J Neurol (2005) 252 [Suppl 3]: III/3–III/9
`DOI 10.1007/s00415-005-2010-6
`
`Fred Lublin
`
`History of modern multiple
`sclerosis therapy
`
`■ Abstract Although the earliest
`recorded description of multiple
`sclerosis (MS) dates back to the
`14th century, it was not until the
`latter years of the 20th that treat-
`ments for this disabling condition
`were found. However, the “road to
`success” has not been without
`hurdles. Trials with both interferon
`alpha and gamma proved unsuc-
`cessful, as did treatment with oral
`myelin, cladribine, sulfasalazine
`and inhibitors of tumour necrosis
`factor. In 1993, interferon beta-1b
`(IFNβ-1b) became the first therapy
`proven to be effective in altering
`the natural history of relapsing-
`
`F. D. Lublin, MD (쾷)
`Corinne Goldsmith Dickinson Center
`for Multiple Sclerosis
`Mount Sinai Medical Center
`New York, NY 10029-6574, USA
`Tel.: +1-212/241-6854
`Fax: +1-212/423-0440
`E-Mail: fred.lublin@mssm.edu
`
`remitting MS (RRMS). This was
`followed by successful trials with
`IFNβ-1a and glatiramer acetate. In
`1998, a European trial showed
`IFNβ-1b to be also beneficial in
`the treatment of secondary pro-
`gressive MS (SPMS). A similar trial
`in North America failed to reach
`its primary endpoint but was
`effective across secondary end-
`points, highlighting how different
`methodology and patient popula-
`tions can lead to inconsistent
`results and, thus, making compa-
`risons across trials difficult. The
`trend for early intervention in MS
`with IFNβ was recently supported
`by the CHAMPS (Controlled High-
`risk Avonex MultiPle Sclerosis)
`and ETOMS (Early Treatment of
`Multiple Sclerosis) studies using
`once-weekly IFNβ-1a. Both trials
`demonstrated delayed conversion
`to clinically definite MS in patients
`with a clinically isolated syndrome
`and magnetic resonance imaging
`
`(MRI) findings suggestive of MS.
`Two directly comparative trials of
`high- (250 μg IFNβ-1b or 44 μg
`IFNβ-1a) and low-dose (30 μg
`IFNβ-1a) IFNβ (INCOMIN
`[INdependent COMparison of
`INterferons] and EVIDENCE
`[EVidence of Interferon Dose-
`response: European North Ameri-
`can Comparative Efficacy]) sup-
`port the superior efficacy of the
`higher dose and/or more frequent
`administration for treating RRMS.
`Since MS entered the treatment
`era in 1993, therapies for RRMS,
`SPMS and, more recently, progres-
`sive-relapsing MS have been devel-
`oped. There is now a much better
`understanding of the pathogenesis
`of the disease, but new and im-
`proved therapeutic approaches are
`still needed.
`
`■ Key words multiple sclerosis ·
`therapy · interferon beta-1b
`
`JON 2010
`
`Charcot’s contribution extended to the development of
`diagnostic criteria, which included the now-famous
`triad of “nystagmus, tremor and scanning speech”. He
`also identified many important histological features, in-
`cluding loss of myelin. This paper reviews the develop-
`ment of current treatment strategies for MS.
`
`Introduction
`
`The earliest recorded description of multiple sclerosis
`(MS) dates back to the 14th century, but it was the French
`neurologist, Jean-Martin Charcot (1825–1893), who
`made the first definite links between the symptoms of
`MS and the pathological changes seen in post-mortem
`samples. He described the condition as “sclerose en
`plaques” and recognised MS as a distinct disease entity.
`
`Merck 2013
`TWi v Merck
`IPR2023-00049
`
`

`

`III/4
`
`A brief history
`
`In the 1960s, corticosteroids were introduced to reduce
`the severity of relapses. They are, however, not effective
`at reducing the number of relapses or the rate of disease
`progression.This was followed in the 1970s and 1980s by
`trials with a variety of immunosuppressant agents, in-
`cluding cyclophosphamide, cyclosporine, azathioprine,
`methotrexate and glatiramer acetate (GA) (copolymer
`1) [2]. These studies examined the effect of treatment on
`exacerbations of MS, thus providing a useful platform
`for the development of assessment tools for use in later
`studies. However, it was not until the late 1980s that the
`concept of
`immunomodulation was extensively ex-
`plored, and this was assisted by the development of non-
`invasive monitoring methods.
`In 1981, the new imaging technique, magnetic reso-
`nance imaging (MRI), dramatically improved the visu-
`alisation of the brain and spinal cord, enabling lesions to
`be quantified in the living patient. The pioneering work
`of Ian Young in this field correctly predicted the future
`value of MRI scanning in the diagnosis and monitoring
`of MS [31]. He suggested that the technique may help
`measure the severity of the disease and, thus, be used to
`evaluate the effect of therapeutic regimens on disease
`progression. The technique was refined by Robert
`Grossmann in 1986,who discovered that gadolinium en-
`hancement was a marker of inflammation [8]. Gadolin-
`ium-enhanced MRI scans provide a way of identifying
`new and active lesions. MRI has become an established
`method of monitoring disease progression in clinical
`trials.
`The interferons have a unique place in the history of
`drug development in that studies in man preceded ani-
`mal studies. In early trials, interferon gamma was found
`to provoke acute exacerbations of MS, which ceased
`when the drug was removed. Attention shifted to inter-
`feron alpha and interferon beta (IFNβ) as they were
`known inhibitors of interferon gamma, and IFNβ was
`shown to be well-tolerated when compared with inter-
`feron alpha. The pivotal IFNβ-1b trial was published in
`1993 and heralded the start of the therapeutic era in MS
`and the introduction of IFNβ-1b into the USA – the first
`therapy proven effective in altering the natural history
`of relapsing-remitting MS (RRMS) [11, 29]. Although
`the pivotal trial did not use gadolinium in the imaging
`protocols, a study by Stone et al. clearly showed that
`IFNβ-1b had a dramatic effect at reducing gadolinium-
`enhancing lesions [26].
`The pivotal IFNβ-1b study was followed in subse-
`quent years by successful trials in RRMS with IFNβ-1a
`and the non-interferon agent GA [11, 13, 15]. In 1998, a
`study undertaken in Europe showed that IFNβ-1b was
`also successful in the treatment of secondary progres-
`sive MS (SPMS) [7].
`However, the “road to success” in the treatment of MS
`
`has not been without its challenges. Unsuccessful stud-
`ies have included experimental treatment with a range
`of promising agents. Whilst we now have a much better
`understanding of the pathogenesis of the disease, there
`is a continued need for improved therapeutic ap-
`proaches for MS.
`
`MS and clinical trials
`
`Exemplary clinical trials incorporate blinding to treat-
`ment, randomisation and the selection of appropriate
`patients and outcome measures.The classification of MS
`into four distinct clinical patterns (namely RRMS,
`SPMS, primary progressive and progressive-relapsing
`MS) has also played an important role in ensuring that
`homogeneous populations are assigned to clinical trials,
`even though precise biological definitions are not yet
`available [17].
`Comparison between current treatments in clinical
`trials is made difficult by the lack of prospectively de-
`signed,fully-blinded,head-to-head trials.Interpretation
`of data obtained from different studies is fraught with
`difficulty because of differences in inclusion and exclu-
`sion criteria, different use of placebo control, and diffe-
`rences in duration of treatment, which impact upon
`measures of efficacy. Furthermore, there are no labora-
`tory studies (including MRI findings) that meet Food
`and Drug Administration requirements for a surrogate
`marker of prognosis.
`In terms of outcome variables, relapse rate in MS is a
`routine measure of disease activity that is easy to quan-
`tify and included in almost all trials. Assessment of dis-
`ability as a measure of disease progression is equally, if
`not more, important. MRI assessment of gadolinium-
`enhancing lesions provides useful information about
`acute disease activity, but interpretation of T2 lesion
`load is more problematic because of the heterogeneous
`nature of these lesions, and because lesion load is a mea-
`sure of disease burden rather than disease activity. Nev-
`ertheless, it still provides strong evidence of treatment
`effects.
`An important principle when interpreting clinical
`trial data is that of coherence. A study in which all out-
`comes point to the same effect, even if they are not all
`statistically significant, provides confidence that the
`outcomes observed are real. It is also important that the
`treatment duration in a clinical trial is long enough to
`provide meaningful information about expected bene-
`fits.For example,in an early study with sulfasalazine,the
`results at 18 months showed a marked reduction in dis-
`ease progression relative to placebo, but at the end of the
`planned 3-year study duration no differences were ob-
`served between placebo and active treatment [18].
`
`

`

`III/5
`
`Placebo
`50 μg Betaferon
`250 μg Betaferon
`
`P = 0.0363
`
`n = 14
`
`P = 0.0002
`
`n = 70
`
`P = 0.0055
`
`n = 72
`
`n = 61
`
`n = 16
`
`n = 13
`
`P = 0.0015
`
`P = 0.0012
`
`n = 72 n = 61
`
`n = 72 n = 62
`
`n = 59
`
`n = 77
`
`n = 73
`
`n = 73
`
`n = 75
`
`30
`
`25
`
`20
`
`15
`
`10
`
`05
`
`-5
`
`-10
`
`Percent Change From Baseline (Median)
`
`Year 1
`Year 2
`Year 3
`Year 4
`Year 5
`Fig. 2 Effect of IFNβ-1b on T2 MRI lesion area over 5 years in patients with RRMS
`(from [12] with permission of Lippincott Williams & Wilkins)
`
`study was the substantial proportion of patients who did
`not complete 2 years of treatment,and intention-to-treat
`analysis showed an 18 % reduction in relapse rate.
`Glatiramer acetate (copolymer 1) was investigated in
`a 2-year, double-blind, placebo-controlled study involv-
`ing 251 patients with RRMS who were randomised to re-
`ceive placebo (n = 126) or GA (n = 125) at a dosage of
`20 mg by daily subcutaneous injection for 2 years, with
`an 11-month extension period [15]. The primary end-
`point was a difference in the MS relapse rate. The mean
`number of documented relapses during the initial 2-
`year, double-blind phase of the study was 1.19 ± 0.13 for
`patients receiving GA and 1.68 ± 0.13 for those receiving
`placebo; a 29 % reduction in favour of GA (P = 0.007)
`[15].Long-term follow-up at 6 years indicated that open-
`label treatment with GA continued to protect against
`worsening disability [30]. Between years 3 and 7, the pa-
`tients initially receiving placebo were switched to active
`treatment, meaning there was no control against which
`to measure effect. However, although these patients ben-
`efited from active therapy, they failed to “catch up” with
`patients originally assigned to GA, demonstrating the
`importance of early treatment.
`
`Treatment of RRMS
`The original IFNβ-1b study included 372 patients with
`RRMS who were randomised to receive placebo, or
`IFNβ-1b 50 μg or 250 μg (1.6 or 8.0 MIU) self-adminis-
`tered by subcutaneous injection every other day for 2
`years, with an optional 1-year extension [11]. Due to
`staggered enrollment, some patients received treatment
`for 5 years or more. The results indicated that IFNβ-1b
`250 μg was associated with a reduction in relapse rate of
`approximately 30 % compared with placebo over the 5
`years of the study (Fig. 1) [12]. The reductions after 3–5
`years (28–30 %),although comparable to those seen dur-
`ing the first 2 years of the study (28–33 %), failed to at-
`tain statistical significance because of the declining pa-
`tient numbers in the study at each successive time point.
`The risk of progression at 2 years also showed a strong
`trend and magnitude of effect in favour of IFNβ-1b
`treatment, but the study was not powered to measure an
`effect on this outcome. Clinically important and statisti-
`cally significant reductions in MRI T2 lesion load with
`IFNβ-1b in comparison with placebo were also achieved
`throughout the 5-year follow-up period (Fig. 2). These
`findings clearly demonstrate the clinically important
`benefit of treatment with IFNβ-1b in patients with
`RRMS.
`The pivotal study of IFNβ-1a in RRMS included 301
`patients who were randomly assigned to treatment with
`placebo or IFNβ-1a 30 μg administered by intra-muscu-
`lar injection once a week [13]. This was the first study to
`use a sustained one-point change in Expanded Disabil-
`ity Status Scale (EDSS) score as a primary efficacy vari-
`able. Follow-up at 2 years indicated that treatment with
`IFNβ-1a reduced the risk of sustained EDSS progression
`in comparison with placebo (21.9 % vs. 34.9 %, respec-
`tively; P = 0.02) over the 2-year study period. The sub-
`group of patients treated with IFNβ-1a for at least 2
`years also had significantly fewer exacerbations and
`fewer gadolinium-enhanced brain lesions than those
`treated with placebo. However, the concern over this
`
`33%
`P < 0.001
`
`1.50
`
`1.44
`
`28%
`P = 0.030
`
`Placebo
`50 μg
`250 μg
`
`When to begin treatment
`
`Pathological and MRI studies suggest that axonal dam-
`age may be an early event in the evolution of MS, and ev-
`idence is accumulating that, in the early phases of the
`disease, axonal damage is largely a consequence of in-
`flammatory processes [4, 10, 27, 28]. As the mechanism
`of action of IFNβ in MS is anti-inflammatory, improved
`results could be predicted with earlier rather than later
`treatment of MS.
`In the CHAMPS (Controlled High-risk subjects
`Avonex® MultiPle Sclerosis prevention) study, 383 pa-
`
`1.22
`
`1.18
`
`1.04
`
`0.96
`
`28%
`P = 0.084
`
`0.92
`
`0.85
`
`0.80
`
`24%
`P = 0.166
`
`0.88
`
`30%
`P = 0.393
`
`0.81
`
`0.66
`
`0.68 0.67
`
`0.66
`
`0.57
`
`1
`
`2
`
`3
`
`4
`
`5
`
`1.25
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`Relapse Rate
`
`Study Year
`Fig. 1 Effect of IFNβ-1b on annual relapse rate in RRMS over 5 years [12]
`
`

`

`the study compared with patients receiving IFNβ-1a
`once weekly (36 %). This corresponded to a significant
`increase of 42 %, favouring IFNβ-1b-treated patients
`(P = 0.036).
`Similar findings were obtained in the EVIDENCE
`(EVidence for Interferon Dose Effect: European-North
`American Comparative Efficacy) study, which com-
`pared IFNβ-1a at 44 μg given subcutaneously 3 times
`a week with a once-weekly regimen of IFNβ-1a given
`intra-muscularly at 30 μg to patients with RRMS [21].
`The results at week 48 show that the more frequent,
`high-dose (44 μg) regimen was associated with a 23 %
`reduction in the number of patients suffering a first re-
`lapse (Fig. 3).
`Not all studies have shown an increase in efficacy
`with increased dosing. Data from a study comparing
`once-weekly single (30 μg) with double-dose (60 μg)
`intra-muscular IFNβ-1a in 802 patients with RRMS for
`at least 3 years failed to show a reduction in disease pro-
`gression with the higher dose at any point during the 3-
`year study [3]. It is possible, therefore, that frequency of
`dosing may be as important as the actual dose.
`
`Studies in SPMS
`The European study with IFNβ-1b in SPMS included 718
`patients (EDSS score 3.0–6.5), of whom 360 were ran-
`domly assigned to receive IFNβ-1b 250 μg by subcuta-
`neous injection every other day, and 358 patients were
`assigned to receive placebo [7]. Patients were followed
`up for 3 years after the start of treatment. IFNβ-1b was
`shown to delay disease progression by between 9 and 12
`months. In the placebo group, 49.7 % of patients had
`confirmed progression at 3 years compared with 38.9 %
`in the IFNβ-1b group (P = 0.005), representing a relative
`reduction of 21.7 %.
`
`48%
`-23%
`
`37%
`
`Avonex 30 μg qw
`
`Rebif 44 μg tiw
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`to First Relapse (%)
`
`Cumulative Probability of Time
`
`0
`
`4
`
`8
`
`12 16 20 24 28 32 36 40 44 48
`Week
`
`HR 0.70, P = 0.003 Cox proportional hazards model
`
`Fig. 3 Kaplan-Meier estimates of cumulative probability of relapse during the EV-
`IDENCE trial (from [21] with permission of Lippincott Williams & Wilkins)
`
`III/6
`
`tients who had a first acute clinical demyelinating event
`(optic neuritis, incomplete transverse myelitis or brain-
`stem or cerebellar syndrome), and evidence of demyeli-
`nation on MRI of the brain, were randomly assigned to
`receive weekly intra-muscular injections of IFNβ-1a
`30 μg or placebo [14]. During 3 years of follow-up, the
`cumulative probability of developing clinically definite
`MS (CDMS) was significantly lower in the IFNβ-1a
`group than in the placebo group. The relative risk was
`0.56 with a 95 % confidence interval of 0.38–0.81
`(P = 0.002). These findings showed that initiating treat-
`ment with IFNβ-1a at the time of a first demyelinating
`event was beneficial for patients with brain lesions on
`MRI that indicated a high risk of CDMS.
`Similar findings were achieved in the ETOMS (Early
`Treatment Of MS) study, in which IFNβ-1a was given
`subcutaneously at a dose of 22 μg once a week to patients
`who had initial findings suggestive of MS within the pre-
`vious 3 months [5]. In this study, the time to the occur-
`rence of the second relapse (i. e. MS according to Poser’s
`criteria) in 30 % of patients (i. e. the 30th centile) was
`used to define conversion to CDMS; this was 569 days in
`the IFNβ-1a group compared with 252 days in the
`placebo group. The hazard ratio (0.65) showed a statis-
`tically significant benefit with IFNβ-1a relative to
`placebo (P = 0.023) when adjusted for baseline lesion
`count and time from first attack to randomisation. Im-
`portantly, in this study the therapeutic benefit on re-
`lapses was supported by MRI findings showing that both
`lesion activity and the accumulation of lesion burden
`were reduced compared with placebo. The efficacy of
`IFNβ-1a in these two studies in RRMS reinforces the
`concept of early intervention.
`
`Treatment intensification
`
`In addition to starting treatment early in the course of
`the disease, there is good evidence to suggest that better
`results are obtained with high-dose (250 μg IFNβ-1b, 44
`μg IFNβ-1a) IFNβ rather than with low-dose IFNβ-1a.A
`study of two IFNβ-1b doses (50 μg and 250 μg every
`other day) against placebo found that the 250 μg dose
`improved the reduction in annual relapse rate by 34 %
`relative to placebo, while the reduction with 50 μg was
`8 % [11]. The effect was not as substantial in the subcu-
`taneous IFNβ-1a efficacy trial, with improvements in
`annual relapse rates relative to placebo of 29 % and 33 %
`for 22 μg and 44 μg IFNβ-1a, respectively [23].
`The INCOMIN (INdependent COMparison of INter-
`feron) trial showed the benefit of high-dose, high-fre-
`quency IFNβ-1b (250 μg every other day) over once-
`weekly IFNβ-1a (30 μg) in the prevention of relapse in
`patients with RRMS [6].A higher proportion of patients
`receiving 250 μg IFNβ-1b (51 %) remained free from re-
`lapse (the primary outcome measure) for the duration of
`
`

`

`In the North American study in SPMS (a 3-year, mul-
`ticentre, double-blind, placebo-controlled trial) 939 pa-
`tients were randomised to receive IFNβ-1b 250 μg every
`other day, 160 μg/m2 every other day or placebo. Treat-
`ment with IFNβ-1b resulted in significant improvement
`(compared with placebo) on all outcome measures in-
`volving clinical relapses, newly active MRI lesions and
`accumulated burden of disease on T2-weighted images
`[22]. However, the study failed to show a difference be-
`tween active treatment and placebo in terms of disease
`progression – the primary outcome measure. There are
`several possible explanations for the difference between
`the primary outcomes of the European and North Amer-
`ican trials, but one is that the North American study ap-
`peared to enrol patients at a more advanced stage of
`their disease. An analogous study that examined the ef-
`fect of IFNβ-1a treatment in SPMS revealed similar find-
`ings [25]. This may imply that IFNβ may be more effec-
`tive at preventing accumulation of disability in earlier
`stages of the disease or in patients experiencing more
`exacerbations.
`Finally, mitoxantrone 12 mg/m2 has been shown to
`significantly reduce the probability of EDSS progression
`in patients with SPMS when compared with placebo
`over a period of 2 years [9]. However, given the potential
`cumulative cardiotoxicity of mitoxantrone, it should be
`reserved for patients in whom disease progression can-
`not be controlled by established immunomodulatory
`therapeutics.
`
`Other therapeutic approaches
`
`A number of unsuccessful Phase II studies have been
`undertaken with a variety of agents. Although negative,
`some of this work nevertheless provides valuable infor-
`mation that may guide future research. Studies with
`cladribine in primary progressive MS and SPMS, for ex-
`ample, showed evidence for a good response in terms of
`gadolinium-enhancing lesions in the absence of any
`benefit on clinical parameters, suggesting a dissociation
`between inflammatory changes and relapses in progres-
`sive MS [24].
`Studies with altered peptide ligand showed that ad-
`ministration of this substance was associated with a po-
`tentiation of exacerbations of MS, suggesting the possi-
`bility that myelin basic peptide is involved in the
`pathogenesis of MS [1].
`
`III/7
`
`Oral tolerance has been tested as a therapeutic strat-
`egy in MS using the oral administration of myelin. A
`multicentre trial controlled for patient gender and
`steroid treatment was conducted in which myelin was
`administered orally to over 500 early RRMS patients. In-
`dividuals received either 300 mg of bovine myelin or ca-
`sein daily and were monitored for exacerbation, EDSS
`and MRI. Contrary to studies in experimental autoim-
`mune encephalomyelitis animals, daily administration
`of bovine myelin did not significantly improve disease
`in MS patients.
`Results from a number of small studies show that the
`administration of tumour necrosis factor (TNF) alpha
`inhibitors also appears to exacerbate MS [16, 20]. These
`findings are paradoxical – TNF inhibitors are clearly ef-
`fective in animal models of MS, and are also widely used
`in the treatment of other autoimmune conditions such
`as rheumatoid and psoriatic arthritis and inflammatory
`bowel disease. Further research is, therefore, required to
`fully understand the role of TNF in the pathogenesis of
`MS.
`A Phase III, placebo-controlled trial of linomide in
`715 patients with RRMS (n = 90) or SPMS (n = 625)
`found that the drug caused coronary artery disease in a
`number of patients, and the trial was halted 1 month af-
`ter completion of enrollment [19].
`
`Conclusions
`
`Interferon beta-1b was the first immunomodulatory
`therapy to be approved for the treatment of RRMS, and
`is the only IFNβ to receive a licence for SPMS therapy.
`The development of new agents is a long, drawn-out, of-
`ten unsuccessful process, as the number of recent fail-
`ures illustrates. However, the long-term safety and effi-
`cacy of IFNβ treatment is unquestionable, with over 10
`years of clinical experience as evidence. Future studies
`will focus on going beyond the currently approved
`dosages and earlier intervention to prevent initial neu-
`ronal damage with the proven disease-modifying thera-
`pies. Furthermore, opportunities for pharmacological
`intervention into the immune processes contributing to
`MS exist for future research, offering the possibility of
`more effective therapies. It is hoped that ongoing re-
`search will expand our knowledge of the appropriate
`targets for intervention, enabling more effective thera-
`pies to be developed.
`
`

`

`III/8
`
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