TREATMENTS FOR
`MULTIPLE SCLEROSIS
`
`Fred D. Lublin
`
`ABSTRACT
`
`The field of multiple sclerosis entered the treatment era in 1993, over a decade
`ago, and now enjoys the availability of five marketed disease-modifying agents.
`This is an enviable position, not yet obtained in most other serious neurologic
`diseases. Despite this, the current agents provide only a modest benefit, and
`improvements in therapeutic options will be welcome. Therapy of multiple
`sclerosis centers on immunomodulation and immunosuppression, in keeping with
`the known immunoregulatory abnormalities in this illness. Treatment consists
`primarily of use of corticosteroids for acute exacerbations and for disease
`modification, either interferon or glatiramer acetate. More severe disease can be
`treated with mitoxantrone. Other agents have been utilized, but the basis for their
`use is less compelling.
`
`Treatment of multiple sclerosis (MS)
`can be divided into three types:
`treatment of acute exacerbations, dis-
`ease-modifying therapies, and symp-
`tomatic therapies. For this chapter,
`we will discuss the first two. Symp-
`tomatic therapies are discussed in a
`separate chapter.
`
`TREATMENT OF ACUTE
`EXACERBATIONS
`The treatment of acute exacerbations
`of MS has centered on use of cortico-
`steroids or adrenocorticotropic hor-
`mone (ACTH). Few well-designed,
`controlled studies on steroid use have
`been done since the initial study by
`Rose and colleagues in 1970. In that
`study, patients treated with ACTH
`administered intramuscularly (IM) over
`2 weeks, beginning at 80 units daily,
`improved more rapidly than those
`treated with placebo. The beneficial
`effect was only evident
`for a few
`weeks, however, with no long-term
`difference seen between the two
`groups, as a proportion of patients
`will recover some degree of function
`
`spontaneously after an acute attack.
`Subsequent studies have utilized in-
`travenous methylprednisolone (IVMP).
`Although none of these studies are
`considered pivotal, they suggested a
`short-term benefit from steroid. While
`there are little data to recommend one
`form of corticosteroid over another or
`the optimal dosing schedule, most cen-
`ters utilize a 3- to 5-day course of IVMP
`1 g daily, optionally followed by a short
`course of rapidly tapered oral predni-
`sone. A meta-analysis of three studies
`comparing the effect of intravenous (IV)
`high-dose steroid to placebo on re-
`covery using the Expanded Disability
`Status Scale (EDSS) confirmed the
`benefit of high-dose steroid when
`assessed up to 28 days after treatment
`(Miller et al, 2000). The same study
`evaluated two dose-testing regimens
`and could not find a short-term differ-
`ence between high-dose and low-dose
`steroids. Approximately 85% to 92% of
`patients improve with IVMP versus
`33% to 40% of controls after 1 week
`of therapy (Durelli et al, 1985). Anoth-
`er meta-analysis looked at a number
`
`KEY POINT:
`
`A The treatment
`of acute
`exacerbations
`of MS has
`centered
`on use of
`corticosteroids
`or adrenocor-
`ticotropic
`hormone.
`
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`120
`
`Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`EXHIBIT 1046, Petitioner TWi
`IPR2023-00049, -00050
`
`Page 1 of 22
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`

`

`KEY POINT:
`
`A It is not clear
`whether
`equivalent
`doses of oral
`steroids are as
`beneficial as
`those given
`intravenously.
`
`studied
`and colleagues
`Sellebjerg
`the effect of oral methylprednisolone
`500 mg/d for 5 days followed by
`a taper as
`treatment of
`relapses
`seen within 4 weeks (Sellebjerg et al,
`1998). In this randomized, placebo-
`controlled, blinded trial of 51 patients,
`those treated with high-dose oral
`steroids did better than placebo on
`EDSS and Scripps score when assessed
`up to 8 weeks after therapy. Side
`effects were modest and tolerable.
`The authors suggested that the advan-
`tage of IVMP was due to the doses
`employed rather than the route. The
`tolerability of high-dose oral steroids
`has been assessed by Sellebjerg and
`colleagues (1998) and Metz and col-
`leagues (1999). Sellebjerg found that
`oral methylprednisolone 500 mg/d for
`5 days was well tolerated. Gastrointes-
`tinal symptoms (mostly heartburn),
`insomnia, and hot flashes were signif-
`icantly more common in the steroid-
`treated group. Most adverse events
`were mild, and none were serious.
`Metz and colleagues reported on the
`tolerability of treating 21 patients (15
`oral, 6 IV) with either 1250 mg/d of
`
`121
`
`FIGURE 6-1
`
`Change in EDSS from onset of an exacerbation.
`Treatment with intravenous steroid had an
`immediate and prolonged effect.
`
`EDSS = Expanded Disability Status Scale;
`MP = methylprednisolone.
`
`of steroid trials during acute exacer-
`bations and found that the data sup-
`ported an effect of steroids on short-
`term improvement but could not
`substantiate an effect on long-term
`outcome or subsequent relapse rate
`reduction (Brusaferri and Candelise,
`2000).
`A study of an adhesion molecule
`blocker (see below),
`in which there
`was a placebo group and a group that
`received IV methylprednisolone 1 g/d
`for 3 days demonstrated that methyl-
`prednisolone was significantly better
`than placebo (or the adhesion mol-
`ecule blocker) at reducing measures of
`disability and impairment. This effect
`persisted through at
`least 90 days
`(Figure 6-1). The safety of using oral
`steroids, in moderate doses (60 mg/d
`to 100 mg/d) was a concern following
`the Optic Neuritis Treatment Trial,
`where an increased frequency of re-
`current optic neuritis was seen in the
`oral steroid–treated group. These re-
`sults have neither been confirmed nor
`refuted by additional studies.
`It is not clear whether equivalent
`doses of oral steroids are as beneficial
`as those given intravenously. In one
`study, 35 patients in relapse were
`treated with either IV or oral methyl-
`prednisolone, 500 mg/d for 5 days. No
`difference was found in EDSS at day
`5 or day 28 after treatment. However,
`patients were entered up to 4 weeks
`after onset of their relapses (Alam et al,
`1993). In another study, using unequal
`dosing, 42 patients were treated with
`oral methylprednisolone 48 mg/d for
`7 days, followed by 24 mg/d for 7 days,
`and then 12 mg/d for 7 days, while 38
`patients were treated with IVMP 1 g/d
`for 3 days. There was no significant
`difference in EDSS at 4 weeks. Again,
`patients were entered within 4 weeks
`of the onset of their relapses (median
`duration from onset of symptoms was
`13 days in the IV group and 8.5 days in
`the oral group) (Barnes et al, 1997).
`
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`
`EXHIBIT 1046, Petitioner TWi
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`Page 2 of 22
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`

`

`"TREATMENTS FOR MULTIPLE SCLEROSIS
`
`oral prednisone in 2 divided dosages
`on alternate days for 5 doses or 1000
`mg IVMP infused on alternate days for
`5 doses. All received an 18-day oral
`prednisone taper starting at 60 mg/d.
`Both therapies were well
`tolerated
`and produced similar side effects.
`The commonest were (in descending
`order of frequency) insomnia, heart-
`burn, weight gain/edema, mood change,
`headache, and urinary frequency. Spe-
`cific tests for gastric permeability re-
`vealed modest
`increases
`for both
`treatments and less than occurs with
`2 doses of aspirin.
`Problems with prior oral and IV
`steroid reports center on the fact that
`patients were entered into the studies
`up to 8 weeks after onset of an
`exacerbation. This is likely too long a
`delay after onset and thus includes
`patients who are already undergoing
`spontaneous recovery, potentially mask-
`ing a therapeutic difference in treat-
`ments. Further, no study has adequate
`numbers of patients to reach a statis-
`tically valid conclusion regarding the
`efficacy of oral versus IV therapy.
`Additionally, the IV and oral doses
`have not been comparable in that the
`
`dose for each route of administration
`has not accounted for the factors that
`lead to a difference of plasma levels.
`Approximately 80% of orally ingested
`methylprednisolone is absorbed from
`the gastrointestinal tract to the plas-
`ma, but at higher doses only 50% to
`60% may be absorbed.
`A multicenter, randomized, blinded
`clinical trial comparing 1 g of IVMP
`to 1.4 g of methylprednisolone orally
`for acute exacerbations evaluated
`within 7 days of onset is currently in
`progress.
`The importance of treating acute
`exacerbations was highlighted by an
`analysis of the placebo groups from
`several of the recent clinical trials of
`disease-altering therapies (Lublin et al,
`2003). As the patients were followed
`with assessments every 3 months, one
`could gauge the effect of an acute at-
`tack on measures of neurologic func-
`tion, ie, EDSS and Scripps score. The
`analysis revealed that a measurable
`worsening of both scores was ap-
`parent within 3 months after the ex-
`acerbation and persisted through
`subsequent study visits. For the EDSS,
`residual deficit was seen in 42% of all
`
`KEY POINTS:
`
`A Problems with
`prior oral and IV
`steroid reports
`center on the
`fact that patients
`were entered
`into the studies
`up to 8 weeks
`after onset of an
`exacerbation.
`
`A The importance
`of treating acute
`exacerbations
`was highlighted
`by an analysis
`of the placebo
`groups from
`several of
`the recent
`clinical trials of
`disease-altering
`therapies. A
`measurable
`worsening of
`both scores was
`apparent within
`3 months after
`the exacerbation
`and persisted
`through
`subsequent
`study visits.
`
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`122
`
`FIGURE 6-2
`
`Residual deficit measured from before to after an
`acute exacerbation.
`
`EDSS = Expanded Disability Status Score.
`
`Reprinted with permission from Lublin FD, Baier M, Cutter G.
`Effect of relapses on development of residual deficit in multiple
`sclerosis. Neurology 2003;61:1528–1532. Copyright # 2003,
`AAN Enterprises, Inc.
`
`Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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`Page 3 of 22
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`

`

`KEY POINTS:
`
`A There is good
`evidence that
`plasmapheresis
`may improve
`recovery from an
`attack of severe
`inflammatory
`demyelination,
`as occurs in MS,
`if steroids fail.
`
`A Over the past 11
`years, the field of
`MS therapeutics
`has evolved
`from one that
`offered no
`disease-modifying
`therapies to
`the present,
`where five
`approved agents,
`representing
`three different
`classes of drugs,
`are available.
`
`123
`
`exacerbations, with a mean residual
`worsening of 0.27 EDSS points (Fig-
`ure 6-2). For
`the Scripps
`score,
`residual deficit was seen in 50% of
`patients, with a mean residual wors-
`ening of 1.1 points. When one looks
`at those exacerbations that produced
`measurable deficit during the flare-up,
`the numbers are even more impres-
`sive, with 57% having residual deficit
`of 0.57 EDSS units. These results pro-
`vide compelling data that relapses are
`detrimental and that incomplete re-
`covery from relapses is an important
`cause of accrued disability. Therefore,
`therapies that reduce relapse rate may
`be beneficial,
`independent of
`their
`ability to affect the progressive aspect
`of this illness.
`The use of adhesion molecule
`blockers was a theoretically attractive
`approach to treating acute exacerba-
`tions,
`in the hope that by blocking
`trafficking of
`lymphocytes into the
`central nervous system (CNS), one
`could lessen the effects of an acute
`attack. Two trials attempted to utilize
`this approach. The first employed a
`monoclonal antibody directed against
`CD11/CD18 in an attempt to block
`LFA1 on lymphocytes as well as
`adhesion molecules on macrophages
`and neutrophils. Patients were treated
`with either 1 of 2 doses of
`the
`monoclonal antibody, methylprednis-
`olone 1 g/d for 3 days, or placebo, with
`provisions for a steroid rescue. Treat-
`ment had to be initiated within 7 days
`of the acute attack. The results did not
`demonstrate any effect of the adhe-
`sion-blocking agent, but demonstrated
`that
`IVMP produced a significantly
`better outcome than placebo (or the
`monoclonal antibody) that persisted
`through at least 90 days (Figure 6-1).
`Based on animal studies demonstrat-
`ing an amelioration of experimental
`autoimmune encephalomyelitis, a sec-
`ond study employed natalizumab, a
`monoclonal antibody directed against
`
`the integrin VLA-4 on lymphocytes.
`In this study, patients were entered
`within 96 hours of the acute exacer-
`bation. This
`study also failed to
`demonstrate a beneficial effect from
`blocking adhesion molecules. These
`results suggest that at the time an
`acute exacerbation becomes clinically
`apparent it is too late to attempt to
`block the entry of cells into the CNS.
`Alternatively,
`the entire approach
`may be wrong. Additional studies are
`underway to determine if more chron-
`ic therapy with adhesion molecule
`blocking agents will affect the course
`of MS (see discussion of natalizumab
`below).
`
`Plasmapheresis
`Plasmapheresis has no known role in
`altering the long-term clinical course
`of MS. However, there is good evi-
`dence that plasmapheresis may im-
`prove recovery from an attack of
`severe inflammatory demyelination,
`as occurs in MS, if steroids fail. One
`study demonstrated significant func-
`tional improvement in 42% of patients
`treated with plasmapheresis who had
`failed to respond to IV corticosteroids
`(Weinshenker et al, 1999).
`
`DISEASE-MODIFYING
`THERAPIES
`Over the past 11 years, the field of
`MS therapeutics has evolved from
`one that offered no disease-modifying
`therapies to the present, where five
`approved agents, representing three
`different classes of drugs, are available
`(Hartung et al, 2002; IFNB Multiple
`Sclerosis Study Group, 1993; Jacobs
`et al, 1996; Johnson et al, 1995; PRISMS
`Study Group, 1998). The development
`of these agents has been based on
`our understanding of the immunopa-
`thogenesis of MS, and, almost para-
`doxically, the results of some clinical
`trials have caused a rethinking of as-
`pects of immunopathogenesis.
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`Page 4 of 22
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`

`

`"TREATMENTS FOR MULTIPLE SCLEROSIS
`
`The initial successful clinical trials
`in MS were in established, active,
`relapsing-remitting (RR) MS. Subse-
`quent trials targeted secondary pro-
`gressive (SP) MS, with less impressive
`and less consistent
`results (Cohen
`et al, 2002; European Study Group,
`1998; Secondary Progressive Efficacy,
`2001). The field of MS therapeutics
`was pushed further along with the
`successful outcome of two trials of
`patients with clinically isolated syn-
`dromes, ie, first attacks consistent with
`demyelinating disease that do not
`meet the criteria for definite MS (Comi
`et al, 2001a; Jacobs et al, 2000).
`Based on these results, the field has
`moved from the cautious skepticism
`that greeted the publication of the
`first successful large-scale clinical trial
`of an MS disease-modifying agent
`(DMA)
`in 1993 to a more ready
`acceptance of the utility of the several
`carefully studied, approved, and avail-
`able DMAs in RRMS and even in
`clinically isolated syndromes.
`
`Interferon Beta-1b
`The first study to demonstrate the
`effectiveness of systemically adminis-
`tered interferon beta (IFN-bb) was the
`North American Interferon beta-1b
`(Betaseron) study, which started in
`1988 (IFNB Multiple Sclerosis Study
`Group, 1993). This study utilized a
`double-blind placebo-controlled de-
`sign. The inclusion criteria were
`patients with RRMS, Kurtzke EDSS
`scores of 0 to 5.5 and two or more
`exacerbations in the prior 2 years.
`Data were obtained from 372 patients
`randomized to receive placebo, 1.6
`mIU IFN, or 8 mIU IFN, subcutane-
`ously, every other day. The primary
`outcome measures were reduction in
`annual exacerbation rate and propor-
`tion of exacerbation-free patients. At
`the end of the planned 2-year study,
`patients were offered re-enrollment
`for an additional year to assess pro-
`
`gression of disease, as measured by
`change in EDSS.
`The results of this study, after 2
`years, were that patients who received
`8 mIU of IFN had a significant reduc-
`tion, by almost one third,
`in the
`annual exacerbation rate, as compared
`with placebo-treated patients
`(0.84
`versus 1.27; P = 0.0001). More impor-
`tantly,
`the degree of
`reduction in
`exacerbation rate was most impres-
`sive, almost 50%,
`in those exacerba-
`tions rated as moderate or severe. The
`other primary end point, proportion
`of patients
`remaining exacerbation
`free, also showed a significant differ-
`ence, favoring IFN (8 mIU IFN = 36,
`placebo = 18, P = 0.007). The median
`time to first exacerbation was signifi-
`cantly prolonged, nearly twice as long
`in the 8 mIU group as compared with
`placebo (P = 0.015). Further, there
`were significant
`reductions
`in the
`number and days of hospitalization
`and need for steroids in the IFN-
`treated group. The IFN 1.6 mIU group
`demonstrated a dose-response effect,
`with clinical values between that of the
`8 mIU group and the placebo group in
`most outcome measures.
`The patients in this study had base-
`line and yearly magnetic resonance
`imaging (MRI) scans that were central-
`ly analyzed in blinded fashion. MRI ac-
`tivity was assessed by measuring new
`or enlarging lesions in a subset of 52
`patients who had scans every 6 weeks
`for 2 years. MRI activity was reduced in
`the IFN 8 mIU treatment group by
`80% compared with the placebo group
`(P = 0.0062). The rate of new lesions,
`active lesions, and number of patients
`free of new lesions all significantly fa-
`vored the IFN 8 mIU group. MRI lesion
`burden, measured on T2-weighted
`images, was significantly less at 2 years
`in the treatment group (P < .001).
`By the time all enrolled patients
`had completed 3 years on protocol,
`the total data set
`for the blinded
`
`KEY POINT:
`
`A Based on study
`results, the field
`has moved from
`the cautious
`skepticism that
`greeted the
`publication
`of the first
`successful
`large-scale
`clinical trial
`of an MS
`disease-modifying
`agent in 1993
`to a more ready
`acceptance of
`the utility of the
`several carefully
`studied,
`approved, and
`available disease-
`modifying agents
`in relapsing-
`remitting MS and
`even in clinically
`isolated
`syndromes.
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`124
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`Page 5 of 22
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`

`

`KEY POINT:
`
`A The most
`common side
`effect of
`IFN-bb-1b is
`a flulike
`syndrome
`characterized
`by fevers, chills,
`headache, and
`myalgias.
`
`125
`
`placebo-controlled study included pa-
`tients with a median time on study of
`almost 4 years,
`including a few pa-
`tients who had completed 5 years. The
`analysis of the 3-year data and that for
`the entire data set (all patients, all time
`on study) shows a continued signifi-
`cant decrease in the relapse rate of
`about 30% (P = 0.006, pooled data, all
`patients, all time points on study). The
`same holds true for each individ-
`ual year, although significance was
`achieved individually only for the first
`2 years,
`likely due to loss of power
`from successive dropouts in the later
`years. Progression of disease, assessed
`by the proportion of patients with a
`sustained worsening by one point on
`the EDSS, showed a trend, but not a
`significant difference, in favor of IFN.
`The study was not powered to show a
`change in EDSS but rather to assess
`change in relapse rate. The MRI data
`for all patients over the course of the
`study continued to show a dramatic
`effect from treatment with IFN, with
`no significant increase in lesion bur-
`den through the fifth year. The place-
`bo group increased their T2 burden by
`about 10% per year. This data demon-
`strates a persistence of effect in the
`group response to IFN.
`The most common side effect of
`IFN-bb-1b is a flulike syndrome charac-
`terized by fevers, chills, headache, and
`myalgias. This occurs shortly after
`injection and persists for a variable
`period, usually less than 24 hours. The
`flulike syndrome wanes over weeks
`to months but persists in up to 10%
`of patients. Rarely,
`increases in liver
`enzymes (aspartate aminotransferase,
`alanine aminotransferase) occur, which
`respond to dose reduction or drug
`discontinuation. Liver function should
`be monitored as long as patients are
`on interferon. Redness at the injec-
`tion sites is quite common, and skin
`necrosis at the subcutaneous injection
`site is a rare occurrence.
`
`Subsequently, IFN-bb-1b was tested
`in MS patients with SP disease. In a
`multicenter, double-blind, randomized
`clinical trial conducted in Europe and
`published in 1998 (European Study
`Group, 1998), 718 SPMS patients with
`EDSS of 3.0 to 6.5 and at least two
`exacerbations in the prior 2 years were
`treated with either 8 mIU IFN-bb-1b,
`or placebo. The trial was planned for
`3 years, with the primary outcome
`measure of time to a sustained wors-
`ening of 1 point on the EDSS score
`(0.5 points
`if baseline EDSS was
`greater
`than 5.5). The study was
`stopped shortly prior to the planned
`ending at 3 years because of over-
`whelming evidence of efficacy. The re-
`sults reveal that the IFN-treated group
`had a 22% reduction in rate of
`progression, which translated to a
`12-month delay until reaching similar
`disability levels. Similarly, time to be-
`coming wheelchair bound, EDSS of
`7 or more, was delayed by 9 months.
`There was a significant reduction in
`the relapse rate in IFN-treated pa-
`tients and reduced MRI activity as mea-
`sured by gadolinium-enhancing lesions.
`There was also a significant reduction
`in both T2 and T1 lesion load and
`a lesser degree of N-acetylaspartate
`signal
`loss (a measure of neuronal/
`axonal
`loss) on magnetic resonance
`(MR) spectroscopy. However,
`there
`was not a significant reduction in the
`development of cerebral atrophy, the
`cause for which has been a subject of
`speculation.
`A second study of IFN-bb-1b in SPMS
`was conducted in North America with
`939 patients with evidence of progres-
`sion over the prior 2 years but no
`relapse requirement. In this double-
`blind controlled trial, patients received
`either placebo, 8 mIU IFN-bb-1b, or
`5 mIU/m2 IFN-bb-1b (which averaged
`9.6 mIU for the entire group) subcu-
`taneously every other day. The pri-
`mary outcome measure was the same
`
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`Page 6 of 22
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`

`

`"TREATMENTS FOR MULTIPLE SCLEROSIS
`
`as in the European IFN-bb-1b SP study.
`This planned 3-year study was stopped
`early for inability to achieve a signifi-
`cant difference in the primary out-
`come measure. As opposed to the
`European IFN-bb-1b SP study,
`this
`study did not show a significant dif-
`ference in disability measures between
`the treated groups and the placebo
`group. There were significant differ-
`ences in reduction in relapse rate, MRI
`measures of activity, and burden of
`disease (T2 lesion load).
`There has been considerable spec-
`ulation as to why the North American
`and European SP trials produced such
`different results. At entry, the mean
`EDSS scores were similar (5.1). The
`baseline demographics of
`the two
`populations differed in several ways.
`The North American study patients
`were older, had been diagnosed with
`MS for a longer time, and, perhaps
`most importantly, had fewer relapses
`and fewer gadolinium-enhancing le-
`sions prior to study entry. The latter
`difference could indicate that
`the
`European SP population had a greater
`inflammatory element to their disease
`and thus might respond better to an
`anti-inflammatory agent such as IFN-
`bb-1b. In the European study, however,
`the IFN-treated group had improved
`MR spectroscopic analysis of N-acetyl-
`aspartate, indicating less axonal dam-
`age. A better understanding of the
`causes for the disparity in these study
`results may come as our knowledge
`of the underlying pathogenic mecha-
`nisms of progressive disease increases.
`
`Interferon Beta-1a
`The pivotal trial of IFN-bb-1a (Avonex,
`Biogen, Inc.) in the United States was
`comprised of 301 patients with relaps-
`ing MS who had at least two exacer-
`bations over the prior 3 years and had
`an EDSS score between 1 and 3.5.
`Patients were assigned randomly to
`
`receive IFN 6 mIU (30 mcg) or a
`placebo via IM injection, once weekly
`( Jacobs et al, 1996). The trial was
`designed to last 2 years but was
`terminated prematurely because there
`were fewer dropouts than anticipated.
`As a result, only 57% of the enrolled
`patients completed 2 years and 77%
`completed 18 months. The primary
`outcome measure was the time to
`sustained progression of disability of
`at
`least one point on the EDSS,
`confirmed at 6 months (to lessen the
`chance that changes in EDSS were the
`result of exacerbations). A number of
`clinical and MRI measures served as
`secondary outcomes. The primary
`outcome measure was achieved with
`a 37% reduction in disability progres-
`sion; 22% of patients receiving IFN
`progressed by one or more points
`while 35% of placebo patients pro-
`gressed (P = 0.02) by one or more
`points. In addition, there was a signif-
`icant
`reduction in the annualized
`relapse rate for all patients, all time
`on study, and especially for those
`treated for the full 2 years (18% for
`all patients, all time on study, and
`32% for those completing 2 years).
`In relation to MRI there was a sig-
`nificant
`treatment effect on annual
`gadolinium-enhanced MRI, a measure
`of disease activity, but the effect on
`total
`lesion volume did not reach
`statistical significance at 2 years. The
`side effect profile of
`IFN included
`flulike symptoms (61% IFN versus
`40% placebo), muscle aches (34%
`versus 15%), fever (23% versus 13%),
`chills (21% versus 7%), with no differ-
`ences found for headache, pain, or
`weakness. Overall, the agent was very
`well tolerated. This drug was approved
`by the US Food and Drug Administra-
`tion (USFDA) in 1996 and is widely
`used in the United States. Subsequent
`analyses reveal a reduction in rate of
`development of cerebral atrophy and
`beneficial effects on cognition.
`
`KEY POINTS:
`
`A There has been
`considerable
`speculation as
`to why the
`North American
`and European
`SP trials
`produced such
`different
`results.
`
`A The pivotal trial
`of IFN-bb-1a
`(Avonex, Biogen,
`Inc.) in the
`United States
`was comprised
`of 301 patients
`with relapsing
`MS who had at
`least two
`exacerbations
`over the prior
`3 years and had
`an EDSS score
`between 1 and
`3.5. The primary
`outcome
`measure was
`achieved with a
`37% reduction
`in disability
`progression;
`22% of patients
`receiving IFN
`progressed by
`one or more
`points while
`35% of placebo
`patients
`progressed
`(P = 0.02)
`by one or
`more points.
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`126
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`

`KEY POINTS:
`
`A The IMPACT
`study showed
`a slowing of
`progression
`by 40%, as
`measured by
`the MSFC, in
`patients treated
`with IFN-bb-1a
`compared
`with placebo
`patients, a
`statistically
`significant
`change.
`
`A The CHAMPS
`study ran
`for nearly
`3 years and
`demonstrated a
`reduced risk of
`44% of having a
`second attack in
`patients treated
`with IFN-bb-1a
`(approximately
`50% of
`placebo-treated
`patients had a
`second attack
`compared to
`approximately
`35% of those
`treated with
`IFN-bb-1a).
`
`127
`
`IFN-bb-1a (International
`A trial of
`Multiple Sclerosis Secondary Progres-
`sive Avonex Clinical Trial [IMPACT],
`Avonex) in SPMS was reported in
`2002 (Cohen et al, 2002). This study
`utilized a double dose, 60 g, of IFN-bb-
`1a, given once weekly for 2 years to
`436 patients with SPMS in the United
`States and Canada. The entry criteria
`were SPMS that had progressed over
`the past year in patients with an EDSS
`of 3.5 to 6.5 and an MRI consistent
`with MS. The primary outcome mea-
`sure was a change in the Multiple
`Sclerosis Functional Composite (MSFC)
`(Rudick et al, 2002), a new outcome
`measure that was designed to be more
`sensitive to change than the EDSS. A
`slowing of progression by 40%, as
`measured by the MSFC, was found
`in patients treated with IFN-bb-1a com-
`pared with placebo patients, a statisti-
`cally significant change. Unfortunately,
`no significant improvement as mea-
`sured by sustained change in the
`EDSS, a secondary outcome measure,
`was found. This is not that surprising
`as one of the benefits of the MSFC is
`that the scale requires fewer patients
`than an EDSS-powered study, and thus
`this trial was not powered to show a
`difference in EDSS. There were signif-
`icant benefits seen in relapse rate and
`MRI metrics similar to most other SP
`trials. This was the first major clinical
`trial to employ the MSFC as the pri-
`mary outcome measure. The USFDA
`has not yet recognized the MSFC as a
`validated scale, and thus this study has
`not resulted in a labeling change for
`this form of interferon in SPMS.
`Another
`study with the Avonex
`form of IFN-bb-1a sought to determine
`whether treating individuals who suf-
`fered a single attack of demyelination
`(clinically isolated syndrome) would
`be less likely to develop a second—
`and therefore MS-defining—attack if
`treated with IFN at a dose of 30 g, IM,
`once weekly (Controlled High-Risk
`
`Avonex Multiple Sclerosis Prevention
`Study [CHAMPS]) ( Jacobs et al, 2000).
`This randomized double-blind study
`enrolled 383 patients who suffered a
`single event of either optic neuritis,
`brain stem/cerebellar dysfunction, or
`acute myelitis and had two or more
`abnormalities consistent with demye-
`lination on their MRI scan of the brain.
`Patients had to be screened within
`2 weeks of symptom onset and were
`initially treated with IVMP 1 g/d for
`3 days followed by an oral prednisone
`taper. The study ran for nearly 3 years
`and demonstrated a reduced risk of
`44% of having a second attack in
`those treated with IFN-bb-1a (approxi-
`mately 50% of placebo-treated patients
`had a second attack compared to
`approximately 35% of those treated
`with IFN-bb-1a). There was a favorable
`effect of treatment on MRI metrics,
`as well.
`Another multicenter, placebo-con-
`trolled, clinical trial of IFN-bb-1a (Rebif;
`PRISMS Trial) from a different compa-
`ny (Serono) randomized 560 patients
`with RRMS and Kurtzke scores of 0
`to 5.0 into a placebo group, 6 mIU
`(22 g) IFN-bb-1a, or 12 mIU (44 g) IFN-
`bb-1a administered subcutaneously 3
`times weekly for 2 years (Prevention
`of Relapses and Disability by Interfer-
`on beta-1a Subcutaneously in Multiple
`Sclerosis [PRISMS] Study Group, 1998).
`In this study, patients in both treat-
`ment groups performed significantly
`better than placebo-treated patients in
`respect to reduction in relapse rate
`(the primary outcome measure) (27%
`and 33% reductions for the 22 g and
`44 g groups, respectively), percentage
`of patients relapse free, time to first
`relapse, number of moderate or se-
`vere attacks, steroid use, and hospital-
`izations.
`Time
`to
`confirmed
`progression of disability by an increase
`in one point on the Kurtzke scale
`was also better in the treated groups.
`Analysis of MRI scans in the groups
`
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`

`"TREATMENTS FOR MULTIPLE SCLEROSIS
`
`revealed decreased activity and lesion
`burden in the IFN-treated patients.
`Although the higher-dose group did
`better, there were no significant dif-
`ferences in the major clinical out-
`come measures between the two
`dosing groups. Following the 2-year
`fully blinded portion of this trial, the
`placebo group was randomized to
`either 22 or 44 g, and the whole group
`was observed for an additional 2 years.
`By the end of 4 years there was
`continued evidence of efficacy of the
`IFN and a strong