in patients with RRMS. Since then, the number of DMTs for relapsing forms of MS has grown to include ten agents, with several more on the horizon. Attention in the field is beginning to focus on the development of agents that stop progression and repair damage. These goals may be more difficult to achieve, but several agents in early development appear promising. There is every reason to be optimistic about the future for patients living with MS.

Conflict of interest statement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References

AHC has received research and clinical trial funding from the US National Institutes of Health, US Department of Defence, National MS Society USA, Consortium of Multiple Sclerosis Centres, the Barnes-Jewish Hospital Foundation, Hoffman-La Roche and Sanofi-Aventis, and honoraria or consulting fees from Hoffman-La Roche, Sanofi-Aventis, Novartis, GlaxoSmithKline, Bayer Healthcare, Biogen Idec, Genzyme, Questcor and Teva Neuroscience.

RTN has received research and clinical trial funding from the US National Institutes of Health, National MS Society USA, Consortium of MS Centres, Acorda Therapeutics and Hoffmann-La Roche, as well as honoraria for consulting from Acorda Therapeutics, Bayer Healthcare, Biogen Idec, Genzyme Corp, EMD Serono and Questcor Pharmaceuticals and for speaking from Acorda Therapeutics, Bayer Healthcare, Biogen Idec and Genzyme Corp.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Injectable disease-modifying therapies
  5. Natalizumab
  6. Mitoxantrone
  7. The oral disease-modifying medications
  8. Teriflunomide
  9. Dimethyl fumarate (BG-12)
  10. Laquinimod
  11. Monoclonal antibodies
  12. Remyelinating antibodies
  13. Anti-LINGO-1
  14. rHIgM22
  15. Mesenchymal stem cells
  16. Summary
  17. Conflict of interest statement
  18. References
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