The modern era of disease modifying therapy (DMT) in multiple sclerosis (MS) began in 1993 with the introduction of interferon beta-1b for the treatment of relapsing-remitting multiple sclerosis (RMMS). Since then, the U.S. Food and Drug Administration (FDA) has approved eight new unique therapeutic agents (actually nine products). In other parts of the world, including Europe, Canada, and Australia, an additional agent, alemtuzumab, is available, but the FDA rejected the application in December 2013.

Probably no other area of neurology has seen such a remarkable explosion of new drugs during this period. This therapeutic armamentarium is, of course, good news for patients with relapsing forms of MS, but also creates increasing complexity of decision-making for physicians, hopefully in partnership with their patients.

Currently approved drugs in the U.S. include four injectables: intramuscularly administered interferon beta-1a, subcutaneous interferon beta-1a, interferon beta-1b (two identical products are available under different trade names from different pharmaceutical companies), and the sole injectable non-interferon, glatiramer acetate. One agent, the monoclonal antibody natalizumab, is administered by intravenous infusion. Also administered intravenously, but seldom used because of potentially serious toxicity, is mitoxantrone. In the last few years, the first oral agents—fingolimod, teriflunomide, and dimethyl fumarate—have been approved by the FDA. Each of these medications will be discussed in detail below.

Diagnosis and Risk Stratification

Background and Epidemiology

Before reviewing each agent, we should address the question of which patients are appropriate candidates for treatment. With the widespread availability of magnetic resonance imaging (MRI) in the Western world, it is now common for physicians to encounter patients who were scanned with no suspicion for MS—commonly because of headache or minor head trauma—and whose MRI unexpectedly shows changes characteristic of MS.

Okuda has led a group of investigators who have collected 430 patients from five countries who demonstrate what is known as the "radiologically isolated syndrome" (RIS).(1) Findings on their MRI were characteristic of MS and generally satisfied the Barkhof criteria that were used in the 2000 and 2005 versions of the McDonald diagnostic criteria for the diagnosis of MS.(2) To satisfy the Barkhof criteria, MRIs must meet at least three out of four of the following requirements:

1. Nine or more T2 hyperintense lesions or any gadolinium enhanced lesion;
2. An infratentorial lesion;
3. A juxtacortical lesion;
4. Three or more periventricular lesions.

Approximately one-third of these patients will develop clinical symptomatology consistent with a diagnosis of MS over the next five years. The risk of conversion to MS was higher in males, in younger patients, and in those with spinal cord lesions. Notably, none of these patients developed an alternative diagnosis during the period of follow-up. It is important to emphasize that patients with RIS do not meet any published criteria for MS, as all require the presence of clinical symptoms. Most MS specialists would not recommend treatment at the initial recognition of RIS. However, most would follow these patients with serial MRI and some specialists would consider treatment with disease-modifying therapy (DMT) if new lesions develop, even in the absence of clinical symptoms.

What about patients who present with a first clinical demyelinating episode [such patients have been commonly labeled as "clinically isolated syndrome"(CIS)]? These patients usually manifest signs of either optic neuritis, partial myelopathy or a brainstem syndrome. When CIS patients also have lesions present on brain MRI, they are at extremely high risk of subsequently developing definite MS. In one series from the United Kingdom, 82% of patients developed clinically definite MS by 20 years(3) and among patients in the optic neuritis treatment trial,(4) 56% of patients with one or more lesions developed MS over the subsequent decade. Because of this extraordinary risk for MS, several studies have now addressed the utility of DMTs in patients with CIS and at least two lesions on brain MRI.

Each of the injectable drugs approved for treatment of relapsing-remitting MS (RRMS) has been investigated in a double-blind, placebo-controlled trial. Interferon beta-1a, intramuscular, was studied in the CHAMPS trial;(5) interferon beta-1b in the BENEFIT trial;(6) interferon beta-1a, subcutaneous, in the ETOMS trial(7) (tested in very low dosage) and again in the REFLEX trial,(8) and glatiramer acetate in the PRECisE trial.(9) Each of the studies of standard dose medication resulted in a statistically significant reduction in conversion to clinically definite MS of 35-50%.

Most recently, the first clinical trial of an oral agent has been presented. Similar to the injectable agents, teriflunomide resulted in a 43% reduction in conversion to clinically definite MS compared to placebo.(10) Clearly, initiation of DMT at the first clinical demyelinating event has benefit in delaying conversion to clinically definite MS and most American neurologists recommend initiation of treatment at that time. Still unresolved, however, is the question as to whether this early initiation of DMT conveys a long-term benefit.

Let's now examine each of the disease-modifying agents available.

Interferon Beta-1b

Interferon beta-1b, taken by subcutaneous injection every other day, became the first licensed DMT for relapsing MS, entering the marketplace in 1993. This was followed soon thereafter by interferon beta-1a, administered intramuscularly once a week. The sole non-interferon injectable, glatiramer acetate (GA), administered as a daily subcutaneous injection, was the next MS therapy approved. GA is a large polypeptide, composed of a mixture of the amino acids, glutamic acid, lysine, alanine, and tyrosine. Finally, subcutaneous interferon-beta-1a, administered three times a week, was approved.

Each of these agents demonstrated modest efficacy in randomized placebo-controlled trials on the primary endpoint of reduction in annualized relapse rates.(11)(12)(13)(14) Depending on which particular trial, the magnitude of the reduction was generally between 30 and 35% (although less with weekly IM interferon beta-1a in an intent-to-treat analysis). In head-to-head trials between GA and multiply dosed interferons, no difference was seen in the impact on relapses between the two classes of medication (BEYOND trial comparing interferon beta-1b to GA(15) and REGARD trial comparing subcutaneous thrice weekly interferon beta-1a to GA(16)). The interferon preparations administered several times per week do consistently show a more robust effect on new MRI lesion formation than does GA.

In terms of tolerability, each of the interferon preparations is associated with flu-like symptoms including any combination of low-grade fever, chills, muscle or joint pain, headache and fatigue. With interferon preparations that are administered several times per week, these symptoms typically become markedly less or disappear altogether within a few months. Patients taking weekly IM interferon, however, often continue to experience flu-like symptoms.

Subcutaneous interferon use is associated with generally mild local site reactions, usually consisting of erythema that fades over a couple of weeks. Rarely, skin breakdown is associated. The use of interferon may also be associated with depression or irritability and it should be avoided or used cautiously in patients with a history of significant depression or bipolar disease. Patients taking interferon should be monitored regularly with complete blood counts and determination of liver enzymes.

Glatiramer Acetate

GA, on the other hand, is better tolerated in terms of systemic side effects. No flu-like symptoms occur and most patients complain only of local injection site irritation. This usually consists of mild erythema and swelling, but occasionally the local reaction is more severe. With chronic use of GA, patients, particularly women, develop focal lipoatrophy (loss of fat tissue), which can be cosmetically concerning, at the injection sites.

Patients beginning treatment with GA should also be advised about the infrequent and seemingly random occurrence of an immediate post-injection systemic reaction consisting of some combination of tightness in the chest, flushing of the face, palpitations, shortness of breath, and a feeling of anxiety. These symptoms, which do not appear to represent cardiac dysfunction, occur almost immediately after an injection and subside spontaneously in 10-20 minutes. Patients taking GA do not need to be monitored with any laboratory investigations.

Natalizumab

Natalizumab is a monoclonal antibody directed against the adhesion molecule VLA-4 on the surface of lymphocytes. It prevents the cell from "docking" with VCAM-1, the complementary receptor on the vascular endothelium, thereby keeping the immunogenic lymphocytes from entering the central nervous system. Natalizumab was originally marketed in the U.S. in November 2004, but was voluntarily withdrawn in February 2005 when several cases of progressive multifocal leukoencephalopathy (PML), a very serious and often fatal brain infection caused by the John Cunningham (JC) virus, occurred among patients who had participated in clinical trials.

The drug, which is administered by intravenous infusion every four weeks, was re-introduced to the U.S. market in July 2006, with the institution of a mandatory risk mitigation program aimed to allow early recognition of PML cases. Based on a randomized placebo-controlled double-blind trial, known as AFFIRM, in which natalizumab achieved a 68% reduction in annualized relapse rate, it is, arguably, the most effective agent currently available for treatment of relapsing MS.(17) No head-to-head trials, however, have been conducted comparing natalizumab to another active agent.

Since the reintroduction of natalizumab, much has been learned about the risk of PML associated with its use and the factors that influence that risk.(18) The main risk factor is the presence of JC virus antibody. The risk of PML in an antibody negative patient is extremely low, less than 1:10,000. Slightly more than half the adult Western population is positive by the assay used in the STRATIFY study. Conversion from antibody negative to antibody positive status may, however, occur, so we recommend repeat antibody testing every six months.

The next risk factor is duration of therapy. Even if patients are JC virus ab positive, the risk of PML during the first year of treatment is only about 1:10,000. In the second year, however, it rises to approximately 1:800 and in the third and subsequent years, it is about 1:250. Finally, the risk of PML is further increased (presumably only in JC virus ab positive individuals) when a patient has a history of prior use of immunosuppressive medications (not including steroids or the injectable DMTs).

Natalizumab therapy is generally very well-tolerated. A small percentage of patients develop antibodies to the agent, and rarely an allergic reaction, which may have anaphylactoid features, may occur, particularly with the second infusion. For this reason, patients are monitored for an hour following their hour-long infusion.

Oral DMTs

Fingolimod

Recent years have brought the introduction of the first three oral DMTs, beginning with fingolimod, which was approved by the U.S. FDA in September 2010. Fingolimod, administered once daily as a 0.5 mg capsule, is a sphingosine-1-phosphate receptor (S1PR) modulator, which results in internalization of the S1PR, thereby preventing the egress of lymphocytes from peripheral lymph nodes and thus keeping them out of the CNS.(19)

Because of its mechanism of action, fingolimod results in significant lymphopenia, which has raised questions of the risk of unusual infections or neoplasms in patients who have low lymphocyte counts for prolonged periods of time. In the clinical trials, patients were discontinued from treatment if absolute lymphocyte counts reached 200/µl and persisted. So far, other than an increased risk of herpes infection, particularly herpes zoster, this concern has not been realized.

S1P receptors are present on a variety of other tissues including the heart. Because of this cardiac presence, administration of fingolimod, especially initially, may be associated with bradyarrhythmias. The drug should not be prescribed for patients with significant bradycardia, atrioventricular conduction delays those taking drugs that may affect AV conduction or recent myocardial infarction. Patients are monitored after the first dose for development of bradyarrhythmias.

Another risk with fingolimod treatment is the development of macular edema, which can impair vision. Usually reversible if detected early, macular edema tends to occur within a few months of initiation of therapy (at a frequency of about 1:250). Given this potential risk, patients should receive a baseline ophthalmological examination, a repeat examination 3-4 months after beginning therapy and annually thereafter. Patients also should have either a clear history of chickenpox or varicella immunization or demonstrated antibody levels to varicella prior to treatment. If that is not the case, they should receive varicella immunization at least one month prior to fingolimod treatment.

Fingolimod is an efficacious drug. In its pivotal phase 3 FREEDOMS trial, the 0.5 mg dose resulted in an annualized relapse rate reduction (ARR) of 54%.(19) In a one-year head-to-head trial against weekly intramuscular interferon beta-1a, fingolimod reduced the ARR by approximately twice as much as the interferon.(20) The tolerability of fingolimod is excellent but patients should be regularly monitored by complete blood count and liver panel.

Teriflunomide

The next oral agent approved in the U.S. was teriflunomide, an inhibitor of the enzyme dihydro-orotate dehydrogenase that blocks pyrimidine synthesis in actively dividing cells.(21) This drug, administered orally once daily, was tested in 7 mg and 14 mg doses. Although both doses are available in the U.S., only the 14 mg dose is available in some other countries. The higher dose is more efficacious and does not cause appreciably more adverse events, so there is little reason to use the lower dose.

The drug is well-tolerated with about 2% of patients discontinuing treatment in the phase 3 trials because of gastrointestinal side effects, mainly diarrhea, and fewer than 2% discontinuing because of hair loss. Elevations of liver transaminases may occur, but have rarely been serious. Infrequently, a few patients may develop significant neutropenia. The FDA recommended monthly liver test monitoring for the first six months of treatment and CBC should also be regularly checked.

In two large phase 3 trials, TEMSO(21) and TOWER,(22) teriflunomide reduced the ARR by about one-third. It is the only oral agent that has shown a statistically significant reduction of confirmed disability progression in two pivotal trials. Teriflunomide is the active metabolite of leflunomide, a drug on the market for many years to treat rheumatoid arthritis. Leflunomide has a very good safety record, but it is occasionally associated with unusual infections, particularly tuberculosis, so patients should be tested for that disease prior to use of teriflunomide. Teriflunomide also persists in the body for many months after treatment is discontinued. Therefore, if it is desirable to rid the body quickly of teriflunomide, an accelerated elimination protocol involving administration of either cholestyramine or activated charcoal is employed.

Dimethyl Fumarate

The newest approved oral drug is dimethyl fumarate (DMF), which entered the U.S. market in March 2013. The precise mechanism of action of DMF is uncertain, but one likely possibility is its effect to drive the nrF2 pathway, which has an antioxidant effect. DMF is administered as a 240-mg capsule twice-a-day after a brief titration phase from a lower dose. In two randomized, double-blind trials, DMF resulted, overall, in a 49% reduction of ARR compared to placebo.(23)(24) In the second of these pivotal trials, GA was included as an active comparator. The trial was not powered to show a benefit of DMF over GA but DMF did perform statistically significantly better on some parameters.

Some patients have difficulty tolerating DMF, primarily at the beginning of treatment. About 5% of patients in the clinical trials discontinued therapy because of gastrointestinal side effects including nausea, vomiting, abdominal pain, heartburn or diarrhea. Approximately 2% of patients in the trials discontinued treatment because of flushing, which may include erythema of the face and upper body, warmth and itching.

In our experience, approximately 80% of patients have been able to begin using the drug with little difficulty but about 20% have experienced these side effects initially with considerable discomfort. Even when troublesome, however, the GI symptoms and flushing typically improve substantially over 1-2 months and very few of our patients have needed to discontinue treatment. The GI symptoms are lessened if the drug is administered with meals and, if particularly bothersome, the flushing may be alleviated if the patient takes 325 mg acetylsalicylic acid prior to the dose of DMF. Infrequently, the use of DMF is associated with significant lymphopenia. Therefore, a baseline complete blood count should be obtained prior to the initiation of therapy and periodically thereafter. We also order periodic liver enzyme determinations, just as we do with all agents except GA.

Relatively little information is available about the long-term safety of DMF because it was so recently approved. Some prescribers may derive comfort from the fact that a related preparation of fumarates has been used in Germany for over 30 years to treat psoriasis. Although that agent is not exactly the same, nor administered in the same dosing schedule, it has had a good safety record. At least four cases of PML have been associated with the use of the fumarate psoriasis preparation after more than 180,000 patient-years of experience. In each of those cases, however, extenuating circumstances may have predisposed the patients to PML. In three of the four PML patients, other immunosuppressive agents, which are known to increase the risk for the disease, had also been administered. The fourth patient had experienced prolonged significant lymphopenia. (25)

Since MS so often affects young women, the use of DMT in patients contemplating pregnancy often requires discussion. Interferon, natalizumab, fingolimod and DMF carry Category C pregnancy ratings, meaning that they are best avoided in pregnant women (and those attempting to conceive). Teriflunomide has a Category X label and mitoxantrone has a Category D rating, so there is significant potential for fetal risk with these drugs and they definitely should not be administered during pregnancy.

GA is the only agent with a Category B rating (indicating no known risk to the fetus). Although the official prescribing information cautions about the use of GA during pregnancy, I consider the agent safe and allow women to remain on it during the period of attempted conception and during the pregnancy itself if they so choose, providing their obstetrician is also comfortable with that decision.

Our Approach to Treatment

Given the current availability of so many options for the treatment of relapsing forms of MS, what then is my approach in considering initiation of DMT in a particular patient? I first consider the prognosis of the patient. If the patient's history, examination and imaging do not seem particularly ominous, I consider all agents to be potentially acceptable alternatives.

If the patient is a woman, I then explore the question of whether she is contemplating pregnancy in the near future. If so, I discuss my view about the potential of her using GA during attempted conception and even during the pregnancy itself. If she is comfortable with that plan, I would suggest she initiate therapy with GA.

If pregnancy is not a consideration, then I explain, in detail, each of the drugs, in terms of route and frequency of injection, efficacy, potential for serious adverse events and tolerability. I explain that, if complete (or nearly so) assurance about safety is the patient's paramount concern, she or he should probably initiate treatment with GA or an interferon, given the abundant long-term information about these agents and their extremely good safety record.

On the other hand, if the patient is strongly opposed to the notion of injectable therapy, I steer the patient toward one of the other agents. If very high efficacy of the initial treatment is important to the patient, I tell her (him) that natalizumab is likely the most effective agent but I will only prescribe it if the test for JC virus antibody is negative. If the patient has a strong preference for an oral agent, I reiterate the pros and cons of the three available drugs.

In some patients, the early features of the disease, both clinically and by imaging, augur an aggressive course. In these patients, fortunately encountered infrequently, I emphasize efficacy and encourage the patient to begin natalizumab, again assuming JC virus antibody negativity. If that assay is positive, I suggest the patient initiate treatment with fingolimod or DMF.

It is important to emphasize that, in all cases, I engage the patient in a dialogue. During this conversation, I attempt to convey all the information the patient needs in a manner that is easily understood. I encourage the patient to ask questions and I try to appreciate, not only by the patient's words but by body language as well, what are the individual's concerns.

The goal of this dialogue is to enable the patient to reach a treatment decision with which he or she (as well as the physician) is comfortable. Having this detailed conversation "up front" is likely to result in a greater probability that the patient will tolerate and remain on the particular disease-modifying therapy and will foster a healthy doctor-patient relationship.

Despite the availability of so many drugs, complete control of inflammatory disease activity still often remains an elusive goal. We seek the holy grail of "no evidence of disease activity," a concept that has crept into the clinical trial literature. Even allowing for difficulties with definition and determination of this state, that goal is infrequently obtained with our current arsenal of DMTs. Thus, the need for additional and yet more effective and safe agents remains.

Future Therapies

Fortunately, a rich pipeline of agents under development exists. While it is beyond the scope of this Cyberounds^® to discuss this subject in depth, a few agents currently in phase 3 testing and, therefore, potentially likely to reach the marketplace within the next few years will be noted:

Daclizumab, a monoclonal antibody directed against CD25, blocks the high affinity IL2 receptor, ultimately leading to an increase in natural killer (NK) cells, which, presumably, have a beneficial effect on the regulation of autoimmune cells. Daclizumab, which had a very positive phase 2 trial, is administered as a subcutaneous injection every four weeks.(26)

Ocrelizumab, an anti-CD 20 monoclonal antibody that eliminates B cells, has also, like rituximab before it, had a very successful phase 2 trial,(27) and is nearing completion of its pivotal phase 3 studies. It is administered by intravenous infusion in 6-monthly cycles.

In addition to these agents, additional sphingosine-1-phosphate receptor molecules are in phase 3 testing and ofatumumab, an anti-CD 19 monoclonal antibody also targeting B cells, has had a positive phase 2 trial.

A Word About Progressive MS

Although considerable progress has been made in the development of agents to treat the inflammatory component of MS, focused primarily on the relapsing stage of MS, there has been an unfortunate lack of success in the management of progressive forms of MS, which are likely mediated more by a neurodegenerative process. Currently, there are several ongoing phase 3 studies in both secondary (SP) and primary progressive (PP) MS. These include investigations of natalizumab and siponimod (an S1P receptor modulator) in SPMS, and fingolimod and ocrelizumab in PPMS. Additional attention worldwide is being devoted to understanding and treating these progressive stages of MS, which are responsible for much of the disability associated with the disease.

Summary

The earliest decision in MS therapeutics is whether or not to institute therapy in a particular patient. Once the decision to treat is made, a plethora of issues should come into play. Consideration of how aggressive the disease appears to be in its early course will play a role in the choice of initial therapy. For most patients, discussion of many alternatives is warranted so that the individual can consider relative efficacy, safety and tolerability issues. The goal of this approach is to reach a decision about a treatment with which both the patient and the physician are comfortable. Achieving this outcome will increase the likelihood of long-term adherence to the medication. Despite our current arsenal of options for relapsing forms of MS, room for additional effective and safe medications exist. Fortunately, the pipeline for new drugs remains rich, but the goal of an efficacious drug for progressive forms of MS has so far remained elusive.