Stepped-Care Approach to Treating MS:
`A Managed Care Treatment Algorithm
`
`SHELDON J. RICH, RPh, PhD; IMELDA C. COLEMAN, PharmD; RICHARD COOK, PharmD; DOUGLAS S. HUM, RPh;
`BEN JOHNSON, RPh, MBA; TERRY MAVES, RPh; WILLIAM J. MAZANEC, PharmD, MBA; JAMES R. MILLER, MD;
`WOODROW J. PROVEAUX, PharmD; HOWARD S. ROSSMAN, DO, FACN; and WILLIAM H. STUART, MD
`
`ABSTRACT
`
`OBJECTIVE: To introduce a model treatment algorithm for use in the managed
`care setting as a strategy to provide ongoing disease management and long-term
`care for patients with multiple sclerosis (MS), with the goal of delaying disease
`progression and the associated disability and cognitive dysfunction.
`
`SUMMARY: MS is a chronic inflammatory disorder of the central nervous system
`that is associated with progressive disability and cognitive dysfunction. Currently,
`management of MS involves planning an effective long-term treatment strategy
`that can delay the progression of the disease. This article reviews a typical
`stepped-care approach to treating MS that is based on the concept of a platform
`drug, which is an agent that provides baseline immunomodulatory action
`throughout the course of the disease.
`Considerations for selecting a platform therapy include the effect on the full
`spectrum of MS (disability, relapses, lesion load, and atrophy as well as patient
`compliance and the potential impact of neutralizing antibodies [NAbs]). Currently,
`4 first-line therapies are approved for relapsing MS: the 3 interferon beta (IFNβ)
`products and glatiramer acetate. Of these, the IFNβs are generally recommended
`as platform therapy because all have shown significant effects on relapses, mag-
`netic resonance imaging parameters of the disease, and because intramuscular
`(IM) IFNβ-1a (Avonex) and subcutaneous (SC) IFNβ-1a (Rebif) have been shown
`to slow the progression of sustained disability.
`Patients being treated with IFNβs can develop NAbs to the drug, which can
`lead to a loss of efficacy and subsequent occurrence of breakthrough disease.
`The 3 different formulations of IFNβ are associated with a varying incidence of
`NAbs (IM IFNβ-1a, 5%; SC IFNβ-1a, 24%; IFNβ-1b [Betaseron], 45%). Antibodies
`also form against glatiramer acetate, although their clinical significance needs
`to be elucidated. As the disease progresses or has periods of aggressive activity,
`the stepped-care approach is to add other agents onto the platform therapy to
`improve control of the disease.
`
`CONCLUSION: Stepped care, as outlined in this model treatment algorithm for the
`managed care setting, is an effective method to achieve the fundamental goal of
`MS treatment, that is, to delay disease progression and the associated disability
`and cognitive impairment.
`
`KEYWORDS: Multiple sclerosis, Stepped care, Treatment algorithm
`
`J Manag Care Pharm. 2004;10(3)(suppl S-b):S26-S32
`
`Multiple sclerosis (MS) is a chronic demyelinating disease
`
`of the central nervous system. Natural history data sug-
`gest that in a majority of patients diagnosed with clini-
`cally definite MS, the disease progresses from an initial relapsing-
`remitting form to a secondary progressive type.1 Delaying pro-
`gression of the disease and the associated disability and cognitive
`dysfunction is one of the fundamental goals of MS therapy. To
`achieve this objective, an individualized, dynamic, long-term
`treatment strategy should be implemented along with ongoing
`monitoring of disease activity. The treatment plan should be able
`to adapt to the changing needs of the individual patient, based on
`clinical findings of disease progression, severity of MS symptoms,
`increase of disease burden on magnetic resonance imaging (MRI),
`and development of neutralizing antibodies (NAbs).
`Approved first-line therapies for relapsing-remitting MS
`include the 3 interferon beta (IFNβ) products: intramuscular (IM)
`IFNβ-1a, (IM IFNβ-1a [Avonex, Biogen Idec Inc., Cambridge,
`MA]); subcutaneous (SC) IFNβ-1a (SC IFNβ-1a [Rebif, Serono,
`Inc., Rockland, MA]); and IFNβ-1b (Betaseron, Berlex
`Laboratories, Montville, NJ) and glatiramer acetate (Copaxone,
`Teva Neuroscience, Inc., Kansas City, MO).2 Consequently, these
`drugs are used as baseline immunomodulatory agents (platform
`drugs) in the treatment of MS. These treatments are proven to
`slow various aspects of MS; however, most patients will experi-
`
`Authors
`
`SHELDON J. RICH, RPh, PhD, is president, SJR Associates, LLC, West Bloomfield,
`Michigan; clinical assistant professor, University of Michigan, Ann Arbor; and
`adjunct assistant professor, Wayne State University, Detroit, Michigan; IMELDA C.
`COLEMAN, PharmD, is clinical pharmacist, BlueCross/BlueShield of Louisiana,
`Baton Rouge; RICHARD COOK, PharmD, is manager, clinical and quality pro-
`grams, Blue Care Network of Michigan, Grand Rapids; DOUGLAS S. HUM, RPh,
`is director of pharmacy services, Medica Health Plans, Minnetonka, Minnesota;
`BEN JOHNSON, RPh, MBA, is pharmacy contract manager, Intermountain Health
`Care, Salt Lake City, Utah; TERRY MAVES, RPh, is pharmacy director, Touchpoint
`Health Plan, Appleton, Wisconsin; WILLIAM J. MAZANEC, PharmD, MBA, is
`vice president, clinical and formulary management, CuraScript, Orlando, Florida;
`JAMES R. MILLER, MD, was director, Multiple Sclerosis Center, Columbia-
`Presbyterian Medical Center, Columbia University, New York, New York (now
`retired); WOODROW J. PROVEAUX, PharmD, is clinical pharmacy director, Care
`First BlueCross/BlueShield, Baltimore, Maryland; HOWARD S. ROSSMAN, DO,
`FACN, is medical director, Multiple Sclerosis Center, Michigan Institute For
`Neurological Disorders, Farmington Hills; WILLIAM H. STUART, MD, is medical
`director, Multiple Sclerosis Center of Atlanta, Georgia.
`
`AUTHOR CORRESPONDENCE: Sheldon J. Rich, RPh, PhD, President, SJR
`Associates LLC, 4223 Fieldbrook Rd., West Bloomfield, MI 48323-3207.
`Tel: (248) 932-8500; Fax: (248) 932-2972; E-mail: SJRAssociates@aol.com
`
`Copyright© 2004, Academy of Managed Care Pharmacy. All rights reserved.
`
`S26 Supplement to Journal of Managed Care Pharmacy JMCP June 2004 Vol. 10, No. 3, S-b www.amcp.org
`
`MYLAN INC. EXHIBIT NO. 1031 Page 1
`
`

`
`Stepped-Care Approach to Treating MS: A Managed Care Treatment Algorithm
`
`FIGURE 1
`
`Diagnosis and Therapy Selection
`
`Clinically isolated
`syndrome + MRI to
`support diagnosis
`
`Patient meets diagnostic criteria for MS
`
`Develop therapeutic plan
`and select platform therapy
`
`IFNβ-1a
`(Avonex)
`
`IFNβ-1a
`(Rebif)
`
`IFNβ-1b
`(Betaseron)
`
`Glatiramer
`acetate
`(Copaxone)
`
`Neurologist recommends appropriate therapy based on:
`• Evidence-based efficacy
`• Patient lifestyle: likelihood patient will comply with dosing
`and administration regimen
`• Low immunogenicity
`• Ability for long-term treatment (suitability and tolerability)
`
`• Care management plan
`• Setting expectations
`• Patient education
`
`The decision to initiate treatment for multiple sclerosis (MS) is followed by careful consid-
`eration of the available first-line or “platform” therapies. Educating patients and setting
`realistic treatment expectations are also important factors in designing an effective long-
`term treatment plan. IFNβ = interferon beta; MRI = magnetic resonance imaging.
`
`the platform drug, based on symptoms and disease progression.
`Platform therapy options are the 4 drugs that are approved by the
`U.S. Food and Drug Administration (FDA) for use in relapsing MS:
`IFNβ-1b, IM IFNβ-1a, SC IFNβ-1a, and glatiramer acetate. The rel-
`ative efficacy, side effects, convenience, and compliance issues relat-
`ing to these drugs (discussed in the article by William H. Stuart in
`this supplement) should be considered when evaluating the differ-
`ent platform drugs. IFNβs are recommended as platform therapy
`because they have an impact on relapses and lesions on MRI. In
`addition, IM and SC IFNβ-1a have been shown to slow the pro-
`gression of sustained disability13-16 and IM and SC IFNβ-1b therapies
`have been shown to significantly decrease brain atrophy.17,18
`Given the long-term nature of MS treatment, the clinical aspects
`of the available platform drugs should be given careful considera-
`tion before initiating treatment. The complications that may arise
`due to the generation of NAbs to IFNβ also should be taken into
`account (for a detailed discussion, see the article by Howard S.
`Rossman in this supplement). These complications include
`reduced efficacy of the drug and cross-reactivity of NAbs that make
`switching between IFNβ products impractical. The neurologist
`must consider these factors and assist individual patients in select-
`ing the appropriate agent rather than simply providing general
`information to patients and having them select a drug.
`Ongoing patient education sets realistic expectations for agent
`effectiveness. For instance, after treatment initiation, a patient may
`experience exacerbations or relapses for some time. Generally, the
`IFNs require 3 to 6 months of treatment to become fully effective,
`and glatiramer acetate may take up to 9 months to become fully
`effective. Patients must also be aware of the potential side effects of
`the chosen platform therapy. Some of the common side effects asso-
`ciated with IFNβ treatment are injection-site reactions (mostly SC
`formulations), flu-like symptoms, and headache.19-22 These side
`
`ence disease progression. In patients undergoing treatment with a
`platform drug, ongoing monitoring of disease activity, including
`regular MRI scans, may identify breakthrough disease (i.e., fre-
`quent exacerbations and increased disability). Once identified, cli-
`nicians can add corticosteroids or a number of other secondary
`agents, as necessary, to the platform drug to manage breakthrough
`disease.3 This article reviews issues relating to long-term treatment
`strategies and ongoing disease management in MS and provides a
`model treatment algorithm for use in the managed care setting.
`
`II Diagnosis and Therapy Selection
`Diagnosis
`A single clinical event indicative of demyelination is often the ear-
`liest symptom detected in patients with MS. Typically, patients
`present to their primary care physician with an isolated clinical
`event, for example, optic neuritis in one eye or numbness on one
`side of the body. Once a patient is referred to a neurologist, a diag-
`nosis of clinically isolated syndrome (CIS) is made based on a neu-
`rologic or ophthalmologic examination, or both, confirming the
`clinical event consistent with demyelination involving the optic
`nerve (optic neuritis), spinal cord (incomplete transverse myelitis),
`or brainstem or cerebellum (brainstem or cerebellar syndrome).4
`Following a diagnosis of CIS and exclusion of alternate diag-
`noses, the patient’s risk of developing clinically definite MS
`(CDMS) is evaluated. Historically, a diagnosis of CDMS was made
`following the occurrence of a second clinical demyelinating event.5
`However, because the time between the first and second attacks
`varies considerably, diagnosis and therapy initiation could take
`several years. Many studies have therefore evaluated the risk of
`developing CDMS in patients diagnosed with CIS using paraclin-
`ical measures, such as MRI, evoked potentials, and examination of
`cerebrospinal fluid (CSF) for the presence of oligoclonal bands. Of
`these measures, MRI has been shown to be the most sensitive
`method for predicting the development of CDMS in patients with
`suspected MS.6 Further, the prognostic value of MRI in MS has been
`demonstrated in prospective follow-up studies of patients with
`CIS.7,8 Diagnostic criteria for MS now include MRI as a paraclinical
`diagnostic tool9 because the presence of characteristic MS lesions on
`MRI is associated with a high risk of developing CDMS.7,10,11
`
`Therapeutic Plan Development
`and Selection of a Platform Therapy
`The National Multiple Sclerosis Society recommends initiation of
`treatment as soon as possible after a definitive diagnosis of MS is
`made and also recommends that treatment be initiated in patients
`at high risk of developing MS.12
`Following the decision to initiate therapy, one of the first steps is
`selection of an appropriate platform drug (Figure 1), which is
`defined as an agent that can provide baseline immunomodulatory
`action throughout the course of the disease. Platform treatment may
`be adequate treatment for many patients for years; however, for
`patients with aggressive disease, additional agents can be added to
`
`www.amcp.org Vol. 10, No. 3, S-b June 2004 JMCP Supplement to Journal of Managed Care Pharmacy S27
`
`MYLAN INC. EXHIBIT NO. 1031 Page 2
`
`

`
`Stepped-Care Approach to Treating MS: A Managed Care Treatment Algorithm
`
`aggravates or leads to other symptoms, causing a cycle of inter-
`dependent symptoms. Disease progression also can lead to a wide
`range of complicating symptoms requiring additional treatments.
`Educating primary care physicians and nurses to identify symp-
`toms that the patient is experiencing, and encouraging patients to
`avoid using multiple over-the-counter medications, vitamins, and
`herbal preparations are important symptom management tools.
`Not all drugs listed in the following section are approved by the
`FDA for use in MS. These drugs are discussed to educate phar-
`macists about medications that neurologists empirically have
`found useful and commonly prescribe for patients with MS.
`Spasticity. Impairment of muscle function is one of the most
`common symptoms of MS, affecting an estimated 40% to 75% of
`patients,28,34,35 and spasticity accounts for most of the physical dis-
`ability seen in MS patients. Nonpharmacologic treatment options
`for spasticity include carefully planned, physician recommended
`exercise regimens (including aerobic exercise, stretching exercises
`to improve flexibility, and both active and passive movements that
`incorporate the full range of motion) and relaxation techniques
`(such as yoga, meditation, biofeedback, and tai chi). Pharma-
`cologic treatments include baclofen (GABAB-receptor stimulator
`[Lioresal]), tizanidine (α-adrenergic receptor agonist [Zanaflex]),
`and benzodiazepines.
`Fatigue. Fatigue is reported by 80% to 97% of patients with MS
`and is characterized by a lack of energy, an overwhelming sense of
`tiredness, or a feeling of exhaustion.36,37 Nonpharmacologic man-
`agement of fatigue involves treating symptoms in patients that lead
`to fatigue, such as depression and sleep disturbances, and improv-
`ing patient mobility through exercise. Pharmacologic treatments
`include the off-label use of modafinil (Provigil).38,39 The N-methyl-
`D-aspartate antagonist amantadine (Symmetrel), methylphenidate
`(Ritalin), and amphetamines also are used off-label to treat fatigue.29
`Depression. The lifetime prevalence of depression among
`patients with MS is 47% to 54%. Nonpharmacologic treatment con-
`sists of psychotherapy,40-42 and pharmacologic agents used to treat
`depression include selective serotonin reuptake inhibitors (SSRIs
`[e.g., fluoxetine, sertraline, paroxetine, escitalopram, and citalo-
`pram]), tricyclic antidepressants (e.g., amitriptyline and nortripty-
`line), and atypical antidepressants (e.g., bupropion and venlafaxine).
`Bladder dysfunction. Bladder symptoms are experienced by
`80% to 96% of patients with MS and include overactive bladder
`(detrusor hyperreflexia) and urinary retention (overactive sphinc-
`ter).43 Treatment for overactive bladder consists of anticholinergics
`(e.g., oxybutynin and tolterodine), and treatment for urinary
`retention involves the off-label use of α-adrenergic antagonists
`(e.g., tamsulosin, doxazosin, and terazosin).29,43
`Pain. Approximately 65% of patients with MS experience
`acute and subacute painful syndromes, the extent and impact of
`which are often underestimated.44,45 Paroxysmal neuropathic pain
`is acute and intense; may worsen with age and disease progres-
`sion27; and includes trigeminal neuralgia, which is triggered by
`sensory stimuli at various points on the face or head, Lhermitte’s
`
`FIGURE 2
`
`Ongoing Disease Management
`
`IFNβ-1a-Rebif
`IFNβ-1b-Betaseron
`(SC)
`
`At 12 months and if
`breakthrough disease
`
`IFNβ-1a-Avonex
`(IM)
`
`Glatiramer
`acetate
`
`Breakthrough disease
`
`Check patient compliance
`
`Test for neutralizing antibodies*
`High titer (≥20)
`
`Low titer (<20)
`
`Symptomatic
`
`Asymptomatic
`
`Asymptomatic
`
`Symptomatic
`
`Alter
`therapy.
`
`Consider
`long-term implications
`and repeat NAb test in
`6 months.If persistent,
`alter therapy.
`
`Possibly do not
`alter therapy.
`
`Follow-up
`and evaluate fur-
`ther. Possibly alter
`therapy.
`
`Switch to
`an IFN.
`
`• MRI to monitor disease
`• Symptom management
`
`* Wait at least 30 days after last corticosteroid
`treatment if patient is being treated with corticosteroids.
`
`Consider
`combination therapy
`
`A dynamic treatment strategy consists of altering treatment as needed based on
`periodic monitoring of multiple sclerosis symptoms, disease burden on magnetic
`resonance imaging (MRI), patient compliance, and formation of neutralizing
`antibodies. IFNβ = interferon beta; IM = intramuscular; SC = subcutaneous.
`
`effects can be managed, and appropriate patient education and
`ongoing monitoring can improve the experience and minimize the
`risk of patient noncompliance. Glatiramer acetate also is associated
`with injection-site reactions, including lipoatrophy.23 Additional side
`effects with glatiramer acetate include chest pain, lymphadenopathy,
`and postinjection systemic reactions.24
`
`II Ongoing Disease Management
`
`Effective, dynamic treatment strategies require initiation of plat-
`form therapy followed by regular, ongoing monitoring of patients
`for MS symptoms and disease activity. Ongoing monitoring of
`patients with MS can aid early detection of breakthrough disease.
`Occurrence of breakthrough disease is identified on an individual
`basis based on unacceptable disease progression. Possible criteria
`to assist in this determination include disability progression
`(e.g., increase of ≥1 point on the Expanded Disability Status
`Scale), multiple relapses in a short time span (e.g., ≥2 relapses in
`6 months after 1 year of IFNβ therapy), development of new neu-
`rologic deficits, or deterioration evident on MRI.3,25 Factors such as
`poor patient adherence and development of NAbs can contribute
`to the occurrence of breakthrough disease in patients on a plat-
`form drug and should therefore be monitored as well (Figure 2).
`
`Symptom Management
`The most common symptoms of MS are spasticity, fatigue, sexual
`dysfunction, bladder dysfunction, pain, and cognitive dysfunc-
`tion. Other frequently noted symptoms include depression, bowel
`dysfunction, paroxysmal symptoms, and weakness.26-33 Many MS
`symptoms can be interrelated such that one untreated symptom
`
`S28 Supplement to Journal of Managed Care Pharmacy JMCP June 2004 Vol. 10, No. 3, S-b www.amcp.org
`
`MYLAN INC. EXHIBIT NO. 1031 Page 3
`
`

`
`Stepped-Care Approach to Treating MS: A Managed Care Treatment Algorithm
`
`phenomenon caused by cervical cord lesions, and dystonic
`spasms from paroxysmal dystonia. Treatment options for such
`pain include anticonvulsants, antispasmodics, and surgery.
`Constant neuropathic pain also can occur and may require the use
`of anticonvulsants, nonsteroidal anti-inflammatory drugs, opioid
`narcotics, nerve blocks, or tricyclic antidepressants.44,45
`Sexual dysfunction. Approximately 48% to 75% of patients
`with MS may experience sexual dysfunction.29 In men with MS,
`symptoms include erectile dysfunction, ejaculatory disorders, and
`difficulty achieving orgasm.46,47 In women with MS, symptoms
`include reduced libido; reduced, altered, or painful sensations;
`reduced lubrication; difficulty achieving orgasm; and anxiety about
`incontinence.48,49 Nonpharmacologic treatment options include
`addressing psychophysiologic issues that can contribute to sexual
`dysfunction; pharmacologic treatments include drugs for erectile
`dysfunction and lubricants. Discontinuation of SSRIs associated
`with sexual side effects also may be considered. Alternatives to SSRIs
`include tricyclic antidepressants and monoamine oxidase inhibitors.
`Cognitive dysfunction. Impairment of cognitive processes is
`reported by 45% to 65% of patients with MS and is the symptom
`that is of greatest concern to patients.50 Cognitive dysfunction
`most often includes impairment in learning and memory, atten-
`tion, and information processing.51 Nonpharmacologic cognitive
`rehabilitation is the main treatment option because, currently, no
`medications are approved for the treatment of cognitive impair-
`ment in MS.52 Because the occurrence or progression of cognitive
`dysfunction is an indicator of active disease, treatment options for
`this symptom are the same as those used to delay the progression
`of the physical symptoms of MS (i.e., IFNβ and glatiramer
`acetate). IM IFNβ-1a has been shown to delay progression of
`cognitive dysfunction in patients with MS.53
`
`Use of MRI to Monitor Disease Activity
`Subclinical disease activity detected using MRI plays an impor-
`tant role in the longitudinal management of MS. Typically, lesions
`seen on MRI and used to assess disease activity include hyperin-
`tense lesions on T2-weighted images, hypointense lesions on
`T1-weighted images, and gadolinium-enhanced lesions on post-
`contrast images. Another measure that is being increasingly
`accepted as an important MS outcome is MRI measurement of
`CNS atrophy.54 Increase in lesion load and progressive atrophy on
`MRI often may be clinically silent. Because brain MRI can detect
`disease activity that is subclinical, it is considered a more
`sensitive measure of disease activity than clinical findings.55
`Generally, insurance coverage for MRI is available for the pur-
`pose of diagnosis but not necessarily for ongoing disease moni-
`toring. Given that MRI measures can detect asymptomatic wors-
`ening of disease and thus help in making preemptive alterations
`to the treatment plan, it is recommended that MRI be performed
`periodically in patients with MS. Ideally, MRI should be per-
`formed every 12 months in patients with MS who are asympto-
`matic and more often (every 6 months) in patients who are
`
`TABLE 1
`
`Recommended Magnetic
`Resonance Imaging Protocol
`
`Brain, axial
`• T1 noncontrast
`• T1 postcontrast
`• T2
`• Fluid-attenuated inversion recovery (FLAIR)*
`Brain, sagittal
`• T1 noncontrast
`• FLAIR
`Spinal
`• T1 sagittal
`• T2 sagittal
`• T2 axial
`• Postcontrast (T1 axial, T1 sagittal)
`*FLAIR is recommended to increase the sensitivity and specificity of hyperintense MS lesions.
`
`symptomatic. Recommended MRI protocols are shown in Table 1.
`
`Testing for Neutralizing Antibodies
`In patients with MS undergoing treatment with IFNβ, formation
`of NAbs to IFNβ can lead to a loss of efficacy of the drug and sub-
`sequent occurrence of breakthrough disease.56,57 Antibodies also
`form against glatiramer acetate, although their clinical significance
`needs to be elucidated.58 Early detection of NAbs through period-
`ic testing can make the neurologist aware of the potential for
`recurrence of symptoms in patients who are NAb-positive.
`The 3 different formulations of IFNβ are associated with vary-
`ing incidences of NAbs: IM IFNβ-1a, 5%; SC IFNβ-1a, 24%;
`IFNb-1β, 45%. (For a detailed discussion, see the article by
`Howard S. Rossman in this supplement.) Consequently, the guide-
`lines for NAb testing depend on which IFNβ product is being
`used as the platform drug. For patients using the more immuno-
`genic IFNβ products (IFNβ-1b and SC IFNβ-1a), testing for NAbs
`should be done at 12 months or if breakthrough disease occurs.
`Patients who are being treated with the less immunogenic
`IM IFNβ-1a only need to be tested if breakthrough disease occurs.
`The NAbFeron (IFNβ) antibody test (Athena Diagnostics) is
`the most commonly used, commercially available assay for NAbs.
`The cytopathic effect assay for NAbs, recommended by the World
`Health Organization, is based on the ability of NAbs in serum to
`interfere with the antiviral effects of IFNβ on human lung carci-
`noma cells.59 NAbs are quantitatively expressed in neutralizing
`titers (a neutralizing titer is defined by a 50% inhibition of the
`activity of 10 IU/ml IFNβ). The threshold for NAb-positivity is
`defined by the presence in patient serum of NAb titers ≥20. The
`NAb titer appears to influence the persistence of NAbs. Patients
`with NAb titers >100 are more likely to remain NAb-positive for
`years. Patients treated with corticosteroids should not be tested
`for NAbs until 30 days after the last corticosteroid dose because
`corticosteroid treatment can temporarily suppress NAbs.
`For symptomatic patients with high NAb titers (≥20), therapy
`alteration is recommended. For those with high titers who are
`asymptomatic, the NAb test may be repeated in 6 months. If NAbs
`are persistent, then therapy should be altered. For patients with low
`
`www.amcp.org Vol. 10, No. 3, S-b June 2004 JMCP Supplement to Journal of Managed Care Pharmacy S29
`
`MYLAN INC. EXHIBIT NO. 1031 Page 4
`
`

`
`Stepped-Care Approach to Treating MS: A Managed Care Treatment Algorithm
`
`FIGURE 3
`
`Management of Breakthrough Disease
`Using Combination Therapy
`
`Combination Therapy
`
`Acute management:
`• Continue platform therapy (immunomodulator)
`• Initiate corticosteroids as needed
`
`Stabilized breakthrough
`
`Continue platform therapy
`
`Continued breakthrough
`
`Continue platform therapy
`plus
`Maintenance pulse corticosteroids
`and/or
`Stage IIIA: oral immunosuppressant
`and/or
`Stage IIIB: IV immunosuppressant
`
`Acute management of breakthrough disease involves the use of pulse corticosteroid
`therapy to stabilize the disease and continuing treatment with the first-line or
`“platform” drug. Continued breakthrough disease requires addition of either
`maintenance pulse corticosteroid therapy or a secondary agent to the platform drug.
`
`titers of NAbs (<20) who are symptomatic, further evaluation and
`follow-up (including retesting in 6 months) should be considered
`before making any alterations to therapy. For asymptomatic
`patients with low NAb titers, no alteration to therapy is needed.
`One of the concerns regarding testing for NAbs is expense. The
`cost of the NAbFeron test is estimated at $600.59 However, given
`that yearly costs of IFNβ therapy may exceed $15,000, the benefit
`of identifying NAb-positive patients and switching them to alternate
`treatments is likely to be economically viable in the long term.59
`
`II Management of Breakthrough Disease
`
`In general, for the purpose of designing a treatment plan, the MS
`disease process can be categorized into 3 stages. Stage I is the early
`part of the disease, Stage II involves acute breakthrough disease on
`treatment, and Stage III is characterized by continued break-
`through disease despite treatment. Depending on their response
`to therapy, and disease fluctuations and progression, patients may
`move from one stage to another and back.
`
`Acute Breakthrough Disease
`Management of breakthrough disease in Stage II involves the use
`of pulse corticosteroids. Typically, intravenous (IV) methylpred-
`nisolone 1 g/day is administered over 1 to 4 hours for 3 to 5
`days.60 The platform drug is continued during the management of
`breakthrough disease.
`
`drug in patients with breakthrough disease. Further, increasing the
`dose of IFNβ or the frequency of administration may lead to
`increased incidences of adverse events and NAbs.61-64 In addition, in
`patients who develop NAbs to IFNβ, switching between the 3 IFNβ
`formulations is not feasible because of the cross-reactivity between
`antibodies to the different IFNβ products.61 Thus, the available treat-
`ment options for this chronic disease are reduced.
`Combination therapy (i.e., addition of another agent to the
`platform drug) is the most effective way of managing continued
`breakthrough disease. An ideal agent for combination therapy is
`one that has biologic activity in MS with a mechanism of action
`that differs from the platform drug, provides synergistic efficacy,
`and has a low likelihood of additive toxicity.25 Initially, mainte-
`nance pulse corticosteroids are added to the platform drug to sta-
`bilize breakthrough disease. In patients who require additional
`therapy, corticosteroids are followed by immunosuppressants or
`cytotoxic agents. Oral cytotoxic agents (eg, methotrexate, azathio-
`prine, or mycophenolate mofetil) should be tried first (Stage IIIA)
`with IV cytotoxic agents (e.g., mitoxantrone and cyclophos-
`phamide) being used as necessary (Stage IIIB). With the exception
`of mitoxantrone, which is approved for use in MS, these agents are
`approved for use in other diseases and are used off-label in the
`treatment of MS.3 Often, a physician’s experience with an agent
`and the cost of the drug influences the choice of agent when
`designing a combination therapy regimen.25
`A number of novel immunomodulatory agents also are under
`investigation for the treatment of MS, mostly in phase I studies (Table
`2). Phase II clinical trials have been reported with some agents,
`including the nonpeptide chemokine receptor antagonist, BX-471,
`and the humanized monoclonal antibody to α4β1-integrin, natal-
`izumab.65,66 Natalizumab is currently being studied in phase III trials.
`
`II Conclusions
`
`One of the fundamental treatment goals in MS is to delay the pro-
`gression of disease and the associated disability and cognitive
`impairment. A stepped-care approach is an effective method for
`achieving this treatment objective and consists of the following:
`(a) initiating therapy with a platform drug in patients diagnosed
`with CDMS or patients with a CIS and at high risk of developing
`CDMS; (b) monitoring disease progression by assessing the sever-
`ity of MS symptoms, noting the presence and number of lesions
`on MRI, and testing for NAbs; (c) identifying breakthrough
`disease early based on ongoing monitoring of disease activity; and
`(d) managing breakthrough disease.
`
`DISCLOSURES
`
`Continued Breakthrough Disease and Combination Therapy
`Options available for the management of continued breakthrough
`disease in Stage III are switching from one platform drug to anoth-
`er, changing the dose of the current platform drug, and initiating
`combination therapy (Figure 3). No controlled studies have assessed
`the benefits of switching or of increasing the dose of the platform
`
`Funding for this paper was provided by Biogen Idec Inc. All authors received
`an honorarium from Biogen; author Ben Johnson has also previously received
`an honorarium from Berlex. Author Sheldon J. Rich does consulting work for
`Biogen and participates in the Biogen and Berlex speakers bureaus; author
`James R. Miller participates in the Biogen lecture bureau; author Howard S.
`Rossman is a consultant and speaker for Biogen, Teva Neuroscience, and
`Serono, Inc., and has received compensation for clinical research from these
`companies.
`
`S30 Supplement to Journal of Managed Care Pharmacy JMCP June 2004 Vol. 10, No. 3, S-b www.amcp.org
`
`MYLAN INC. EXHIBIT NO. 1031 Page 5
`
`

`
`Stepped-Care Approach to Treating MS: A Managed Care Treatment Algorithm
`
`TABLE 2
`
`Novel Immunomodulatory Agents for Use in Combination Therapy for Multiple Sclerosis
`
`Immunomodulatory Agent
`Natalizumab (Antegren)
`
`BX-471
`Minocycline
`Simvastatin (Zocor)
`Pentoxifylline
`Estriol
`Rituximab (Rituxan )
`TCR peptide (NeuroVax)
`T-cell vaccination
`Stem cell transplantation
`All-trans retinoic acid
`
`Characteristics
`Humanized monoclonal antibody to α4β1-integrin;
`inhibition of leukocyte adhesion and extravasation
`Nonpeptide chemokine receptor (CCR1) antagonist
`Matrix metalloproteinase inhibition
`Immunomodulation, Th2 cytokine promotion
`Phosphodiesterase inhibition, suppression of TNFα and IFNγ production
`Immunomodulation, Th2 shift
`Chimeric murine/human anti- CD20 monoclonal antibody
`Combination of 3 different TCR peptides
`Attenuation of myelin-specific immune responses
`Immunoablation followed by infusion of autologous hematopoietic stem cells
`Potentiation of T suppressor cell function
`
`Reference
`Miller et al. 2003.65
`
`Elices; 2002.66
`Brundula et al. 2002.67
`Stüve et al. 2003.68
`Weber et al. 1998.69
`Sicotte et al. 2002.70
`Saleh et al. 2000.71
`Chou et al. 1994.72
`Correale et al. 2000.73
`Muraro et al. 2003.74
`Qu et al. 1998.75
`
`Author Sheldon J. Rich served as principal author of the study. Study
`concept and design were contributed primarily by Rich and authors Howard
`S. Rossman and William H. Stuart. Analysis and interpretation of data were
`contributed by all authors. Drafting of the manuscript was primarily the work
`of Rich, and its critical revision was the work of all authors. Administrative,
`technical, and/or material support was provided by Biogen Idec Inc.
`
`REFERENCES
`
`1. Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple
`sclerosis: a geographically based study, I: clinical course and disability. Brain.
`1989;112:133-46.
`2. Galetta SL, Markowitz C, Lee AG. Immunomodulatory agents for the tr