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`-l!I4
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`Multiple
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`Sclerosis
`
`CLINICAL AND LABORATORY RESEARCH
`
`20th Congress of the European
`Committee for Treatment and Research
`in Multiple Sclerosis
`9th Annual Meeting of Rehabilitation in MS
`
`October 6-9, 2004
`Austria Center, Vienna, Austria
`
`Sawai (IPR2019-00789), Ex. 1013, p. 001
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`

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`t4 iiItIPe 00( Y SCIENCE LIBRARY
`Scierosis
`
`CLINICAL AND LABORATORY RESEARCH
`
`ICE THIS MATERIAL MAYBE PRQTFCj
`(CO YRIGHT LAW (TITLE 17U.S. CC
`
`Volume 10 • Supplement 2 • September 2004
`CONTENTS
`Paper Abstracts
`Session
`Page
`
`Young Scientific Investigators' Session
`Experimental models of MS
`Atypical manifestations of MS
`Multidisciplinary aspects of rehabilitation (RIMS)
`Immunology and immunotherapy of MS
`MRI - pathology correlations
`Methods and strategies in MS rehabilitation (RIMS)
`Plenary Session 1
`Biological fluid markers in MS
`Primary progressive MS
`Mechanisms of axonal damage, neuroprotective strategies
`Genetics and familial MS
`Alternative therapies in MS
`Plenary Session 2
`Closing Session
`
` 97
`SiQo
`Slol
`S102
`S103
`S104
`S106
`S107
`S108
`S109
`Sill
`S113
`S114
`S115
`S116
`Poster Viewing I
`Page
`Poster topics
` 116
`S127
`S133
`S138
`S140
`S147
`S153
`S155
`S163
`S174
`Poster Viewing II
`
`Neuropsychology
`Quality of life in MS
`Healthcare systems
`Alternative therapies for MS
`Rehabilitation in MS
`Symptomatic management
`Pthology
`Epidemiology
`Immunology
`Clinical aspects of MS
`
` 196
`S200
`S203
`S211
`S219
`S222
`S234
`
`Experimental models in MS
`Neurobiology
`Genetics
`Surrogate markers
`Neurophysiology
`Imaging
`Immunotherapy
`
`www.multiplesclerosisjournal .com
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`Abstract numbers
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`5-16
`22-25
`26-31
`R33-R35
`39-42
`43-48
`R50-R53
`58-59
`60-65
`66-71
`80-85
`97-91
`99-102
`112
`115-116
`
`Poster numbers
`
`P117-P155
`P156-P178
`P179-P195
`P196-P200
`P201-P224
`P225-P245
`P246-P255
`P256-P284.
`P285-P328
`P329-P412
`
`P413-P429
`P430-P439
`P440-P470
`P471-P500
`P501-P512
`P513-P553
`P554-P695
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`Sawai (IPR2019-00789), Ex. 1013, p. 002
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`Multiple Sclerosis
`
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`Sawai (IPR2019-00789), Ex. 1013, p. 003
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`

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`/
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`;258
`
`Abstracts
`Immunotherapy
`
`relapse rate and the number of active lesions in MR-imaging in relapsing-
`remitting MS. The doses of ivlg used for treatment in relapsing-remitting
`MS have varied 10-fold and the optimal dose of ivlg for treating MS is still
`unknown. Mg has several effects on the immune system that could have a
`beneficial influence on disease processes in multiple sclerosis (MS)
`Significant changes in serum levels of circulating cytokines after infusions
`of ivlg have been observed. As Interleukin-6 (IL-6) and Interleukin-10 (IL-
`10) play important role as pro- and anti-inflammatory factors, in viva
`modulation of these cytokines may account for immunomodulatory and
`anti-inflammatory effect of intravenous Ig therapy. In order to better
`understand mechanism of action of low-dose ivlg cyclic therapy we have
`investigated serum levels of IL-6 and IL-10 before and a day after ivlg
`infusion in patients with multiple sclerosis. Methods: Serum levels of IL-6
`and IL-10 were assayed in 20 patients with MS before and 24 hours after
`infusion of 5g In = ii) and 2.5g In 9) ivlg. Results: We have not observed
`significant changes of pro-inflamatory IL-6 nor anti-inflammatory IL-b
`serum levels after infusions of ivlg in both doses of 2,5g and 5g.
`Conclusion: Hereby presented data suggest that potential therapeutic
`effect of low-dose ivlg treatment in MS is not mediated by changes of pro-
`inflammatory IL-6 nor anti-inflammatory IL-b. As the modulating influ-
`ence of ivlg on cytokines seems to be dose-dependent observation of serum
`levels of cytokines after ivlg might give important indications in determin-
`ing ideal dosage of ivlg in treatment of MS.
`
`P639
`
`humunglobulin treatment of relapsing-remitting multiple sclerosis - a
`retrospective data analysis
`M. Baudr, S. Kremer, M. Freidel, Octapharma GmbH, FA Neurologiel
`Psychiatrie (Langenfeld, Kaltenkirchen. D)
`
`The efficacy of immunoglobulin (IVIG) in the treatment of patients with
`multiple sclerosis (MS) is still under discussion. Though it has been used
`for many years the results presented in clinical trials are not yet accepted
`as sufficient to license this drug for MS treatment. Thus retrospective
`observation studies might further support the available results. In this
`retrospective observation study neurologists treating in medical offices or
`outdoor-patient departments in hospitals had been asked to report about
`IVIG treatment and its efficacy by number of relapses and by expanded
`disability status score (EDSS) for patients who fulfil certain inclusion
`criteria. Finally data of 54 patients reported by- 21 study sites could be
`analysed. About 70 % of the patients had stopped a pretreatment and
`started with intravenous immunoglobulin (IVIG) for reason of adverse drug
`reaction, treatment failure or other contraindication. The mean annual
`relapse rate decreased by 62 % from 1.55 ±0.72 (median: 1,5) during the 2
`years before start of IVIG therapy to 0.59±0.57 (median: 0,5) within the
`first two years after start of WIG therapy ( p <0.0001). The annual relapse
`rate (ARR) improved in 81 % of the patients and remained constant in
`further 11 %. Disability improved in 18 % of patients by at least 1 EDSS
`point. Mean EDSS slightly but insignificantly increased. In conclusion the
`results confirm what has been reported from clinical trials that IVIG is
`efficient to reduce relapse rate and to stabilize disease progression of
`relapsing remitting multiple sclerosis. They thus add value to justify the
`use of IVIG at least in cases where licensed therapies are contraindicated.
`
`P640
`
`The effect of IVIG treatment on visual outcome after acute optic neuritis
`H.G. Roed, A. Lan gkilde, F. Sellebjerg, M. Loutitzen, P Bang, A. Moerup, J.L.
`Frederiksen, University Hospital of Copenhagen. Statens Serum Institute
`(Glostrup, Hvidovre, Copenhagen, DK)
`Objective: The aim of the study was to investigate if intravenous
`immunoglobulin (WIG) treatment initiated within 30 days after onset of
`optic neuritis (ON) could improve visual outcome after six months.
`Background: ON is a well characterized model of an MS relapse, and
`may occur as part of MS or as a clinically isolated syndrome. JVIG
`treatment decreases relapse rate and the accumulation of clinical disability
`and reduces the number of new lesions on MRI om patients with MS. IVIG
`treatment does not appear to have major effects on stable clinical deficits.
`No previous controlled trials have investigated the efficacy of IVIG
`treatment in ON. Design/Methods: The study was a double-blind,
`randomized, placebo-controlled study of 68 patients with acute ON.
`
`Multiple Sclerosis
`
`Treatment was initiated within 30 days after symptom onset. Patients
`were treated with 0.4 g/kg bodyweight of IVIG or placebo at day 1, 2, 3, 30,
`and 60. Visual acuity, color vision, and contrast sensitivity were assessed at
`baseline and at days, 7, 30, and 180. Visual evoked potential (VEP) and
`Gadolinium-enhanced magnetic resonance imaging (MRI) studies were
`performed prior to treatment and at days 30 and 180. New relapses were
`recorded throughout the study period. The primary outcome measure was
`contrast sensitivity after 6 months. Secondary outcome measures were:
`contrast sensitivity at other time points, and visual acuity, colour vision,
`VEP, new or enhancing lesions on MRI, and new relapses. Results: 68
`patients were randomized. A total of 64 patients completed 6 months of
`clinical follow-up. Four patients discontinued medication because of
`adverse events. The randomization code was broken for one patient due
`to a serious adverse advent. Our results showed no difference at baseline or
`at follow-up visits in visual outcome, measured by contrast sensitivity,
`visual acuity and color vision or number of relapses in the study period
`between patients treated with IVIG and patients treated with placebo.
`Patients in the IVIG group had significantly more lesions at badline at day
`30 and 180 no difference between groups was found. Conclusions: Our
`study showed no improvement in visual outcome at any time-point in
`patients treated with WIG compared to placebo. Treatment with WIG does
`not appear to influence the duration or outcome of ON.
`
`P641
`
`Intravenous immunglobulins before, (luring and after pregnancy - a
`therapeutic option in multiple sclerosis?
`I. Ringel, S. Adler, U. Zetti, University of Rostock (Rostock, D)
`
`Background: Two thirds of multiple sclerosis (MS) patients are women,
`and the average age of onset overlaps the childbearing years. The PRIMS
`study (Confavreux et al., 1998) showed that the relapse rate decreases
`significantly during pregnancy in MS patients, while it increases after.
`delivery. Haas (2000) treated 43 MS patients with high dose intravenous
`immunglobulins (IVIG) after delivery and found a lower increase of
`exacerbation rates as compared with the untreated patients of the PRIMS
`study. The current therapeutic recommendations for most immuntherapies
`include an early start after onset of MS but also the discontinuation before
`pregnancy. We performed a study to evaluate the benefit of IVIG during the
`phase before and in the first months of pregnancy when the patients had to
`stop other immunmodulatory therapies. Methods: We studied 18 patients;
`11 women had a wish of pregnancy. Another seven women became
`pregnant while they were on an interferon treatment. Six patients received
`no treatment before pregnancy while five patients were treated with WIG.
`After onset of pregnancy nine patients received WIG and nine patients had
`no treatment. After delivery all patients but one received WIG. Results: We
`found a decrease of the relapse rate in the IVIG treated patients already
`before pregnancy from 2.4 to 0.8 relapses per year, but after onset of
`pregnancy there was no further reduction of exacerbations. The untreated
`patients showed a reduction of relapses only when pregnancy started from
`1,3 to 0.4 relapses per year, but during pregnancy the rate of relapses was
`comparable with the rate in the treated patient group. After delivery there
`was no increase of post partum exacerbation in the 17 IVIG treated
`patients. Conclusion: It seems that treatment with WIG before onset of
`pregnancy may reduce the rate of exacerbations compared with untreated
`patients. We did not see a benefit of IVIG therapy during pregnancy beyond
`the "natural protection". The positive effect of postpartum IVIG treatment
`confirms previous reports in the literature.
`
`Eu me rate
`
`P642
`
`A prospective, open-label, phase II study of oral fumarate therapy for the
`treatment of relapsing-remitting multiple sclerosis
`S. Schimrigk, N. Brune, K. Heliwig, M. Rieks, V Hoffmann, D. Pbhlau, H.
`Przuntek, St. Josef Hospital, Ruhr University (Bochum, D)
`
`Background: Oral fumarate is an effective and safe therapy for the
`treatment of psoriasis. Similar to psoriasis, the inflammatory process in
`
`Sawai (IPR2019-00789), Ex. 1013, p. 004
`
`

`

`multiple sclerosis (MS) is thought to be mediated by a T helper I (THI)-
`type cytokine reaction due to global immune suppression or a TH2-
`mediated bystander suppression. Objective: To evaluate the safety and
`efficacy of oral fumarate therapy (Fumaderm) in patients with relapsing-
`remitting MS (RRMS). Methods: An exploratory, prospective, open-label
`study of oral fumarate therapy was conducted in patients with RRMS. The
`study consisted of four phases, a 6-week baseline, an 18-week treatment, a
`4-week wash-out, and a second 70-week treatment phase. All patients were
`treated with oral fumarate therapy, with the dosage slowly titrated up to a
`maximum of 6 tablets per day (720 mg daily) in the first treatment period
`and up to 3 tablets per day (360 mg daily) in the second treatment period.
`Safety was assessed by physical and neurologic exams, blood chemistry/
`hematology, electrocardiogram, and urinalysis. The primary outcomes
`were the number and volume of gadolinium-enhancing (Gd +) lesions/on
`serial Ti-weighted magnetic resonance imaging (MRI) scans. Clinical
`outcomes included Expanded Disability Status Scale (EDSS) score,
`ambulation index (Afl, and nine-hole peg test (9-HPT). Results: Ten
`patients with RRMS were enrolled in the study; 3 patients discontinued
`the study during the first 3 weeks of treatment. Mild to moderate
`gastrointestinal discomfort was initially experienced by 6 of 7 patients,
`but decreased gradually during the first 6 weeks of treatment in all
`patients. All other side effects were generally mild and transient.
`Significant reductions from baseline in the number of Gd+ lesions were
`observed starting after week 12 of treatment with fumarate (p <0.05). In
`addition, there were significant reductions from baseline in Gd + lesion
`volume starting after week 12 (p <0.01). EDSS scores, Al, and 9-HPT
`remained stable or slightly improved from baseline in all patients;
`however, these effects wer&not statistically significant. Conclusions: Oral
`fumarate therapy significantly reduced the number and volume of Gd+
`lesions over 70 weeks of treatment. All patients were clinically stable
`throughout the study and there were no serious adverse events. These
`findings indicate that oral fumarates may be a promising new treatment for
`RRMS.
`
`P643
`
`Oral fumarate therapy alters cytokine production in patients with
`relapsing-remitting multiple sclerosis
`N. Brune, S. Schimrigk, D. Meier, M. RieksM. Krone, V Hoffmann, K
`Heliwig, D. Pohlau, H. Przuntek, St. Josef Hospital, Ruhr University
`(Bochum, D)
`
`Background: The pathophysiology of multiple sclerosis (MS) is thought
`to be mediated, in part, by a shift from a T-helper (TH)2-type cytokine
`profile (interleukin [IL]-4, IL-b, tumor growth factor ETGF]-p) to a TH1-
`type cytokine profile (IL-2, tumor necrosis factor [TNF]-a, IFN-'y). TH2-
`type cytokines influence T-cell apoptosis and down regulate soluble
`adhesion molecule (sICAM-1)-mediated inflammatory processes. Oral
`fumarate therapy has been shown to reduce disease activity in psoriasis
`through stimulation of a TH2-type cytokines. Objectives: To investigate
`the effects of oral fumarate therapy (Fuanaderm) on cytokine profiles, T-
`cell apoptosis, and 5ICAM-1 in patients with relapsing-remitting MS
`(RRMS). Methods: This was a prospective, 28-week, open-label study in
`patients with RR MS. Enrolled patients had at least 1 relapse in the year
`prior to enrollment, at least I active lesion on magnetic resonance
`imaging (MEl) scans, and an Expanded Disability Status Scale (EDSS)
`score of 2.0 to 6.0. The study consisted of three phases: pre-treatment
`baseline (6 weeks), treatment (18 weeks), and post-study (4 weeks).
`During treatment, all patients received oral fumarate therapy; dose was
`titrated to 720 mg daily (6 tablets). Intracellular production of TH1- and
`TH2-type cytokines by peripheral blood mononuclear cells (PBMCs) and
`T-cell apoptosis were measured by flow cytometry during baseline, after
`6, 12, and 18 weeks of treatment, and at post study. Serum levels of
`sICAM-1 were measured using enzyme-linked immunosorbent assay.
`Results: Seven of 10 enrolled patients completed the study. A
`significant increase (126%) in CD4+ cells producing IL-10 was observed
`over 18 weeks of treatment compared with baseline and the post-study
`period. A corresponding 50% increase in the rate of apoptosis in TH
`cells was observed after 6 weeks of treatment and declined to baseline
`levels after an addition 6 weeks of treatment. There were no significant
`changes in IL-4, TGF-, or TH1-type cytokine production. The total
`number of PBMCs and serum levels of sICAM-1 remained stable.
`
`Abstracts
`Immunotherapy
`
`S259
`
`Conclusions: Oral fumarate appears to increase TH-cell apoptoais,
`which may lead to increased IL-10 production and immune deviation
`toward a predominantly TH2-type cytokine profile. Further study of oral
`fumarate therapy for the treatment of RRMS appears warranted.
`
`Laquinimod
`
`P644
`
`Pharmacokinetic evaluation in a double blind, randomised, phase II
`study of oral laquinimod versus placebo in patients with relapsing
`multiple sclerosis
`0. Nordle, B. Sparre, A. Linde, T Nederman, P0. Gunnarsson, Active
`Biotech AB (Lund, S)
`
`Objective: The objective was to study the pharmacokinetics (PK) of
`laquinimod and its relationship to the effect on development of active
`lesions. Background: In the clinical evaluation of the present phase II
`study, laquinimod at 0.3 mg/day showed evidence of biological activity
`on development of active lesions in relapsing multiple sclerosis (R-MS)
`patients. The present evaluation presents the PK of laquinimod during
`24 weeks of daily oral treatment. The PK properties of laquinimod have
`previously been evaluated in single and repeat dose safety and tolerance
`studies in healthy volunteers as well as in secondary progressive MS
`patients. No dependencies in the PK due to sex or time were observed.
`The PK up to 0.6 mg/day was linear, but there was a slight decrease in
`the clearance at higher dose levels (1.2-2.4 mg/day). Furthermore, the
`clearance in MS patients was slightly lower than in healthy volunteers.
`Methods: Patients with R-MS (n = 209) were randomised to placebo, 0.1
`or 0.3 mg/day. The PK evaluation was based on a population PK
`approach as sparse blood samples were collected from the patients. A
`one-compartment model was fitted to laquinimod plasma concentration
`data and the significance of various covariates was tested. The model
`was used to calculate the individual systemic exposure, and the
`relationship between the systemic exposure and the development of
`active lesions was evaluated. Results: Daily treatment for 24 weeks did
`not affect the PK of laquinimod. Furthermore, linear PK was indicated.
`The clearance value in the females was 17% lower than in the males.
`The clearance decreased with increasing EDSS score with about 7% per
`EDSS unit. There was a significant relationship between the systemic
`exposure and response, both for the cumulative number of active lesions
`in patients with more than two active lesions at baseline and for the
`cumulative volume of gadolinium enhanced Ti lesions in patients with
`a baseline volume above the median. These results suggest that a higher
`dose than 0.3 mg/day may further increase the effect on development of
`active lesions. Conclusions: The analysis of the systemic exposure in
`relation to the development of active lesions revealed that the best effect
`was found in the patients with the highest exposure.
`
`Minocycline
`
`P645
`
`Minocycline treatment increases IL-12 p40 and s-VCAM in RRMS
`B. Zabad, L. Metz, W. Yang, University of Calgary (Calgary, CAN)
`
`Background: The ability of minocycline to alleviate many neurological
`diseases is being increasingly recognized. Minocycline has multiple
`activities, including the inhibition of microglia activation, T cell
`proliferation and modulation of levels of several inflammatory cytokines.
`It is also a direct inhibitor of MMP enzymatic activity. Because of these
`multiple immunomodulatory properties and efficacy in a murine model
`of MS minncycline was tested in 10 patients with relapsing-remitting
`multiple sclerosis (RRMS). Material and Methods: Eight women and 2
`men with active RRMS received oral minocyclineloomg twice daily for
`
`Multiple Sclerosis
`
`Sawai (IPR2019-00789), Ex. 1013, p. 005
`
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