Clinical Management of Multiple Sclerosis:
`The Treatment Paradigm and Issues of Patient Management
`
`WILLIAM H. STUART, MD
`
`ABSTRACT
`
`OBJECTIVE: To summarize the conclusions of an expert panel of neurologists
`specializing in multiple sclerosis (MS) convened for the purpose of creating a
`treatment algorithm with regard to the clinical management of MS. The panel
`was sponsored by the Health Science Center for Continuing Medical Education
`and the University of Medicine and Dentistry of New Jersey and supported by
`an educational grant from Biogen Idec, Inc.
`
`SUMMARY: MS is a chronic demyelinating disease characterized by a variable
`clinical course. Currently, there is no cure for MS, and the management of MS
`requires lifelong treatment with disease-modifying agents. Some patients
`respond well to therapy for many years, whereas others may have aggressive
`disease that is more difficult to manage. Hence, given the variable nature in the
`course of MS and patients’ response to treatment, neurologists must individual-
`ize care for their patients.
`An MS treatment algorithm was recently developed by a panel of neurolo-
`gists who are MS experts to provide community neurologists with best-practice
`protocols for treating and managing their MS patients. The panel of experts
`categorized MS into 3 different stages, with patients transitioning between the
`stages based on their response to therapy and disease progression. Stage I
`represents MS early in the progression of the disease, during which platform
`drug therapy is recommended (i.e., interferon beta-1b [IFNβ-1b], IFNβ-1a, or
`glatiramer acetate). The results of randomized, controlled clinical trials suggest
`that IFNβ is the optimal choice for platform therapy. Despite treatment with plat-
`form therapy, it is common for patients to experience some ongoing symptoms
`and periodic exacerbations of the disease (annual relapse rate of 0.59 to 0.84
`on treatment); such relapses should not be considered treatment failures and
`are best managed with steroids. Stage II represents acute breakthrough disease
`(i.e., when the clinical activity becomes more frequent or severe). This stage is
`best managed by the addition of pulse corticosteroids to the platform drug.
`Stage III represents continued breakthrough disease and is best managed by
`the addition of immunosuppressants to the platform drug.
`
`CONCLUSION: The MS treatment algorithm provides an educational resource for
`physicians. It should assist all health care professionals involved in the manage-
`ment of MS patients and enhance their ability to improve quality of life for these
`patients over the course of the disease.
`
`KEYWORDS: Multiple sclerosis, Breakthrough disease, Treatment algorithm
`
`J Manag Care Pharm. 2004;10(3)(suppl S-b):S19-S25
`
`sclerosis (MS):
`
`F our different clinical courses have been defined in multiple
`
`• a relapsing-remitting form (RRMS), which is the most common
`(85%) and generally the presenting form of the disease;
`• a secondary progressive form that generally develops in
`patients suffering from RRMS;
`• a primary progressive form (10%) characterized by steady
`decline in function; and
`• a progressive-relapsing form (5%) that begins with a progres-
`sive course characterized by occasional attacks.1,2
`Figure 1 depicts the typical progression of MS if untreated.
`The first treatment for MS demonstrating clear medical benefit
`was reported in 1952 and involved the use of corticotropin, which
`enhanced recovery from relapse.3 More recent developments have
`involved immunomodulatory agents such as interferon beta-1b
`(IFNβ-1b); 2 different formulations of IFNβ-1a; glatiramer acetate;
`and mitoxantrone, which is generally reserved for the more pro-
`gressive forms of the disease because of toxic adverse effects. All of
`the agents approved for the treatment of RRMS have been shown
`to reduce relapse rates in large-scale, randomized, double-blind,
`placebo-controlled, prospective studies.4-7 Additionally, both
`IFNβ-1a products have been shown to reduce sustained disability
`progression in relapsing MS6,7 and decrease progression to clini-
`cally definite MS when administered during the early phases of the
`disease.8,9
`Despite the availability of treatments with demonstrated effica-
`cy, approximately 45% of patients with relapsing MS in the United
`States are not currently receiving disease-modifying therapies
`
`FIGURE 1 Progression of Untreated Multiple Sclerosis
`
`Author
`
`WILLIAM H. STUART, MD, is medical director, Multiple Sclerosis Center of
`Atlanta, Georgia.
`
`AUTHOR CORRESPONDENCE: William H. Stuart, MD, Medical Director,
`Multiple Sclerosis Center of Atlanta, Peachtree Neurological Clinic,
`3200 Downwood Circle, Suite 55, Atlanta, GA 30327. Tel: (404) 351-0205;
`Fax: (404) 351-4187; E-mail: whstuart@aol.com
`
`Copyright© 2004, Academy of Managed Care Pharmacy. All rights reserved.
`
`.
`MRI = magnetic resonance imaging; Gd+ = gadolinium-enhanced.
`
`www.amcp.org Vol. 10, No. 3, S-b June 2004 JMCP Supplement to Journal of Managed Care Pharmacy S19
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`Mylan Pharms. Inc. Exhibit 1041 Page 1
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`Clinical Management of Multiple Sclerosis: The Treatment Paradigm and Issues of Patient Management
`
`TABLE 1
`
`Expanded Disability Status Scale13
`Score Description
`
`of this expert panel with regard to the clinical management of MS
`and to introduce the proposed treatment algorithm.
`
`0.0
`1.0
`1.5
`2.0
`2.5
`3.0
`
`3.5
`
`4.0
`
`4.5
`
`5.0
`
`5.5
`6.0
`
`6.5
`
`7.0
`
`7.5
`
`8.0
`
`8.5
`
`9.0
`9.5
`10.0
`
`Normal neurologic examination
`No disability, minimal signs on 1 of 7 functional systems*
`No disability, minimal signs on 2 functional systems
`Minimal disability in 1 functional system
`Minimal disability in 2 functional systems
`Moderate disability in 1 functional system or
`Mild disability in 3–4 functional systems, although fully ambulatory
`Fully ambulatory but with moderate disability in 1 functional system
`and mild disability in 1–2 functional systems or
`Moderate disability in 2 functional systems or
`Mild disability in 5 functional systems
`Fully ambulatory without aid, up and about 12 hours a day despite
`relatively severe disability; able to walk 500 meters without aid
`Fully ambulatory without aid, up and about much of day, able to work a
`full day, may otherwise have some limitations of full activity or require
`minimal assistance
`Relatively severe disability; able to walk 300 meters without aid
`Ambulatory without aid for about 200 meters; disability impairs full daily
`activities
`Ambulatory for 100 meters; disability precludes full daily activities
`Intermittent or unilateral constant assistance (cane, crutch, or brace)
`required to walk 100 meters with or without resting
`Constant bilateral support (canes, crutches, or braces) required to walk
`20 meters without resting
`Unable to walk beyond 5 meters even with aid; essentially restricted to
`wheelchair, wheels self, transfers alone; active in wheelchair about
`12 hours a day
`Unable to take more than a few steps, restricted to wheelchair, may need
`aid to transfer; wheels self, but may require motorized chair for full day’s
`activities
`Essentially restricted to bed, chair, or wheelchair but may be out of bed
`much of the day; retains self-care functions; generally effective use of arms
`Essentially restricted to bed much of the day, some effective use of arms,
`retains some self-care functions
`Helpless bed patient, can communicate and eat
`Unable to communicate effectively or eat/swallow
`Death
`
`* Functional systems are pyramidal, cerebellar, brainstem, sensory, bowel and bladder,
`visual, cerebral, and other.
`
`(DMTs).10 This “treatment gap” could represent 180,000 individuals,
`based upon estimates that 400,000 people suffer from MS in the
`United States.11 Although the American Academy of Neurology
`(AAN) and the National Multiple Sclerosis Society state the impor-
`tance of treating MS early upon diagnosis, no comprehensive
`guidelines on the treatment of MS factor-in the variability of dis-
`ease course. Consequently, a need exists for recommendations that
`will assist health care providers in the management of MS by pro-
`viding a set of best-practice protocols.
`A treatment algorithm has been developed based upon the con-
`sensus of a panel of 15 neurologists with extensive experience in
`treating MS patients (hereafter referred to as the expert panel).
`Sponsored by the Health Science Center for Continuing Medical
`Education and the University of Medicine and Dentistry of New
`Jersey and supported by an educational grant from Biogen Idec
`Inc., the expert panel’s express purpose was to develop a treatment
`consensus for MS to be collated in the form of a treatment algo-
`rithm. The objective of this article is to summarize the conclusions
`
`II Evaluating Multiple Sclerosis Therapies
`
`Two types of immunomodulatory therapies may be used as first-
`line treatment for patients with RRMS: IFNβ products (IFNβ-1b,
`intramuscular (IM) IFNβ-1a (IM IFNβ-1a [Avonex, Biogen Idec
`Inc., Cambridge, MA]), or subcutaneous (SC) IFNβ-1a (SC IFNβ-
`1a [Rebif, Serono, Inc., Rockland MA]), and glatiramer acetate.
`For treatment decisions, physicians must consider the efficacy of
`each agent in terms of sustained disability, relapse rate, lesion load,
`brain atrophy, and cognitive function.12 In addition, the physician
`may consider that some therapies, such as IM IFNβ-1a and SC
`IFNβ-1a, may reduce the relative risk of progression to clinically
`definite MS when initiated during the early stages of MS.8,9
`Furthermore, the efficacy of each agent must be weighed against
`potential side effects, the risk for immunogenicity, and whether the
`dosing regimen fits into the patient’s lifestyle (i.e., the likelihood
`that patients will be compliant with the medication). Individual
`variability in clinical course and symptoms further complicate
`treatment choice.
`In order to assist physicians with MS therapy selection, the
`expert panel developed a treatment algorithm using evidence-
`based evaluations of the results of pivotal studies assessing each
`DMT as a treatment for relapsing MS. The results of these trials,
`each of which was a randomized, double-blind, placebo-controlled
`multicenter study, are briefly summarized in the following sections.
`
`Sustained Disability
`In the pivotal phase III studies of each DMT, sustained disability
`was defined as a worsening of ≥1.0 point on the Expanded
`Disability Status Scale (EDSS)13 either for a period of 6 months (IM
`IFNβ-1a) or a less stringent, 3 months (all other agents) (Table 1).
`In the pivotal phase III trial of IFNβ-1b, performed by the IFNB
`Multiple Sclerosis Study Group, treatment with IFNβ-1b 8 million
`international units subcutaneously every other day produced a
`29% reduction in the progression of sustained disability at 3 years
`compared with placebo; however, this benefit was not statistically
`significant.4 In contrast, both formulations of IFNβ-1a have been
`shown to significantly reduce the progression of sustained disabil-
`ity in patients with MS. In the pivotal phase III trial of IM IFNβ-1,
`which was conducted by the Multiple Sclerosis Collaborative
`Research Group, 30 mcg of IM IFNβ-1a once weekly significantly
`reduced disability progression by 37% compared with placebo
`after 2 years of treatment (P = 0.02).6 The pivotal phase III trial of
`SC IFNβ-1a, performed by the Prevention of Relapses and
`Disability by Interferon-β-1a Subcutaneously in Multiple Sclerosis
`(PRISMS) group, evaluated the efficacy of 2 different dosages of
`SC IFNβ-1a (22 or 44 mcg 3 times weekly). At 2 years, significant
`reductions in the progression of sustained disability were observed
`for both SC IFNβ-1a 22 mcg (22%) and 44 mcg (30%) compared
`with placebo (P<0.005).7
`
`S20 Supplement to Journal of Managed Care Pharmacy JMCP June 2004 Vol. 10, No. 3, S-b www.amcp.org
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`Clinical Management of Multiple Sclerosis: The Treatment Paradigm and Issues of Patient Management
`
`The results of the 2-year pivotal study of glatiramer acetate
`were published in 1995,5 with a follow-up report describing
`results of an 11-month extension period published in 1998.14 The
`initial study indicated that there was no significant effect on pro-
`gression to sustained disability.5 Post hoc analysis of the extension
`trial results revealed a significant decrease in the EDSS score with
`glatiramer acetate treatment.14 However, these latter data should be
`interpreted with caution because post hoc analyses are subject to
`bias and the investigators used atypical statistical analysis methods
`and the less stringent definition of sustained disability (≥1.5-point
`worsening of the EDSS score for 3 months).
`
`Relapse Rate
`Pivotal trials have demonstrated that treatment with each DMT
`significantly reduces annual relapse rates in MS. The magnitude of
`reduction has been shown to be very similar (approximately 30%)
`among DMTs.4-7 A significant effect of IFNβ was apparent in the
`first year of therapy in several studies.7,15
`
`Lesion Load
`Historically, there has been a lack of guidelines and consensus on
`the role of magnetic resonance imaging (MRI) in MS. Its use in
`evaluating the progression of MS is attractive because MRI allows
`a direct examination of a pathological process in the central nerv-
`ous system indicative of disease that can potentially be followed
`serially over a period of time.16 Serial MRI detection of disease
`activity in relapsing forms of MS seems to be significantly more
`sensitive than clinical evidence of disease progression.17-19 A report
`of the Therapeutics and Technology Assessment Subcommittee of
`AAN has recommended the use of MRI for the diagnosis of MS.20
`This recommendation was based upon prospective studies indi-
`cating that the finding of ≥3 T2 lesions at baseline is a very sensi-
`tive predictor of subsequent development of MS. Additionally, the
`committee concluded that the presence of ≥2 gadolinium-enhanc-
`ing (Gd+) lesions at baseline or the appearance of new T2 or Gd+
`lesions on follow-up MRI scans is also predictive of the develop-
`ment of clinically definite MS. For more details on the role of MRI
`assessments in the management of patients with MS, see the arti-
`cle by James R. Miller in this supplement.
`Several MRI end points, including the number and volume of
`Gd+ lesions, the number and volume of T2 lesions, the number of
`new or enlarging T2 lesions, and the volume of T1 hypointense
`lesions, have been studied in multiple trials of DMTs.6, 21-26 The
`major difference between treatments was that, although IFNβ and
`glatiramer acetate reduce Gd+ lesions, which is a marker of active
`inflammation and breakdown of the blood–brain barrier, IFNβ
`products have a more profound effect (82% to 89% reductions)
`compared with glatiramer acetate (29% to 35% reductions).27
`Additionally, the benefit of IFNβ on Gd+ MRI activity is evident
`within 2 weeks, whereas the effect of glatiramer acetate is consid-
`erably less rapid.28
`In the MS treatment algorithm, MRI scans are recommended to
`
`TABLE 2
`
`Adverse Event
`
`Immunomodulatory Adverse Events*
`That May Compromise Compliance34-37
`Therapy, n
`(Drug/Placebo)
`IFNβ-1a-
`IFNβ-1a-
`Avonex Rebif 44 mcg
`351/333
`184/187
`
`IFNβ-1b
`1,115/789
`
`Glatiramer
`Acetate
`201/206
`
`Injection-site reactions
`
`85%/29%
`
`3%/1%
`
`92%/39% 66%†/19%†
`
`Flu-like symptoms
`
`60%/41% 49%/29% 59%/51%
`
`19%/17%
`
`Depression
`
`Fatigue
`
`Chest pain
`
`Pain
`
`NA
`
`NA
`
`18%/14% 25%/25%
`
`NA
`
`41%/36%
`
`NA
`
`NA
`
`11%/7%
`
`5%/2%
`
`8%/5%
`
`51%/42% 23%/21%
`
`NA
`
`21%/11%
`
`28%/25%
`
`Leukopenia
`
`SGPT increased
`
`NA
`
`10%/4%
`
`NA
`
`NA
`
`36%/14%
`
`27%/4%
`
`NA
`
`NA
`
`NA
`17%/4%
`NA
`3%/1%
`SGOT increased
`IFNβ = interferon beta; SGOT = serum glutamate oxaloacetate transaminase;
`SGPT = serum glutamate pyruvate transaminase.
`* Incidence of ≥2% higher frequency in drug-treated patients than placebo.
`† Injection site erythema.
`
`confirm diagnosis and rule out other pathologies. Annual MRI
`scans are also recommended for the management of ongoing MS
`to monitor disease progression and reveal underlying pathology.
`MRI may provide valuable information leading to therapy modifi-
`cation. Additionally, periodic MRI to monitor spinal cord lesions
`should also be considered. Increasing evidence suggests that MRI
`for monitoring of spinal cord lesions, especially spinal cord atro-
`phy, is useful for the evaluation of primary disease and may corre-
`late with progression of disability.29 Given the value of MRI in the
`management of MS, the expert panel strongly recommended that
`insurance coverage be provided for follow-up MRI scans.
`
`Brain Atrophy
`Brain atrophy has been examined using MRI scans in patients who
`received IFNβ. A post hoc analysis of data from the pivotal phase
`III trial of IM IFNβ-1a found a significant reduction in brain atro-
`phy during the second year of treatment.30 The results of a recent
`open-label study found that IFNβ-1b slowed brain atrophy pro-
`gression during the second and third years of treatment.31
`However, an examination of MRI scans from a trial using
`SC IFNβ-1a did not find a significant effect on brain atrophy,
`despite improvements in other MRI and clinical parameters.32
`
`Neutralizing Antibodies
`IFNβs have been shown to have similar incidences of neutralizing
`antibodies (NAbs) in numerous studies. NAbs have been shown to
`reduce the clinical efficacy of IFNβ.33 The incidence of NAbs is
`higher with IFNβ-1b treatment (45% of patients)34 compared with
`IFNβ-1a products. In addition, the incidence of NAbs is higher
`
`www.amcp.org Vol. 10, No. 3, S-b June 2004 JMCP Supplement to Journal of Managed Care Pharmacy S21
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`Mylan Pharms. Inc. Exhibit 1041 Page 3
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`

`
`Clinical Management of Multiple Sclerosis: The Treatment Paradigm and Issues of Patient Management
`
`FIGURE 2 Treatment Outline for Multiple Sclerosis
`
`IFNβ = interferon beta.
`
`with SC IFNβ-1a (24%)35 compared with IM IFNβ-1a (5%) treat-
`ment.36 More details on the development of NAbs to DMTs and the
`implications for clinical practice are provided by Howard S.
`Rossman in this supplement.
`The expert panel recommended that patients at high risk for
`NAbs (i.e., those on a more immunogenic product) be tested for
`NAbs after the first year of treatment, and, if the test results are pos-
`itive, these patients should be retested after another 6 months of
`treatment to confirm NAb status. Patients on a less immunogenic
`product should be tested if they experience disease progression. In
`patients who are NAb-positive, physicians may choose to switch the
`patient to an alternative therapy or to continue with the same treat-
`ment and have the patient undergo retesting in another 6 months.
`
`Side Effects and Compliance
`Successful long-term treatment of MS requires patient compliance
`throughout the course of the patient’s life. Compliance is affected
`by multiple issues, including side effects, frequency of administra-
`tion, perceived efficacy, self-esteem, level of disability, treatment
`convenience, and the support provided by family and health care
`providers.
`DMTs have several side effects that can have a negative impact
`on compliance. For example, injection-site reactions, flu-like
`symptoms, fatigue, chest pain, leukopenia, and elevated hepatic
`enzyme levels occur to varying degrees with these agents (Table
`2).34-37 The most common events are injection-site reactions, which
`occur more frequently with the SC route of administration. Local
`injection-site reactions are a significant issue because necrotizing
`lesions can occur following SC delivery; patients may be unable or
`unwilling to take therapy on a regular basis. Flu-like symptoms
`also occur frequently and are more common during treatment
`with IFNβ versus glatiramer acetate. Approximately 10% of
`patients treated with glatiramer acetate experience a postinjection
`reaction. The symptoms are generally transient and self-limiting
`and may include flushing, chest pain, palpitations, anxiety, dysp-
`nea, constriction of the throat, and urticaria. The product labeling
`for all 3 IFNβ products includes a warning that IFNβ should be
`
`used with caution in patients with depression or severe psychiatric
`symptoms because depression, suicide ideation, and suicide
`attempts have been reported to occur with increased frequency in
`patients receiving IFNβs.34-36 Glatiramer acetate product labeling
`does not contain such a warning.37
`One study that directly compared the 2 formulations of IFNβ-
`1a found that IM IFNβ-1a was associated with a significantly
`lower rate of side effects compared with SC IFNβ-1a. These side
`effects included injection-site disorders (28% versus 83%), liver
`function abnormalities (9% versus 18%), white blood cell abnor-
`malities (5% versus 11%), and lymphopenia (<1% versus 4%).38
`In another comparative study, IFNβ-1b and IM IFNβ-1a were sim-
`ilarly well tolerated, with the exception of a higher incidence of
`injection-site reactions in IFNβ-1b patients compared with
`IM IFNβ-1a patients (37% versus 8%).39 Physicians and patients
`should be aware of and aggressively manage side effects of DMTs.
`This will help to improve compliance with the MS therapy.
`
`II The Physician Treatment Algorithm
`
`Because there is no cure for MS to date, patients and physicians
`need realistic expectations concerning the efficacy of MS therapies.
`Given the multifactorial and heterogeneous nature of MS, each
`patient will respond differently to treatment. Many patients
`respond well to treatment for years, while others may have aggres-
`sive disease, and although initially responsive to therapy, the dis-
`ease eventually progresses. Furthermore, there is no way to predict
`in advance which patients will respond to treatment and for how
`long, highlighting the importance of patient monitoring. The fol-
`lowing sections summarize the expert panel’s recommendations
`for the management of MS throughout the course of the disease,
`categorized into 3 different stages (Figure 2).
`
`Stage I: Maintenance
`Selection of platform therapy. In the development of the MS
`treatment algorithm, a platform therapy has been defined as an
`agent that will provide baseline immunomodulatory action. The
`agent should be a first-line treatment of choice that can be admin-
`istered for an extended period because of the chronic nature of
`MS. The physician’s choice should be based on a balance between
`several factors, including efficacy; incidence of NAbs (in the case
`of IFNβ therapy); side effects; the potential for combination ther-
`apy with other agents should the clinical course dictate; and
`patient compliance, which can be influenced by the agent’s suit-
`ability to the patient’s lifestyle.
`The MS treatment algorithm recommends IFNβ therapy as the
`optimal choice for platform therapy (i.e., the agent to be used
`when initiating treatment in patients presenting with RRMS). This
`recommendation is based upon the efficacy, tolerability, and
`immunogenicity data previously reviewed (see “Evaluating
`Multiple Sclerosis Therapies”). The ideal IFNβ platform therapy
`would be one that has been shown to significantly slow the pro-
`gression of sustained disability, reduce the relapse rate and MRI
`
`S22 Supplement to Journal of Managed Care Pharmacy JMCP June 2004 Vol. 10, No. 3, S-b www.amcp.org
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`Clinical Management of Multiple Sclerosis: The Treatment Paradigm and Issues of Patient Management
`
`lesion activity, and reduce brain atrophy. In addition, the platform
`therapy should be associated with a low risk for developing NAbs,
`a low incidence of side effects, including injection-site reactions,
`and a convenient dosing schedule.
`Relapse management. The use of platform therapies reduces
`but does not eliminate relapses in RRMS.4-7 Regardless of the treat-
`ment, patients are apt to have relapses or acute exacerbations of
`the disease. This does not signify treatment failure. In the pivotal
`studies, annual relapse rates were significantly lower among
`patients treated with DMTs relative to placebo-treated patients but
`still ranged from 0.59 to 0.84 relapses per year on treatment.4-6
`Several factors are important to consider in relapse manage-
`ment. First, relapses may be the result of poor compliance with
`the MS therapy, underscoring the need for physicians to carefully
`monitor patient adherence. Second, it is essential to distinguish
`between disease worsening and a pseudo-relapse because of the
`symptoms of MS, which may mimic a relapse when not adequate-
`ly managed. Physicians must monitor patients for symptoms and
`must educate them to self-monitor and communicate with their
`physician and nurse team on an ongoing basis. Aggressively man-
`aging the symptoms of MS should enhance patient compliance
`with therapy and reduce unnecessary switching of medications.
`Physicians should consider managing these initial relapses
`(while on a platform therapy) with corticosteroids. For example,
`intravenous (IV) methylprednisolone 1 g/day may be adminis-
`tered over 3 to 5 days. Some physicians may prefer an oral taper
`after IV methylprednisolone (e.g., prednisone or oral methylpred-
`nisolone over 6 to 12 days). IV dexamethasone 160 to 180 mg/day
`may also be used followed by an oral taper. Corticosteroid use
`should be adjusted based on patient tolerance.
`
`Stage II: Acute Breakthrough Disease
`Breakthrough disease represents MS in its more progressive stages.
`There is variability among physicians on the precise definition of
`breakthrough disease; however, in clinical trials of MS therapies,
`breakthrough has been defined based upon the following criteria:
`progression of disability, multiple relapses in a short time span,
`further neurologic deterioration, increased disease burden or
`activity detected by MRI, or newly identified cognitive defects.40-43
`Patients on IFNβ who experience breakthrough disease should
`first be tested for NAbs to make sure that the medication is still
`working. Patients who are NAb-positive should be retested in
`6 months; if test results remain positive on retesting, patients then
`should be switched to a less immunogenic DMT. Patients who are
`NAb-negative should continue treatment with the platform thera-
`py and consider the addition of another therapeutic agent.
`
`Management
`Switching and dose escalation. Once breakthrough occurs, one
`option is to switch to a different agent as the platform therapy.
`However, the rationale for switching to a different agent is lacking
`because no adequately controlled studies have been conducted to
`
`examine its potential benefits and limitations. Despite the ongoing
`debate on the potential benefits of increasing the dose of the plat-
`form therapy, there are no clinical trials reporting the efficacy of
`increasing the dose of an immunomodulatory agent following
`breakthrough disease. Furthermore, there is evidence that increas-
`ing the dose of IFNβ may not provide additional benefit and may
`lead to increased side effects and a higher incidence of NAbs.44-47
`Combination therapy. Breakthrough disease in MS could rep-
`resent a shift to a more neurodegenerative phase of the disease,
`beyond the inflammatory component that platform therapies have
`been targeting. Another option for treating patients with break-
`through disease is to add another agent to the platform therapy
`(i.e., combination therapy). Combination therapy has been effec-
`tive for the treatment of cancer, infectious diseases, and rheumatoid
`arthritis, with dramatically better outcomes than monotherapy.48
`Given these considerations and the heterogeneous nature of MS, it
`is likely that the use of a combination of therapies that complement
`one another will have beneficial effects in patients with MS.48,49
`Patients who are NAb-negative should continue treatment with
`the platform therapy in addition to initiating a pulse treatment
`schedule of corticosteroids (1 g/month or 1 g/day for 5 days every
`4 months), followed by an oral steroid taper.19 Issues to be con-
`sidered in the use of high-dose pulse corticosteroids include short-
`term indigestion, heartburn, exacerbation of peptic ulcers, gas-
`troesophageal reflux, fluid retention, weight gain, and a metallic
`taste in the mouth. In the long term, osteoporosis, diabetes, and
`hypertension must be considered.50-52
`
`Stage III: Continued Breakthrough Disease
`In the face of continued breakthrough disease in patients who are
`NAb-negative, the potential agents for use in combination with
`platform therapy can be separated into 2 general categories: cyto-
`toxic agents and immunomodulatory agents. The rationale for
`using these agents stems from the fact that MS is considered an
`autoimmune disease, and as such, they may slow autoimmune
`destruction. Cytotoxic agents include methotrexate, azathioprine,
`mitoxantrone, cyclophosphamide, mycophenolate mofetil, and
`cladribine; immunomodulatory agents include pulse corticos-
`teroids, IV immunoglobulins, and glatiramer acetate. Some
`additional agents that are currently under investigation for their
`efficacy in MS include anti-infectious agents, antioxidants,
`inhibitors of T-cell activation, natalizumab, and statin drugs.
`Although the use of combination therapy for the treatment
`of MS is still in its infancy, there are numerous recently com-
`pleted and ongoing clinical trials exploring various treatment
`combinations.53 Some of the more commonly used agents
`that have been combined with IFNβ include mitoxantrone,
`cyclophosphamide, and azathioprine.
`
`II Conclusions
`
`While there is no cure for the chronic progressive disease of MS,
`current therapies can modify the course of the disease. The thera-
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`www.amcp.org Vol. 10, No. 3, S-b June 2004 JMCP Supplement to Journal of Managed Care Pharmacy S23
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`Mylan Pharms. Inc. Exhibit 1041 Page 5
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`Clinical Management of Multiple Sclerosis: The Treatment Paradigm and Issues of Patient Management
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`pies selected must be tailored to suit the current status of the
`patient and should be initiated during specific treatment “win-
`dows.” These treatment windows represent stages in the disease
`during which appropriate therapy has the greatest chance to
`significantly alter the course of the disease.
`In order to develop the physician treatment algorithm, the MS
`disease process was categorized into 3 different stages. Patients
`will transition between stages depending upon their response to
`therapy and disease progression (Figure 2). Stage I represents MS
`early in the progression of the disease. Management is recom-
`mended using a platform drug (IM IFNβ-1a, SC IFNβ-1a, IFNβ-
`1b, or glatiramer acetate). Based on the results of pivotal studies,
`IFNβ is the optimal choice for platform therapy. The ideal IFNβ
`platform therapy would have the following characteristics: ability
`to significantly slow disability progression; ability to reduce
`relapse rate, MRI lesion activity, and brain atrophy; low immuno-
`genicity; a low incidence of side effects, including injection-site
`reactions; and a convenient dosing schedule. Relapses should be
`treated with corticosteroids. Stage II represents acute break-
`through disease that is managed by the addition of pulse cortico-
`steroids to the platform drug. Stage III represents continued
`breakthrough disease that is managed by the addition of immuno-
`suppressants to the platform drug. It is hoped that this new
`treatment algorithm assists physicians in the management of
`patients with MS and enhances physicians’ ability to improve
`patient quality of life over the course of the disease.
`
`DISCLOSURES
`
`Funding for this paper was provided by Biogen Idec Inc. Author William H.
`Stuart received an honorarium from Biogen.
`
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`
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