Current and Future Directions in MS Management: Key Considerations for Managed Care Pharmacists

BACKGROUND: The management paradigm for multiple sclerosis (MS) continues to evolve and is shifting toward earlier diagnosis, differentiation of patients with varying clinical prognoses, and earlier initiation of treatment in selected individuals. Based on surveys conducted at the 2008 annual conference of the Academy of Managed Care Pharmacy (AMCP) and at regional meetings held in 2009, several topics were identified for which pharmacists indicated a need for new and updated information. OBJECTIVES: To review (a) recent insights into the pathophysiology underlying MS, (b) the improvements in identification of patients with a clinically isolated syndrome (CIS) who will progress to clinically definite MS (CDMS), (c) the current role of magnetic resonance imaging (MRI) and other technologies in the diagnosis and ongoing management of MS, (d) the optimal time to initiate treatment in patients with CIS or MS, and (e) the potential utility of new and emerging therapies in MS management. METHODS: The medical education company PRIME conducted an educational need assessment regarding knowledge of recent developments and future directions in MS management at a symposium held at the Academy of Managed Care Pharmacy Educational Conference in Kansas City, Missouri, on October 17, 2008. This was augmented by an ongoing educational needs assessment initiative that involved a national series of regional dinner meetings for managed care pharmacists on the topic of MS in the first 3 quarters of 2009. Collectively, these needs assessments were designed to determine educational gaps that existed after participants attended the symposia on MS, in an effort to plan a follow-up enduring educational activity that addressed those gaps. Measures of learners post-program intent were collected, as well as specific topic areas recommended for a follow-up activity. SUMMARY: Advances have been made in the understanding of CIS subtypes and refinement of MS diagnostic criteria. Early initiation of treatment in patients with a CIS has been shown to prolong the time to progression to CDMS, delay the development of disability, and may also decrease long term health care costs. In addition, a number of novel therapies for patients with MS are in late stages of clinical development, including several oral medications that are of particular interest to managed care pharmacists. These will provide potentially attractive treatment alternatives for patients with MS, who currently must choose from a selection of injectable drugs.

BACKGROUND: The management paradigm for multiple sclerosis (MS) continues to evolve and is shifting toward earlier diagnosis, differentiation of patients with varying clinical prognoses, and earlier initiation of treatment in selected individuals. Based on surveys conducted at the 2008 annual conference of the Academy of Managed Care Pharmacy (AMCP) and at regional meetings held in 2009, several topics were identified for which pharmacists indicated a need for new and updated information.
OBJECTIVE: To review (a) recent insights into the pathophysiology underlying MS, (b) the improvements in identification of patients with a clinically isolated syndrome (CIS) who will progress to clinically definite MS (CDMS), (c) the current role of magnetic resonance imaging (MRI) and other technologies in the diagnosis and ongoing management of MS, (d) the optimal time to initiate treatment in patients with CIS or MS, and (e) the potential utility of new and emerging therapies in MS management.
METHODS: The medical education company PRIME conducted an educational needs assessment regarding knowledge of recent developments and future directions in MS management at a symposium held at the Academy of Managed Care Pharmacy Educational Conference in Kansas City, Missouri, on October 17, 2008. This was augmented by an ongoing educational needs assessment initiative that involved a national series of regional dinner meetings for managed care pharmacists on the topic of MS in the first 3 quarters of 2009. Collectively, these needs assessments were designed to determine educational gaps that existed after participants attended the symposia on MS, in an effort to plan a follow-up enduring educational activity that addressed those gaps. Measures of learners' post-program intent were collected, as well as specific topic areas recommended for a follow-up activity. SUMMARY: Advances have been made in the understanding of CIS subtypes and refinement of MS diagnostic criteria. Early initiation of treatment in patients with a CIS has been shown to prolong the time to progression to CDMS, delay the development of disability, and may also decrease longterm health care costs. In addition, a number of novel therapies for patients with MS are in late stages of clinical development, including several oral medications that are of particular interest to managed care pharmacists. These will provide potentially attractive treatment alternatives for patients with MS, who currently must choose from a selection of injectable drugs. Managed Care Pharmacy (AMCP) educational conference in Kansas City, Missouri, on October 17, 2008. This was augmented by an ongoing educational needs assessment initiative conducted via a national series of regional dinner meetings for managed care pharmacists on the topic of MS in the first 3 quarters of 2009. Collectively, these needs assessments were designed to determine educational gaps that existed after participants attended the symposia on MS in an effort to plan a follow-up enduring educational activity that addressed those gaps. Measures of learners' post-program intent were collected, as well as specific topic areas recommended for a follow-up activity.

Results of Educational Needs Assessment
More than 100 pharmacists attended the AMCP symposium on MS in October 2008, and to date, more than 350 pharmacists have attended follow-up sessions held throughout the United States. Through PRIME's continuous assessment process, all attendees were surveyed regarding competence and performance in managing MS patients. Data collected during this assessment process showed that approximately 80% of attendees stated that they had a better understanding of current therapeutic options for MS following the AMCP symposium or regional meetings, and 65% of attendees stated that they would seek educational opportunities to enhance their overall knowledge of MS. Topics on which pharmacists requested more education included recent insights into the pathophysiology of MS, the role of imaging in the diagnosis and ongoing management of MS, the optimal time to initiate treatment for MS, and new and emerging MS therapies. As a result of this needs assessment, content for this enduring article was planned with these specific topics in mind.

Immunopathology of MS
Traditionally thought to be primarily an inflammatory demyelinating disease, MS is now recognized to have a significant neurodegenerative component. While heterogeneity exists, most patients with MS exhibit a dual-phase pattern of disease activity, with the early phase dominated by central nervous system (CNS) inflammation caused by infiltration of activated T cells, B cells, and macrophages ( Figure 1). Selective demyelination then begins as neurons are attacked by macrophages, T cells, and antibodies secreted from B cells that have differentiated into plasma cells. 5,6 Although Figure 1 shows only Th1 cells entering the CNS, it has recently been recognized that other T-lymphocyte subtypes (particularly Th17 cells that secrete interleukin-17) are important in the pathogenesis of MS. 7,8 Some axonal loss also occurs early in the MS disease course, perhaps even in pre-clinical stages. 9 Patients with MS gradually transition to a later stage disease that is dominated by neurodegeneration and widespread axonal loss, even though inflammation tends to subside. Because of advances in the understanding of the pathophysiology of MS, the management paradigm has evolved to include both earlier diagnosis and early treatment using M ultiple sclerosis (MS) is a degenerative neurologic disorder that produces a variety of symptoms, with some patients progressing to significant degrees of disability. Over the past 2 decades, advances in therapies for MS have transformed it from a disease of relative despair with few treatment options to one of therapeutic promise. With the introduction and utilization of immunomodulatory therapy in the 1990s, therapeutic goals in MS moved from palliation to disease control. With the advent of newer therapies, disease modification and the potential for a cure may be on the horizon. Advances in MS treatments have led to a wider variety of health care practitioners becoming involved in managing MS, including the introduction of multidisciplinary care coordination teams. The addition of these new MS care providers has brought with it the need to educate these professionals on the topic of MS, its therapeutic options, and future directions.
MS management involves (a) disease management, (b) symptomatic treatment, and (c) patient management. Disease management is of primary importance; as such, disease-modifying therapies (DMTs) are a mainstay of MS management. However, many would advocate that symptomatic treatment is equally important from the standpoint of quality of life. 1 Often forgotten is the fact that there is a person behind the disease and that person management (e.g., psychological, vocational, and marital issues) is essential to any effective MS management program. The pharmacist has an opportunity to be involved in many aspects of MS management.
As with many diseases, advocates of multidisciplinary care for patients with MS believe that such an approach is beneficial in improving patient outcomes. 2 While overall data are inconsistent, studies have suggested that multidisciplinary treatment programs that include a rehabilitation component may result in improved patient experiences. 2 Multidisciplinary treatment programs must include the pharmacist as a core member of the team, especially with the recent upsurge in medication therapy management (MTM) programs following implementation of the Medicare Modernization Act of 2003. 3 While there have been no studies investigating the benefit of MTM programs for patients with MS or their role in the provision of multidisciplinary care for patients with MS, the components of such a program -medication therapy review, personal medication record, medication-related action plan, intervention and/or referral, and documentation and follow-up 4 -are all appropriate methods for the pharmacist to use when interfacing with the MS patient in an ongoing fashion. Based upon this, education of the pharmacist is vital to optimizing outcomes for patients with MS because pharmacists may improve therapy adherence and provide patients with valuable education on disease information and treatment modalities.

Methods
The medical education company PRIME conducted an educational needs assessment on MS at a symposium held at the Academy of In 2008, an international consensus on the differential diagnosis of MS was published, which provides an algorithm to help guide the clinical, laboratory, and MRI evaluations of patients with suspected MS. 16 These recommendations also consider nearly 80 clinical and paraclinical "red flags" of various "strength" classifications that suggest alternative diagnoses. 16,18 Clinically Isolated Syndrome Current McDonald criteria emphasize the importance of early diagnosis of patients with clinically isolated syndrome (CIS). 14,16 CIS is defined as a single, symptomatic neurologic episode that is consistent with MS. The most common symptoms on initial presentation are optic neuritis, ocular motor syndromes (internuclear ophthalmoparesis, nystagmus), ataxia, dysarthria, sensory or motor signs, partial myelitis, and bladder or bowel dysfunction. 19 Many patients with a CIS will have already have lesions on an MRI scan. 19 To improve diagnosis of CIS, the 2005 revisions to the McDonald criteria placed greater significance on the presence of spinal cord lesions on MRI. 14 Approximately 60% to 80% of individuals with a CIS and demyelinating lesions on an MRI will eventually develop immunomodulatory agents that target the underlying inflammatory components. 10,11 As a result, managed care pharmacists are likely to encounter increasing requests for evaluating and approving treatment options for patients with very early MS.

Diagnosis of MS
The McDonald criteria are currently considered the standard for diagnosing MS and were recently reviewed in the Journal of Managed Care Pharmacy. 12 The McDonald criteria require the dissemination in space (DIS) and time (DIT) of MS lesions determined by either clinical, paraclinical, or laboratory analyses (including evaluation of cerebrospinal fluid [CSF] and visual evoked potential [VEP]) and integrate magnetic resonance imaging (MRI) into the diagnosis. 13,14 One of the challenges in diagnosing MS is the overlap of other medical conditions (either demyelinating or nondemyelinating) with respect to both neurological symptoms on patient presentation and the presence of similar appearing lesions on MRI scans. Some of the disorders that can confound the diagnosis of MS are listed in Table 1. 15 However, the underlying pathophysiology of these conditions differs significantly from that observed in patients with MS. 16 A recent study by Marrie et al. (2009) also found that certain comorbidities (e.g., vascular, musculoskeletal, and visual or mental symptoms) may delay the diagnosis of MS for as long as 10 years. 17  was higher than that of the McDonald criteria (72% vs. 60%; no P value provided). For both MRI criteria, a higher risk of conversion from CIS to CDMS was seen in patients with both DIS and DIT, compared with those with either DIS or DIT. The DIT component of both criteria was also more specific than DIS alone. While acknowledging some of the study's limitations, the authors concluded that their revised MRI criteria simplified the McDonald criteria without compromising specificity or accuracy. 25 Korteweg et al. (2009) recently attempted to identify simpler and more sensitive criteria for DIS based on CNS lesion characteristics at the onset of CIS based on single MRI scans. 26 The authors were unable to improve the performance of the current diagnostic criteria for DIS alone using a single unenhanced MRI and concluded that follow-up scans with and without contrast are needed to improve the diagnostic algorithm. 26 Diagnostic criteria for MS will continue to be updated and refined. This is particularly true regarding the role of MRI; technical advancements will need to be incorporated into clinical practice. Other imaging technologies are likely to play an increasing role in the future for both the diagnosis and longitudinal monitoring of patients with CIS and MS.

Is the Current Definition of CIS Adequate?
Several criticisms have been noted regarding current use of the term "clinically isolated syndrome." For example, although CIS is the clinical presentation of relapsing-remitting MS (RRMS), the current definition of CIS does not consider initial presentations that may not be clinical but might be detected by paraclinical and laboratory results. 27 In addition, the current CIS definition does not differentiate between 2 patient populations with different prognoses: individuals who have a single clinical presentation with or without additional symptomatic MRI lesions. [20][21][22] clinically definite multiple sclerosis (CDMS), as will about 20% of CIS patients with normal MRI scans. [20][21][22] The McDonald criteria recognize a new T2 MRI lesion occurring any time after 30 days from CIS onset as evidence of DIT. This facilitates earlier diagnosis of MS by allowing for 2 separate MRI scans (instead of 3) to evaluate disease progression, and 1 clinical attack (instead of 2) if MRI lesions demonstrate DIT or DIS. 14 By eliminating the requirement for DIT and/or a second clinical event, the McDonald criteria speed the diagnosis and more quickly resolve the period for patients when uncertainty exists regarding a definitive diagnosis.
One of the ongoing management challenges is to further improve the identification of patients with CIS who are at high risk for developing CDMS. To address this challenge, 2 modifications or simplifications to the McDonald MRI criteria were proposed in 2006 by Swanton et al: (a) that DIS require at least 1 T2 lesion in at least 2 of 4 CNS locations; and (b) that DIT require a new T2 lesion on a follow-up scan regardless of timing of the baseline scan. 23 Recent data support the second recommendation, with Tur et al. (2008) reporting that the presence of new T2 lesions in patients with CIS increased the risk of relapse regardless of the timing of the reference MRI scan. 24 In a subsequent publication, Swanton et al. (2007) conducted a comparison of McDonald MRI criteria with their proposed changes for predicting progression of CIS to CDMS. 25 This was a retrospective analysis of 208 patients from 4 centers in Europe who had 2 MRI scans within 12 months of CIS onset in whom the specificity and sensitivity of MRI criteria for CDMS were assessed after 3 years. Table 2 provides a more detailed summary of the 2 MRI criteria for DIT and DIS, as well as estimates of their specificity and sensitivity. While the specificity of both criteria was roughly equivalent, the sensitivity of the Swanton criteria   Okuda et al. (2009) published an analysis of a cohort of asymptomatic patients (n = 44) with incidental white matter abnormalities in the CNS suggestive of MS detected in an initial MRI. 28 Neurological examination at baseline was normal in nearly all cases, and every attempt was made to rule out other diseases as responsible for the radiologic abnormalities. Longitudinal clinical and MRI follow-up were conducted in 30 and 41 patients, respectively. Evidence of radiologic progression was seen on an MRI (defined as presence of new foci, gadolinium (Gd) enhancement, or enlargement of pre-existing lesions) in 59% (24/41) of the patients. However, only 33% (10/30) of the individuals converted to CIS or CDMS at a median of 5.4 years using McDonald criteria. In patients who had lumbar puncture, CSF profiles were positive (i.e., presence of unique oligoclonal bands or an elevated IgG index) in 67% (18/27) of the patients; 8 of these patients (44%) developed clinical symptoms of MS. The authors proposed additional diagnostic criteria for RIS (i.e., type 5 CIS) that attempt to eliminate other potential etiologies and improve identification of clinical situations that are actual precursors to MS. It should be noted that 7 patients in this study had already been prescribed a DMT for MS despite the lack of clinical symptoms at the time of presentation. 28 In an editorial in the same Neurology issue that published the Okuda et al. analysis, Bourdette and Simon acknowledged the value of the Okuda study for establishing a framework for which patients with RIS or type 5 CIS might be evaluated and monitored to provide useful insight on the risk of conversion to CDMS but emphasized restraint in using MS medications in these patients in the absence of clinical symptoms, since this is inconsistent with current McDonald guidelines. 30 Notably, there are several different medical conditions in which similar lesions can appear on MRI scans, such as Behcets disease or CNS malignancies. 31 In addition, some individuals may exhibit neurological changes on an MRI that are consistent with MS but remain asymptomatic. 32

Imaging Modalities in MS
MRI plays a major role in the diagnosis and ongoing management of patients with MS. In addition, MRI results have been used as outcome measures in many clinical trials. In 2006, the Consortium of MS Centers (CMSC) published a consensus MRI protocol for imaging of the brain and spinal cord during baseline evaluations and follow-up in patients with MS. 33 The CMSC has recently proposed revisions to their MRI guidelines. 34 According to the 2009 proposed revisions, MRI sequences to be used include sagittal and axial FLAIR (fluid attenuated inversion recovery), axial T2-weighted scans, and axial T1 scans pre-and post-Gd-enhancement. For patients with a CIS (and suspected MS), a baseline brain MRI with Gd is recommended. Spinal cord MRI is recommended when (a) persisting uncertainty exists regarding the diagnosis or the brain MRI is equivocal; and (b) presenting symptoms are at the level of the spinal cord. In To improve description of clinical and radiologic findings at the earliest stages of MS, an international consensus panel recently proposed the division of CIS into more specific subcategories (Table 3). 16 Patients with 1 or more asymptomatic MRI lesions consistent with demyelination (types 1 and 2 CIS) have a higher probability of meeting MS criteria at a later date, and this prognosis correlates with the number and anatomical sites of the lesions. 20 Conversely, patients with monofocal clinical presentation and no MRI lesions (type 3 CIS) have a relatively low risk of developing MS. 22 It was also noted that type 4 CIS (multifocal presentation with no MRI lesions) is probably rare and highlights the importance of a comprehensive differential diagnosis. 16 Type 5 CIS is of particular interest. This classification describes individuals who have no obvious clinical signs and symptoms but have incidental MRI scans showing abnormalities that are highly suggestive of MS lesions. The terms "radiologically isolated syndrome" (RIS) and "subclinical MS" have also recently been used to describe this situation, and identification of patients who fit into this category has increased with expanding use of MRI. 28,29 In a short report describing 4 individuals whose "accidental MRI findings" suggested the presence of MS-like lesions but who were asymptomatic or had nonspecific clinical symptoms, all patients had some neurological deficits (measured either at a baseline evaluation or at a longer follow-up) that were consistent with those reported in patients with MS. 29 This small study utilized several validated neuropsychological instruments (e.g., Modified Card Sorting Test [MCST]) to evaluate attention/concentration and or executive function. In addition, 2 of 3 patients analyzed had oligoclonal bands detected in their CSF, 2 had an elevated immunoglobulin G (IgG) index, and 2 had VEP latency in 1 eye. Four years after the initial MRI scans, 1 of these individ-

Treatment of Patients with CIS: Overview of Clinical Trials
Glatiramer acetate and formulations of IFNβ are immunodulators used as first-line DMTs for the treatment of MS. The overall efficacy and safety of these agents have been described in detail in Ryan et al. (2009). 12 This supplement is designed to provide a specific overview of the use of glatiramer acetate and IFNβ in patients with CIS. Natalizumab and mitoxantrone, which are currently approved only as second-line therapies for MS, are not addressed in detail in this supplement. One of the important questions in MS management is whether early treatment in patients with CIS delays the development of a second clinical event (and therefore a diagnosis of CDMS). To date, 4 randomized, placebocontrolled, phase III clinical trials have been completed using glatiramer acetate or IFNβ formulations that have specifically addressed this question, and at least 1 additional study -Rebif (IFNβ-1a) FLEXible Dosing in Early MS (REFLEX) -is ongoing. Key patient demographics and results from the completed CIS studies are summarized in Table 5. All of the clinical trials in patients with CIS showed statistically significant reductions (39% to 50%) in the risk of developing CDMS when early treatment was initiated. [42][43][44][45] In addition to the probability of developing CDMS, a primary efficacy endpoint in 3 of the studies was the time to conversion to CDMS. In the PreCISe (Study to Evaluate the Effect of Early Glatiramer Acetate [Copaxone] Treatment in Delaying the Conversion to CDMS of Subjects Presenting with a CIS) 42 and BENEFIT (Betaseron [IFNβ-1b] in Newly Emerging MS for Initial Treatment) 43 trials, the 25th percentile time to development of CDMS was prolonged in the active-treatment compared with placebo groups by 115% (722 days vs. 336 days, P < 0.001) and 142% (618 days vs. 255 days, P < 0.001), respectively. In the Early Treatment of MS Study (ETOMS), the 30th percentile time to CDMS was significantly increased by 122% in the IFNβ-1a arm (569 days vs. 252 days, P = 0.034). 45 In all 4 of the CIS trials, there also were significant reductions in either the number patients with established MS, brain MRI with Gd-enhancement should only be considered every 1 to 2 years in individuals with subclinical disease activity but is recommended in patients with unexpected clinical worsening. 34 While conventional MRI has provided the framework for diagnosis and monitoring of patients with MS and contributed significantly to our understanding of the pathophysiology underlying MS, it has some recognized limitations. Conventional MRI sequences have a relatively weak correlation to clinical status, low sensitivity to grey matter involvement and diffuse white matter damage, and limited ability to predict clinical progression. 35,36 Additionally, prolonged T2 relaxation identifies areas with tissue injury, and Gd-enhancement indicates when there is breakdown of the BBB, but neither quantifies the degree of tissue damage. 37 To address these issues, alternative imaging methodologies are currently being used or are in various stages of clinical development. Table 4 provides an overview of some newer approaches and their potential utility in patients with MS. These technologies have also been the subject of several recent comprehensive review articles to which the reader is referred for more details. [35][36][37][38][39][40] It is important to note that the MRI field strength used can have a significant influence on the classification of patients with CIS and MS using current diagnostic criteria.  41 Advances in imaging technologies can be expected to facilitate the diagnosis and monitoring of patients with MS, to improve our understanding of the underlying pathophysiology, and to assist in new drug development. How these new approaches will be used to complement conventional MRI and how they will be incorporated into clinical practice guidelines are still to be determined. individuals with a first clinical event suggestive of MS. More than 500 patients with a recent isolated demyelinating event (e.g., optic neuritis, myelopathy, or brainstem syndrome) and who had brain MRI scans consistent with early MS have been randomized to receive IFNβ-1a (as subcutaneous (SC) injections in one of two dosing schedules -44 mcg 3 times a week or once weekly) or placebo. Patients will be treated for 24 months, or up to the time when they experience a second attack leading to a diagnosis of CDMS. The REFLEX trial completed enrollment in 2008; result data are not yet available. Long-term follow-up of the REFLEX study will be conducted in an extension trial known as RELEXION (www.clinicaltrials.gov).

Key Implications of Clinical Trials for Managed Care Pharmacists
The results of all completed CIS trials and extension analyses provide strong clinical evidence that early treatment with glatiramer acetate or IFNβ significantly prolongs the time to conversion or progression to CDMS and also delays the development of physical disability. Thus, it is generally recommended that patients with CIS be treated at the time of diagnosis or first attack. 10,49,50 This recommendation is supported by the National Clinical Advisory Board of the National MS Society, which states: "Initiation of treatment with an interferon-beta medication or glatiramer acetate should be considered as soon as possible following a definite diagnosis of MS with active, relapsing disease, and may also be considered for selected patients with a first attack who are at high risk of MS." 51 The U.S. Food and Drug Administration approved labels for 3 of the available IFNβ-1 formulations (Avonex, Betaseron, Extavia), and glatiramer acetate (Copaxone) also include indications for patients with CIS (i.e., a first clinical episode and MRI consistent with MS). Disability in patients with MS is associated with increased health care costs. Turpcu and Yu (2008) conducted an analysis of and/or volume of brain lesions seen on MRI. [42][43][44][45] Because of favorable results at interim analyses, the placebo arms of both the PreCISe and CHAMPS (Controlled High-Risk Subjects [IFNβ-1a] Avonex Multiple Sclerosis Prevention Study) trials were closed early, and all patients were then offered open-label treatment with the active drug. 42,45 Since the studies described above were only 2 to 3 years in duration, the effects of continued DMT on the long-term risk for developing CDMS remained unclear. Two of the initial CIS studies, CHAMPS and BENEFIT were extended for longer time periods to address this question. In both the CHAMPIONS (CHAMPS extension) and BENEFIT extension studies, patients originally randomized to active treatment were continued on the same protocol ("early or immediate" treatment groups), and those who received placebo after the original randomization were then switched to open-label active drug ("delayed" treatment groups). In both extension analyses, early treatment resulted in significantly fewer patients developing CDMS. In CHAMPIONS, the risk of developing CDMS at 5 years was reduced by 43% in the immediate treatment compared with delayed treatment group (P = 0.030). 46 In the BENEFIT extension, a 41% risk reduction for developing CDMS was observed in the immediate treatment versus the delayed treatment group at 3 years (P = 0.001). 47 Early treatment also significantly reduced the risk for progression of disability by 40% as measured by the Expanded Disability Status Scale (EDSS) (P = 0.022). 47 The 5-year data from BENEFIT were recently published (September 2009): early treatment with IFNβ-1b delayed the onset of CDMS by 37% (P = 0.003), confirming continuous benefit at 5 years after treatment initiation in patients with CIS. 48 The international REFLEX study is evaluating the effect of a new IFNβ-1a formulation on the time to conversion to MS in  cardiotoxicity, so cumulative dose limits are specified. 57 In addition, all currently approved agents for MS are administered parenterally, and tolerability and adherence are important considerations in patients using injectable medications. Thus, the need exists for development of new drugs for MS with different mechanisms of action, routes of administration, improved clinical efficacy, and more favorable safety profiles. [58][59][60] More than 100 clinical trials of novel strategies in patients with MS are listed on the National MS Society website (www. NMSS.org). The majority of medical therapies in advanced stages of clinical development target peripheral immune mechanisms that predominate in early stage disease -these therapies are oral agents or monoclonal antibodies. In addition, neuroprotection and/or neuroregeneration, as well as improved management of comorbid symptoms, remain as desired therapeutic goals. 58-60 A list of selected investigational agents for MS and their mechanism of action is provided in Table 6; these are discussed in greater detail below.

Oral Agents
There has been considerable interest in developing oral medications for MS. All of the oral agents discussed have recently completed or are currently in phase III evaluation.
Cladribine. Cladribine (2-chloro-2'-deoxyadenosine) is an adenosine-deaminase resistant purine nucleoside analogue that preferentially depletes lymphocytes. This agent currently has several approved indications in oncology for lymphoid malignancies. 61 A number of cladribine studies have been conducted in patients with MS that have been reviewed. 62 Three major MS studies used the relationship between total cost of care and the level of disability based on a meta-analysis of MS pharmacoeconomic studies published from 1966 to 1997 (Figure 2). 52 Both direct and indirect costs of care increased with increasing levels of disability as measured by EDSS scores. With the introduction of DMTs, direct costs now make up a greater percentage of total costs of MS, but indirect costs still remain relatively high. The authors noted that DMTs may help avoid the high costs associated with greater levels of disability. 52 Based on cost data published by Kobelt et al. (2006), 53 Burks (2008) has suggested that early initiation of DMTs in patients with CIS or MS may reduce the overall cost of care by delaying the development of disability (Figure 3). 11 Data from a study recently conducted in Italy are consistent with this finding. These data showed that early use of a DMT in patients with CIS that delayed conversion to CDMS provided a positive incremental cost-effectiveness ratio (ICER) per patient-year compared with no treatment. 54

Emerging Therapies for MS
Although several immunomodulatory agents are available for treatment of MS, these agents reduce relapses only by about 30%. 55 Responses may be influenced by a number of factors, including patient-specific disease characteristics and/or genetics. The immunosuppressive agents natalizumab and mitoxantrone are very effective for reducing MS relapses but can be associated with significant toxicities. For example, natalizumab is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML). 56 Mitoxantrone can cause   more clinically silent lesions on MRI. Subjects will be randomized (1:1:1) to receive 3.5 mg per kg or 5.25 mg per kg cladribine tablets (or matching placebo) administered as 2 or 4 short courses (0.875 mg per kg per course) in 2 or 4 consecutive months during the first year. In year 2, subjects receive 2 additional short treatment courses. In participants who develop CDMS according to McDonald criteria, blinded medication will be discontinued, and maintenance therapy initiated with SC IFNβ-1a. Following the initial 2-year treatment period, CDMS-free patients can enroll in a 2-year maintenance follow-up period where they can receive open-label cladribine if they present with MRI activity. This clinical trial will provide insight into the sustained effects of early cladribine treatment of patients with CIS. 65 Fumarate. BG000012 is an oral formulation of dimethyl fumarate that appears to have multiple novel effects on the immune system in patients with MS. This agent may have both anti-inflammatory and neuroprotective effects. [66][67][68] In a phase IIb study, 257 patients with RRMS were randomized (1:1:1) to receive 1 of 3 oral doses of BG00012 (120 mg once daily, 120 mg 3 times daily, or 240 mg 3 times daily) or placebo for 24 weeks. 69 The primary efficacy outcome was the number of new Gd-enhancing MRI lesions from weeks 12 to 24. Additional endpoints included new or enlarg-an injectable form of the drug, which was found to reduce (a) the number and volume of T1 Gd-enhancing lesions, (b) T2 lesion volume, (c) relapse rates, and (d) progression of disability. An oral formulation of cladribine has also been developed that has been evaluated in patients with relapsing forms of MS, both as monotherapy or in combination with IFNβ-1a. 62 Data from the phase III CLARITY study (CLAdRIbine tablets Treating MS orallY) were released in 2009. Patients with RRMS (n = 1,326) were randomized (1:1:1) to receive 1 of 2 doses of oral cladribine or placebo for 2 years. For the cladribine-tablet groups, subjects received either 2 or 4 courses of 0.875 mg per kg given over 4-5 consecutive days in the first year, then 2 treatment courses in the second year. For the primary efficacy endpoint of relapse rates at 96 weeks, 58% and 55% reductions were seen in the lower dose and higher dose cladribine groups versus placebo, respectively (P < 0.001). The frequency of adverse events was similar in all 3 treatment groups, except for lymphopenia, which was expected based on cladribine's mechanism of action. The most common adverse events in all 3 groups were headaches and nasopharyngitis. 63,64 Cladribine is also being evaluated in a 4-year phase III study in patients with CIS known as ORACLE (ORAl CLadribine for Early MS). 65 For enrollment eligibility, patients must have 2 or Th1 and Th2 lymphocytes and cytokine production toward a Th2-pattern and inhibiting migration of lymphocytes into the CNS. 73 Laquinimod is pharmacologically distinct from and has a more favorable benefit/risk profile than linomide, a structurally related compound that had previously reached phase III studies in patients with MS. In a 24-week phase II study of patients with relapsing MS (n = 209), the group treated with oral laquinimod at 0.3 mg per day had 44% fewer active lesions on MRI compared with placebo (P = 0.050). Subgroup analysis showed that this reduction was more pronounced in patients with at least 1 active lesion at baseline (52% fewer active lesions; P = 0.005). 74 However, in a subsequent 36-week phase IIb trial comparing laquinimod at 0.3 and 0.6 mg per day with placebo in patients with RRMS (n = 306), only the 0.6 mg dose group had a significant reduction (40.4%) in the number of Gd-enhancing lesions on MRI scans (P = 0.005). One of the key safety considerations with this agent was transient and dose-dependent increases in hepatic enzymes. 75 Teriflunomide. Teriflunomide is the active metabolite of leflunomide, an oral anti-inflammatory drug that is widely used in rheumatoid arthritis. This agent binds to dihydro-orotate dehydrogenase and inhibits de novo pyrimidine synthesis in T lymphocytes and other rapidly dividing cells. 76 In a 36-week study of 179 patients with RRMS or secondary progressive MS (SPMS), subjects received oral teriflunomide at either of 2 doses (7 mg or 14 mg per day) or placebo. 77  ing T2-hyperintense lesions, new T1-hypointense lesions, and relapse rates. In the 240 mg 3 times daily BG00012 dose group, significant reductions compared with placebo were reported for (a) the mean number of Gd-enhancing lesions (P < 0.001), (b) new or enlarging T2-hyperintense lesions (P < 0.001), and (c) new T1-hypointense lesions (P = 0.014). A 32% relative reduction in the annualized relapse rate was seen in the high dose BG00012 group, although the study was insufficiently powered to detect a significant difference for this outcome. Adverse events more frequently observed in BG00012 treatment groups included abdominal pain and flushing. Notably, 25% of patients in the 240 mg 3 times daily BG00012 dose group withdrew from the study or discontinued treatment primarily because of adverse events or lack of tolerance. 69 Fingolimod. Fingolimod (FTY720) has a unique mechanism of action. By binding to sphingosine-1 phosphate type 1 receptors on lymphocytes, this agent stops the cells from sensing signals to egress from lymphoid tissue. 70 In a proof-of-concept trial, 281 patients with relapsing MS were randomized (1:1:1) to receive oral fingolimod at 1.25 or 5.0 mg per day or placebo for 6 months. 71 For the 255 patients who completed the study, the total number of Gd-enhancing lesions on MRI and the annualized relapse rate were significantly lower in both fingolimod dose groups compared with placebo (P ≤ 0.010). Dyspnea, diarrhea, nausea, and asymptomatic elevations of alanine aminotransferase were more frequent in the fingolimod treatment groups. 71 In a 24-month phase II extension analysis, reductions in the relapse rate and lesion counts were seen in the patient group that switched from placebo to fingolimod (compared with the placebo phase of the trial), while these parameters remained low in patients who had received continuous fingolimod. 72 Laquinimod. The mechanism of action of laquinimod is incompletely understood, but it is thought that this agent exerts its anti-inflammatory activity in MS by shifting the balance of   87,88 In a small study of 9 patients who were evaluated at 3-month intervals, daclizumab was reported to be significantly effective in reducing total and new contrast-enhancing MRI lesions (P < 0.001) when comparing pre-treatment scans (baseline) with scans taken at all treatment intervals over 27.5 months. For secondary outcomes, daclizumab also significantly reduced relapse rates (P < 0.001) and improved both timed ambulation (P < 0.050) and EDSS scores (P < 0.050) over the course of the trial. Adverse events in the daclizumab group included respiratory tract infections, rash, and transient thrombocytopenia. 87 Results from the larger phase II CHOICE trial have only been presented in abstract form. 88 In this study, patients with active MS despite IFNβ therapy (n = 230) were randomized to receive daclizumab 2 mg per kg every 2 weeks (n = 75) or 1 mg every 4 weeks (n = 78) or placebo (n = 77) in addition to IFNβ. At 24 weeks, the number of new or enlarging Gd-enhancing lesions significantly decreased by a mean of 72% in the high-dose daclizumab group (P = 0.004), but only by 25% in the low-dose group (nonsignificant; P = 0.501), compared with placebo plus IFNβ. Adverse events more commonly observed in daclizumab-treated groups included serious infections. 88,89 Rituximab. Approved for more than a decade for the treatment of B-cell lymphoma, rituximab is also being evaluated in patients with RRMS. In a 48-week phase II trial, subjects were randomized to receive rituximab (1,000 mg on days 1 and 15) or placebo. Patients in the rituximab group had significantly fewer total and new Gd-enhancing lesions on MRI (primary endpoint) from weeks 12 to 24 compared with placebo, and these differences were sustained at 48 weeks (P < 0.001 for all time points). The relapse rate was also significantly lower with rituximab treatment at week 24 (14.5% vs. 34.3%, P = 0.020) and week 48 (23.0% vs. 40.0%, P = 0.040). Adverse events that were more common in the rituximab group included infusion-associated events within the 24 hours after the first infusion (78.3% vs. 40.0%), but these were predominantly mild to moderate in severity and decreased on the second infusion. Urinary tract infections (14.5% vs. 8.6%) and sinusitis (13.0% vs. 8.6%) were more frequent in the rituximab group compared with placebo. 90

Key Implications of Emerging Therapies for Managed Care Pharmacists
All medications currently approved for the treatment of MS are administered by SC or IM injection or IV infusion. Many patients have needle phobia or injection anxiety, particularly at the initiation of therapy. 91 Injection-site reactions are also relatively common with SC formulations, although the introduction of autoinjector technologies has made injections easier and improved patient satisfaction. 92 However, the requirement for being on long-term injections places a burden on patients with MS and may lead to reduced adherence that can compromise treatment efficacy.
Oral medications for MS offer the potential of increasing P < 0.040). Fewer patients in the 14 mg teriflunomide group had increases in disability, and a trend was reported for a lower annualized relapse rate and numbers of relapsing patients in the high-dose group versus placebo. Adverse events that were more common in the teriflunomide treatment groups included nausea, paresthesias, and limb pain. 77 Fampridine. Fampridine (4-aminopyridine) is a voltage-dependent potassium channel blocker. 78 This agent is not a DMT but instead targets specific symptoms in MS. Fampridine may restore action potential conduction in poorly myelinated nerve fibers 79 and influence synaptic transmission and neuronal excitability. 80 Fampridine use has been associated with improvements in strength, ambulation, fatigue, and endurance in patients with MS. 81,82 In a randomized phase III study in patients with any type of MS, subjects who received sustained-release fampridine (10 mg twice daily; n = 229) had improved motor function measures compared with the placebo group (n = 72). 83 For example, the number of responders based on a timed-walk measurement was significantly higher after 14 weeks of treatment with fampridine (35% vs. 8% for placebo, P < 0.001). In addition, timed-walk responders showed greater improvement in 12-item MS walking scale scores compared with timed-walk nonresponders (P < 0.001). 83

Monoclonal Antibodies
Alemtuzumab. Alemtuzumab is a humanized monoclonal that targets CD52 on T cells, B cells, and monocytes and leads to rapid immune depletion. 84 This agent was recently compared with IFNβ-1a in a 36-month phase II study of 334 patients with RRMS. 85 Alemtuzumab was given at doses of either 12 mg or 24 mg per day by intravenous (IV) infusion on 5 consecutive days during month 1 and on 3 consecutive days at months 12 and 24. IFNβ-1a was administered at 44 mcg 3 times weekly SC after dose escalation. For the combined group analysis, alemtuzumab was significantly more effective than IFNβ-1a for (a) reducing the rate of sustained accumulation of disability (9.0% vs. 26.2%, P < 0.001, (b) reducing the annualized relapse rate (0.10 vs. 0.36, P < 0.001), (c) decreasing lesion burden based on T2 imaging (P = 0.005), and (d) increasing brain volume (P = 0.020). In addition, the mean EDSS score improved by 0.39 points in alemtuzumab-treated patients and worsened by 0.38 in the IFNβ-1a group (P < 0.001). Adverse events that were more common in the alemtuzumab group included infections (66% vs. 47%), thyroid disorders (23% vs. 3%), and thrombocytopenic purpura (3% vs. 1%). 85 Daclizumab. Daclizumab is a humanized monoclonal that targets the α-subunit (CD25) of the high affinity interleukin 2 receptor (IL-2R), which is expressed on activated lymphocytes. 86 This agent inhibits CD4+ and CD8+ T-cell activation and is currently approved for the prevention of renal transplant rejection. It is being evaluated in patients with RRMS who have had an inadequate response to IFNβ. In 2 phase II studies, daclizumab (1 mg per kg intravenously every 2 weeks for the first 2 doses, then every 4 weeks) was given in combination with IFNβ for the convenience, comfort, and adherence to therapy. The oral treatments have different mechanisms of action, potentially significant adverse effects, and a relative lack of long-term safety data. Thus, the risk-benefit ratio may be not as favorable as that for the existing treatments. An ongoing question is how will formulary decisions be made regarding the new oral medications for MS if they are approved. In addition, consider the theoretical patient with MS who is currently using an injectable medication whose disease is well controlled with no new symptoms or relapses. What if this patient becomes aware of new oral treatment options and wants to switch therapies? Physicians and other health care prescribers will have to perform due diligence in discussing these issues with such patients. How will the decision be made regarding whether a switch is therapeutically appropriate, and should the new medication be covered by insurance? Managed care organizations can also benefit by addressing these critical issues in advance of anticipated new drug approvals.

■■ Summary
One of the ongoing goals in MS management is to improve identification of patients with CIS who will progress to CDMS and are the best candidates for early treatment with a DMT. Several recent advances have been made in the understanding of CIS subtypes and the refinement of MS diagnostic criteria. Imaging technologies other than traditional MRI are also likely to play an increasing role in MS management. Randomized clinical trials have shown that early treatment with glatiramer acetate and IFNβ formulations in patients with a CIS can prolong the time to conversion or progression to CDMS and delay the development of disability. Early treatment of CIS or MS may also decrease longterm health care costs. In addition, a number of new therapies for patients with MS are in late stages of clinical development, including several oral medications, offering promise for the near future but also potential challenges to managed care.