FINAL PROGRAM AND ABSTRACT BOOK

MS ACADEMIAMultiple sclerosis advanced courseAmsterdam, The NetherlandsOctober 18, 2011

General information

VenueThe course takes place at the:

Sofitel Amsterdam The Grand Oudezijds Voorburgwal 197 1012 EX Amsterdam The Netherlandshttp://www.sofitel.com/gb/hotel-2783-sofitel-amsterdam-the-grand/index.shtml

LanguageThe official language of the course will be English.

LocationAmsterdam is the financial and cultural capital of the Netherlands. Many large Dutch institutions have their headquarters there.Amsterdam's main attractions are its historic canals, the Rijksmuseum, the Van Gogh Museum, Anne Frank House. The old city’s centeris the epicenter of all the architectural styles before the end of the nineteenth century. Most historic buildings in the city’s center andnearby are houses, such as the famous merchant’s houses lining the canals.

Scientific secretariatSerono Symposia International FoundationSalita di San Nicola da Tolentino, 1/b00187 Rome, Italy

Junior Project Manager: Simona GaudiosiTel.: +39 (0)6 420 413 308Fax: +39 (0)6 420 413 677E-mail: info@seronosymposia.org

Serono Symposia International Foundation is a Swiss Foundation with headquarters in 14, rue du Rhône, 1204 Geneva, Switzerland

Organizing secretariatMeridiano Congress InternationalVia Mentana, 2/B - 00185 Rome, ItalyCongress coordinator: Sara GuglielminiTel.: +39 (0)6 88595 211Fax: +39 (0)6 88595 234E-mail: s.guglielmini@meridiano.it

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MS ACADEMIAMultiple sclerosis advanced course

Serono Symposia International Foundation course on:

MS ACADEMIAMultiple sclerosis advanced courseAmsterdam, The Netherlands - October 18, 2011

Aim of the courseAll aspects of multiple sclerosis are currently undergoing continuous updating and improvement, with new insights into thepathophysiology of MS, innovations in diagnostic protocols and widening of the therapeutic options. In this rapidly developing field,the aim of this annual advanced course is to gather together renowned experts who, through state-of-the-art lectures, will provideupdates on the status of MS research and clinical practice. The course will focus particularly on how to optimize the use of availabledrugs, according to disease characteristics and patient needs.

Learning objectivesThis course will offer participants:• Updates on etiologic factors and pathogenetic mechanisms• An overview of diagnostic tools used in patient screening and follow-up • Criteria to optimize treatment administration • A glimpse into future therapies

Target audienceThis program is appropriate for neurologists having MS as their main area of practice and scientists working in the field.

AccreditationSerono Symposia International Foundation (www.seronosymposia.org) is accredited by the European Accreditation Council forContinuing Medical Education (EACCME) to provide the following CME activity for medical specialists. The EACCME is an institutionof the European Union of Medical Specialists (UEMS), www.uems.net

The conference “MS Academia – Multiple Sclerosis Advanced Course” (Amsterdam, The Netherlands - October 18, 2011) isdesignated for a maximum of 6 hours of European external CME credits. Each medical specialist should claim only those credits thathe/she actually spent in the educational activity. EACCME credits are recognized by the American Medical Association towards thePhysician's Recognition Award (PRA). To convert EACCME credit to AMA PRA category 1 credit, please contact the AMA.

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All Serono Symposia International Foundation programs are organized solely to promote the exchange and dissemination of scientific and medical information. No formsof promotional activities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the namedspeakers, and do not represent an endorsement or recommendation on the part of Serono Symposia International Foundation. This program is made possible thanks tothe unrestricted Educational grant received from: Centre d’Esclerosi Multiple de Catalunya, ComtecMed, Congrex Sweden, Congrex Switzerland, Cryo-Save, Datanalysis,Esaote, European Society of Endocrinology, Fondazione Humanitas, Fundación IVI, ISFP International Society for Fertility Preservation, ISMH International Society of Men’sHealth, K.I.T.E., Merck Serono, Ministry of Health of the State of Israel, Sanofi Aventis, University of Catania, Vall d'Hebron University Hospital.

Scientific committeeGiancarlo Comi Department of NeurologyInstitute of Experimental NeurologyVita-Salute San Raffaele UniversityMilan, Italy

Hans-Peter HartungDepartment of NeurologyHeinrich-Heine-UniversityDusseldorf, Germany

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Fred D. LublinCorinne Goldsmith Dickinson Center for Multiple sclerosisMount Sinai School of MedicineNew York, NY, US

List of speakers and chairmenAlberto AscherioDepartment of Epidemiology and NutritionHarvard School of Public HealthHarvard Medical SchoolBoston, MA, USA

Frederik BarkhofDepartment of RadiologyImage Analysis Center (IAC)VU University Medical CenterAmsterdam, The Netherlands

Giancarlo Comi Department of NeurologyInstitute of Experimental NeurologyVita-Salute San Raffaele UniversityMilan, Italy

Mark S. FreedmanMultiple Sclerosis Research UnitThe Ottawa HospitalOttawa, Canada

Gavin GiovannoniDepartment of NeurologyInstitute of Cell and Molecular ScienceQueen Mary University London & Barts and The London NHS TrustLondon, UK

Hans-Peter HartungDepartment of NeurologyHeinrich-Heine-UniversityDusseldorf, Germany

Jan HillertDepartment of Clinical NeuroscienceKarolinska InstitutetStockholm, Sweden

Letizia LeocaniInstitute of Experimental NeurologyUniversity Vita-Salute IRCCSSan Raffaele HospitalMilan, Italy

Fred D. LublinCorinne Goldsmith Dickinson Center for Multiple sclerosisMount Sinai School of MedicineNew York, NY, USA

Xavier MontalbanMultiple Sclerosis Center of Catalonia Unit of Clinical Neuroimmunology Vall d’Hebron University HospitalBarcelona, Spain

Christine Stadelmann-NesslerDepartment of NeuropathologyGeorg August UniversityGöttingen, Germany

Jerry WolinskyDepartment of NeurologyThe University of Texas Health Science Center at HoustonHouston, Texas, USA

Scientific Program

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Chairman: Giancarlo Comi, Italy

09.00 L1: GenesJan Hillert, Sweden

09.30 L2: Environment and nutritionAlberto Ascherio, USA

10.00 L3: PathologyChristine Stadelmann-Nessler, Germany

10.30 L4: ImmunopathogenesisHans-Peter Hartung, Germany

11.00 Discussion

11.20 Coffee break

Chairman: Fred D. Lublin, USA

11.40 L5: MS: diagnosis and prognosisXavier Montalban, Spain

12.10 L6: Neurophysiology in diagnosis and monitoringof MSLetizia Leocani, Italy

12.40 L7: MRI in diagnosis and monitoring of MSFrederik Barkhof, The Netherlands

13.10 Discussion

13.20 Working Lunch

Etiology and pathogenesisSession I

DiagnosisSession II

Chairman: Hans-Peter Hartung, Germany

14.15 L8: Symptomatic treatmentFred D. Lublin, USA

14.45 L9: Current disease modifying drugs: evaluatingthe evidenceMark S. Freedman, Canada

15.15 L10: Safety issuesGavin Giovannoni, UK

15.45 Coffee Break

16.00 L11: Treatment individualization and monitoringGiancarlo Comi, Italy

16.30 L12: Future therapiesJerry Wolinsky, USA

17.00 Discussion

17.30 End of the course

TreatmentSession III

Tuesday - October 18, 2011

08.00 Registration

08.45 Serono Symposia International Foundation (SSIF) OpeningGiancarlo Comi, SSIF Scientific Committee President

Disclosure of faculty relationships

Serono Symposia International Foundation adheres to guidelines of the European Accreditation Council for Continuing MedicalEducation (EACCME) and all other professional organizations, as applicable, which state that programs awarding continuingeducation credits must be balanced, independent, objective, and scientifically rigorous. Investigative and other uses forpharmaceutical agents, medical devices, and other products (other than those uses indicated in approved product labeling/packageinsert for the product) may be presented in the program (which may reflect clinical experience, the professional literature or otherclinical sources known to the presenter). We ask all presenters to provide participants with information about relationships withpharmaceutical or medical equipment companies that may have relevance to their lectures. This policy is not intended to excludefaculty who have relationships with such companies; it is only intended to inform participants of any potential conflicts soparticipants may form their own judgments, based on full disclosure of the facts. Further, all opinions and recommendationspresented during the program and all program-related materials neither imply an endorsement, nor a recommendation, on the partof Serono Symposia International Foundation. All presentations solely represent the independent views of the presenters/authors.

The following faculty provided information regarding significant commercial relationships and/or discussions of investigational ornon-EMEA/FDA approved (off-label) uses of drugs:

Alberto Ascherio Declared no potential conflict of interest.

Frederik Barkhof Declared receipt of honoraria or consultation fees from: UCB, Bayer Sharing Pharma, Sanofi-Aventis,Novartis, Roche, Merk-Serono.Declared to be member of a company advisory board, board of directors or other similar group: UCB,Bayer Sharing Pharma, Sanofi-Aventis, Novartis, Roche.

Giancarlo Comi Declared receipt of honoraria or consultation fees from: Sanofi Aventis, Serono Symposia InternationalFoundation, Teva, Pharmaceutical Ind. Ltd., Bayer-Schering, Biogen Dompé, Merck-Serono Int.

Mark S. Freedman Declared receipt of research or educational grants from: BayerHealthcare and Genzyme.Declared receipt of honoraria or consultation fees from: BayerHealthcare, BiogenIdec, EMD Canada,Novartis, Sanofi-Aventis, Teva Canada Innovation. Declared to be a member of a company advisory board, board of directors or other similar group:BayerHealthcare, BiogenIdec, Merck Serono, Novartis, Sanofi-Aventis, Celgene.

Gavin Giovannoni Declared receipt of grants for Consulting fees from Bayer-Schering Healthcare, Biogen-Idec, Genzyme,GlaxoSmithKline, GW Pharma, Merck-Serono, Novartis, Protein Discovery Laboratories, Teva-Aventis,Vertex Pharmaceuticals and UCB Pharma.Lecture fees from Bayer-Schering Healthcare, Biogen-Idec, Pfizer, Teva-Aventis, VertexPharmaceuticals.Grant support from Bayer-Schering Healthcare, Biogen-Idec, GW Pharma, Merck-Serono, Merz,Novartis, Teva-Aventis and UCB Pharma.

Hans-Peter Hartung Declared receipt of honoraria or consultation fees from: Sanofi Aventis, Teva, Pharmaceutical Ind. Ltd.,Bayer-Schering, Biogen Dompé, Merck-Serono Int., Novartis.Declared to be member of a company advisory board, board of directors or other similar group:Biogen, Novartis, Merk-Serono.

Jan Hillert Declared no potential conflict of interest.

Letizia Leocani Declared no potential conflict of interest.

Fred D. Lublin Declared receipt of grants from Acorda Therapeutics, Inc.; Biogen Idec; Novartis PharmaceuticalsCorp; Teva Neuroscience, Inc., Genzyme, Sanofi- Aventis, NIH; NMSS, Bayer HealthCarePharmaceuticals, Biogen Idec, EMD Serono, Inc., Novartis, Pfizer, Teva Neuroscience, Genmab,Medicinova, Actelion, Allozyne, Sanofi-Aventis, Acorda, Questcor, Avanir, Roche, Celgene, Abbott,MorphoSys, Johnson & Johnson. Current Financial Interests/Stock Ownership: Cognition Pharmaceuticals, Inc.

Xavier Montalban Declared to receipt of honoraria or consultation fees from: Bayer Schering, Biogen Idec, Merck-Serono,Novartis, Teva, Sanofi-Aventis, Almirall.

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Disclosure of faculty relationships

Christine Stadelmann-Nessler Declared to receipt of honoraria or consultation fees from: Bayer and Merk Serono.

Jerry Wolinsky Declared to receive speaker honoraria from: Bayer HealthCare, Biogen Idec, Celgene,Consortium of MS Clinics, Eli Lilly, Hoffman La Roche, National MS Society, Novartis, SanofiAventis, Serono Symposia International Foundation, Texas Neurological Society, Teva and TevaNeurosciences, University of Alabama at Birmingham.Royalties are received for outlicensed monoclonal antibodies through the UTHSCH to Millipore(Chemicon International) Corporation since 1993.Research or contractual support from the Clayton Foundation for Research, the NIH [2 U01NS045719‐06 (PI of the subcontract to UTHSCH for image analysis) and 2RO1 EB002095‐06A1(CoI)], the NMSS (RC‐1019 A5) and sanofi aventis.

Declared no potential conflict of interest.

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Abstracts

L1 - Genes

The success within the past few years have to identify genes of importance for complex diseases such as multiple sclerosis (MS) isremarkable. This is essentially explained by methodological advances in combining large clinical material with high thru-putgenotyping techniques. As a consequence, we now have a list of over 50 genes or chromosomal loci for which very strong evidenceindicates an influence in determining the risk of an individual I developing MS. The prime objective with risk gene identification hassince long been increased understanding of the early triggering events in MS pathogenesis. As such clues for disease mechanisms,the new list of MS genes may eventually prove to be immensely important. In brief, most of the new genes are of clear importancefor inflammation, thus supporting the hypothesis that MS is primarily a disease with autoimmune features. This presentation willbriefly address which genes are and how we came to identify them.

The presentation will also cover the current level of understanding and potential usefulness of genetic markers in diagnosis,prognosis and treatment decisions, i.e. the extent to which these or similar markers are associated with idea characteristics otherthan onset of disease. In brief, we have a considerable way to go before genetics may add substantially to the diagnostic accuracyin the MS clinic. Likewise, genetic markers have so far not enabled us to predict the future course of our patients, but may be ofsome use if analysed in concert with other factors. Finally, there are already some examples of genetic factors influencing theresponse to treatment in autoimmune disorders, including MS.

In summary, the genomics mission in MS, expected to be completed within 5-10 years, has already proven to be a success. Hopefullt,this will eventually be turned into practical consequences for patients and neurologists.

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Jan HillertDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

L2 - Environment and nutrition

While genetic susceptibility explains the clustering of MS cases within families, the changes in MS risk that occur with migrationcan only be explained by changes in the environment. The strongest known risk factor is infection with the Epstein-Barr virus (EBV).MS is extremely rare in individuals who are not infected with EBV, but it has been shown in a longitudinal study that their MS riskincreases sharply following EBV infection. As compared with uninfected individuals, the hazard of developing MS is at least 10 foldshigher among individuals infected with EBV in childhood and over 20 folds higher among individuals infected in adolescence or laterin life. Although the mechanisms underlying this association remain unclear, these data provide strong evidence of a causal relationbetween EBV infection and MS risk. There are, however, several aspects of the epidemiology of MS that are not explained by EBV,including the epidemics of MS in the Faroe islands, and the reduction in MS risk among migrants from high to low prevalence areas.These observations suggest that either there are different EBV strains, with different propensity to cause MS, or other factors arealso involved.

An increased risk of MS in individuals with vitamin D insufficiency has been proposed to explain the strong latitude gradient in MSprevalence. This is an attractive hypothesis, because vitamin D has important effects on immune responses and can effectivelyprevent autoimmune disease in several experimental models. Results of case-control studies that relied on prevalent MS cases andrecall of past exposure to sunlight and vitamin D intake have been mixed and potentially affected by selection and recall biases.However, in a recent case-control study of individuals presenting with a first demyelinating episode, higher levels of vitamin D, sunexposure, or actinic damage were found to be associated with a reduced MS risk. Two longitudinal studies have been so farcompleted. In the first, based on assessment of vitamin D intake from diet and supplements, risk of MS was found to be 30% loweramong women in the highest quintile as compared to those in the lowest quintile. In the second study, conducted among youngadults in the US Army and Navy, vitamin D status was assessed by averaging multiple season-adjusted measures of 25(OH) vitaminD. During an average of 5-years of follow-up, MS risk among healthy young adults with high serum levels of 25(OH) vitamin D (> 100nmol/L) was about 60% lower than in individuals of the same age and sex with low serum 25(OH)D levels. If confirmed, these findingssuggest that a high proportion of MS cases could be effectively prevented by vitamin D supplementation. The doses required wouldbe substantially higher than those currently recommended, but still within a very safe range. Possible genetic heterogeneity inresponses to vitamin D need to be further investigated.

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Alberto AscherioDepartment of Epidemiology and Nutrition, Harvard School of Public Health, Harvard Medical School, Boston, MA, USA

L3 - Pathology

Multiple sclerosis (MS) pathology is characterized by demyelination, inflammation, axonal damage and loss, and gliosis. Axonaldamage and loss are considered the key factors determining the persistent clinical deficit in MS patients. Remyelination is thoughtto protect axons from further damage and to limit progressive axonal loss. However, remyelinated lesions are relatively scarce in thechronic disease phase. In contrast, in early stages of lesion formation, immediately after demyelination, oligodendroglial cellsforming myelin sheaths are abundant in MS lesions. Experimental evidence suggests that trophic factors derived from inflammatorycells may stimulate myelin repair. However, our data in a model of toxic demyelination suggest that the remyelinative response islargely unaffected by an adaptive immune response.

This presentation will provide an update on recent developments in MS pathology and sum up current knowledge on remyelinationin MS and relevant experimental models.

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Christine Stadelmann-NesslerDepartment of Neuropathology, Georg August University, Göttingen, Germany

L4 - Immunopathogenesis

Abstract not in hand at the time of going to press.

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Hans-Peter HartungDepartment of Neurology, Heinrich-Heine-University, Dusseldorf, Germany

L5 - MS: diagnosis and prognosis

Abstract not in hand at the time of going to press.

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Xavier MontalbanMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain

L6 - Neurophysiology in diagnosis and monitoring of MS

The availability of new disease-modifying treatments for multiple sclerosis (MS) has raised interest on paraclinical measures fordisease monitoring and for assessing response to therapy. Evoked potentials (EPs) reflect function of central sensory and motorpathways affected by MS. EPs abnormalities may detect subclinical lesions, confirm the involvement of sensory and motor pathwaysin the presence of vague disturbances, provide indication on the demyelinating nature of the disease process and on its functionalimpact. Their value in the diagnosis of definite MS is much lower than that of MRI, more sensitive to brain and cervical spinal cordlesions. More promising is the application of EPs in the assessment of disease severity and in monitoring the evolution of nervousdamage. Cross-sectional and longitudinal studies have demonstrated a good correlation between disability and evoked potentialabnormalities. As a consequence, they can be utilised to monitor the progression of demyelination and axonal damage. Therefore,they are potentially useful as paraclinical end-point in phase III clinical trials to evaluate the efficacy of new therapies which canmodify the natural course of the disease, while they are of limited value in phase II clinical trials because of their low sensitivity todisease activity. Moreover, evoked responses can be useful in testing the effects of drugs potentially modifying central conduction.Finally, recent evidence indicates that EPs performed early in the disease may help predicting a worse future progression in the longterm. If confirmed, these data suggest a possible usefulness of EPs in the early identification of patients who are more likely developfuture disability, thus requiring a more frequent monitoring or being potential candidates for more aggressive disease-modifyingtreatments.

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Letizia Leocani 1, Giancarlo Comi 21 Institute of Experimental Neurology, University Vita-Salute IRCCS, San Raffaele Hospital, Milan, Italy2 Department of Neurology, Institute of Experimental Neurology, Vita-Salute San Raffaele University, Milan, Italy

References:1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction

6 1206-1212. 2 - Filicori M, Cognigni GE, Pocognoli P et al. 2003 Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and

Metabolism 14, 267-273.

L7 - MRI in diagnosis and monitoring of MS

Neuroimaging, and especially magnetic resonance imaging (MRI), is often being used to demonstrate dissemination of lesions in theCNS in patients with multiple sclerosis (MS). In the McDonald diagnostic criteria for MS, as proposed by an international panel[Polman et al.], strong emphasis is placed on the use of information derived from MRI. In this setting, where one relies more heavilyon MRI than previously, a high specificity is warranted.

MRI in the McDonald 2010 criteriaTo demonstrate dissemination in space (DIS) and dissemination time (DIT), the international panel has chosen to rely on the criteriaby the MAGNIMS group [Montalban et al.], which have been shown to be more specific (and accurate) than previous criteria.

The DIS criteria include at least 2 lesions, in 2 separate locations:

• Juxtacortical

• Periventricular

• Infratentorial• spinal cord

The DIT criteria based on MRI include:

• gadolinium-enhanced and non-enhancing lesions at any time even at presentation• a new T2 lesion at follow-up

Spinal cord MRI is often usefulIn cases where there is doubt about the applicability of the brain MRI criteria (older patients, cerebrovascular risk-factors), theperformance a spinal cord scan can be extremely helpful, since incidental cord lesions are extremely uncommon in ageing andcerebrovascular disease, and very frequent in MS (even in patients without cord symptoms or signs). Other indications for a spinalcord scan include: primary progressive MS, cord presentation, and rarely, a negative brain scan with strong clinical suspicion of MS.The use of MRI in the spinal cord has recently been reviewed by the MAGNIMS group [Lycklama]

Monitoring treatment using MRISerial MRI shows a vast amount of disease activity that goes undetected clinically. To a large extent, the significance of suchsubclinical activity remains undetermined. The number of active (gadolinium-enhancing) lesions is closely linked to (concurrent)relapse-activity, but its predictive value wears off over time, and the predictive value for evolution of disability is limited (as is the casefor relapses). Measures of cerebral atrophy form (serial MRI) may prove more effective in this regard. While MRI plays a major rolein evaluating the effect of new therapies in randomized clinical trials, its importance in monitoring individual patients remainsuncertain. If any, the usefulness of MRI may be to rule out subclinical relapses in patients, when there is doubt about the institutionor modification of anti-inflammatory treatment [Rio].

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Frederik BarkhofDepartment of Radiology, Image Analysis Center (IAC), VU University Medical Center, Amsterdam, The Netherlands

References:- Lycklama G, et al. Lancet Neurol. 2003;2:555-62- Montalban XM, Neurology. 2010;74:427-34- Polman CH, et al. Ann Neurol. 2011;69:292-302- Rio J, et al. Nat Rev Neurol. 2009;5:553-60

L8 - Symptomatic treatment

In this exciting era of disease modifying therapies for MS, it is easy to overlook the importance of skilled, aggressive managementof the patient's symptoms. While disease modifying therapies are designed to alter the future disease course of MS, symptommanagement is designed to deal with the patient's current conditions. Modern comprehensive Care of patients with MS requirescareful attention to both strategies. As multiple sclerosis, can affect any part of the central nervous system, the symptoms that mayresult can be broad ranging and multiple. Some of the common symptoms that may need management include fatigue, spasticity,weakness, in coordination, impaired mobility, tremor, paroxysmal symptoms, bladder dysfunction, pain, cognitive impairment,psychological and psychiatric problems. There are therapeutic strategies for treating each of these symptoms. Some, such asbladder dysfunction, have a number of successful therapies. Others, such as tremor and cognitive dysfunction are more difficult tomanage. As a part of comprehensive MS care, one should take a holistic, multimodal view of therapy, taking into consideration allof the patients symptoms and other medical conditions. For example, a patient that is to be treated for depression, who alsocomplaints of fatigue, might do better with an activating antidepressant, rather than one that could sedate. Another example wouldbe to consider utilizing an agent that has anti-cholinergic side effects in an individual who has a hyperactive bladder; and the reversefor someone who has a tendency to urinary retention. It is also important to remember that our current disease modifying therapiesalso have potential side effects and complications that require monitoring.

What is most important is to remember that comprehensive symptom management is a critically important aspect of all MS care,and all MS patients, from the very benign to the most malignant. Careful attention to each individual patient's symptoms and thepotential therapies for those symptoms will vastly improve the quality of life of our patients.

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Fred D. LublinCorinne Goldsmith Dickinson Center for Multiple sclerosis, Mount Sinai School of Medicine, New York, NY, USA

L9 - Current disease modifying drugs: evaluating theevidence

As new therapies enter the marketplace, we must evaluate the evidence supporting their efficacy in order to compare their relativevalue for our patients. Patient populations, diagnostic definitions, and especially the response of placebo groups have changed overthe years, making it nearly impossible to simply compare efficacy outcomes from various trials. A perfect example is to compare thesame medication and the effect it achieved over a decade of various trials evolving to date; contemporary studies yield greaterefficacy, yet medications have not really changed. Evidence based approaches help to iron out these differences and concentrate on“absolute” efficacy, which can be reduced to a more conservative comparator, the “number needed to treat” or NNT. These NNTvalues are not perfect comparators either, since they may underestimate true treatment effects, especially when rates of theoutcome measure become very small such that overall differences between treatment and placebo groups is also reduced. (This isin fact the case with more recent trials where relapse rates in the placebo group have fallen below 0.5 attacks per year and wellbelow the treated relapse rates of yesteryear.) Though statistically the effects are proven, the magnitudes become even more difficultto compare.

In current studies, all activity measures are considered independent of each other; patients having relapses need not be also havingMRI activity or EDSS progressions. In fact, the same patient may have all three or any combination thereof and be counted morethan once on each outcome. Another way to assess the various medications is to examine their ability to maintain patients “free ofdisease”. It is much better to consider that a given treatment will keep people “free of disease” activity rather than simply not being“as bad” as if they were taking placebo or a different agent. Such an analysis would then obviate the problem we have of looking atfor instance relapses, and assuming that if there were “0” relapses, then that patient was helped by the treatment; but if weconsidered progression, we might find that the same patient progressed 2 points on their EDSS. Clearly you can’t be “good” on onemeasure and “bad” on another. In order to be “disease activity free (DAF)”, a patient must have no relapses and no MRI activity andno EDSS progression. One caveat from this approach is that many patients are in fact “disease-free” owing to their natural history,but that number is known since we still have a placebo-comparator group. Another would be that any type of activity would rendera patient not DAF and this would be governed by the most frequent event, which would undoubtedly be MRI. Differences in thenumber of clinical or MRI assessments could easily skew results, since “the more you look – the more you find”. Nevertheless thistype of analysis has been producing interesting results. One might consider the opposite approach (i.e. to count relapses only if thesame individual had MRI activity AND EDSS progression) in order to count only the most meaningful of negative events. However, inthat circumstance, the outcome is determined by the least frequent event, which would be EDSS progression, requiring a very largesample size to determine a treatment effect that is based on a very small segment of the study population.

Future trials focusing on outcome measures such as relapse rates will no doubt require many more patients to show what studiesa decade or more ago did with a fraction of the patients. Still one should have an approach to compare agents based on known,validated outcome measures. We must also be careful to weigh primary outcomes on their individual merits without some of themore exploratory outcomes, no matter how compelling they may be. For example, an agent that may show only modest effects onrelapses, but markedly affects brain volume (atrophy) can be construed as powerful if one puts a lot of emphasis on the MRI outcomeeven though it is not the primary. If brain atrophy was more important than relapse reduction, it needs to be made the primary andrandomization would then be based on it. It cannot simply be assumed that randomization to insure the groups are equal in termsof their overall risk of having a relapse, need not be also equally distributing patients based on their risk of losing brain volume. Todo so would be to first select the groups based on known and perceived “risks of atrophy”, and then randomizing them accordingly.

It is also not enough to consider just the perceived benefits of an agent, without taking into account any risk of “harm” that mightbe taken in order to gain the benefit; a similar conservative measure of this is the “number needed to harm” or NNH. It is the true“benefit to risk” ratio that will undoubtedly take over as the mainstay for comparing contemporary and future treatments. Onemethod could be to compare the “likelihood of help vs. harm” by simply calculating the NNT vs the NNH. However, as new agentswith different properties loom for the treatment of MS, we are discovering that although the “benefits”, based on validated outcomemeasures, can be comparable, the “harm” however is not and each new agent seems to bear its own new type of “harm”.

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Mark S. FreedmanMultiple Sclerosis Research Unit, The Ottawa Hospital, Ottawa, Canada

L10 - Safety issues

Multiple sclerosis (MS) is the most common non-traumatic disabling condition to afflict young adults. Although the prognosis of MSis highly variable, given sufficient time the majority of people with MS will become disabled. In the case of established MS disease-modifying therapies the long-term impact of these therapies on MS prognosis is not fully defined and in the case of the neweremerging therapies it is unknown. Despite this there is a consensus that early aggressive treatment, in the relapsing phase of thedisease, will prevent or at least delay the progressive stage of the disease. The problem associated with the more aggressivetherapies, be they induction or escalation therapies, is that they come with greater risks. For example, mitoxantrone-relatedleukaemia, natalizumab-associated progressive multifocal leukoencephalopathy (PML), alemtuzumab-associated autoimmunediseases, opportunistic infections and possibly treatment-related malignancies. How do we balance the risks of these therapies withtheir potential long-term benefits? In this talk I will review the prognosis of MS and the rationale for treating aggressively early andon and provide some strategies for de-risking these therapies for people with MS. In addition, the talk will focus on education andthe role of the professional patient in helping make the right decision regarding individualised treatment plans.

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Gavin GiovannoniDepartment of Neurology, Institute of Cell and Molecular Science, Queen Mary University London & Barts and The London NHS Trust, London, UK

L11 - Treatment individualization and monitoring

Current disease-modifying therapies for multiple sclerosis (MS) include interferon (IFN) beta (subcutaneous [sc] and intramuscular[im]) glatiramer acetate, mitoxantrone, and natalizumab, are characterized by specific safety and efficacy profile. These therapieshave demonstrated clear efficacy in clinical trials and in postmarketing studies; however the full response on long term is rare. Thisopens the requirement of alternative therapies in order to achieve the goal of obtaining full control of the disease. Fingolimod hasbeen recently approved by Regulatory Authorities and other potential new treatments are in different phases of development. Theavailability of multiple therapeutic options permits the ambitious target of a full control of disease activity in multiple sclerosis. MSevolution is quite variable from patient to patient with possibility of a very aggressive course from the onset.

Early and accurate assessments may help to identify patients who require more aggressive therapeutic options. The definition ofindividual prognostic factor with the history of previous treatments will contribute to define the best candidate therapy for a givenpatient at a specific time of disease evolution. In the future, it may become possible to use also pharmacogenomic information toindividualize treatment. Recent studies have confirmed the association between glypican 5 gene polymorphisms and response toIFN-beta treatment. Close monitoring of the response to treatment with clinical biomarkers will be fundamental in order to allowrapid shift from a treatment to another.

Patient adherence to prescribed treatment is hugely variable and can influence decision-making. An assessment of each patient’sbenefit-to-risk preferences may also help to identify those patients who are willing to accept additional risks in exchange forpotentially greater clinical efficacy.

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Giancarlo ComiDepartment of Neurology, Institute of Experimental Neurology, Vita-Salute San Raffaele University, Milan, Italy

L12 - Future therapies

The early to mid‐1990s saw the introduction of the first evidence‐based, disease modifying therapies for multiple sclerosis.Subsequently, our therapeutic armamentarium has grown, but as elegantly reviewed in earlier presentations, substantial unmetneeds remain. Nevertheless, our experiences with current registered therapies provide an important benchmark with which toevaluate newer drugs in active clinical development. Fortunately, the pipeline of new therapeutic agents to control inflammatoryaspects of the disease is quite rich, as approaches that might limit progressive phase aspects of the disease or stimulate repair arebeing sought. In this lecture, we will consider where these newer agents reside in the therapeutic pipeline and review in some detailthose drugs with the shortest potential time lines to the clinic. The development programs for alemtuzumab, fumarate, laquinimodand teriflunomide are the drugs most likely to receive regulatory review and possible approval within the next 12 months. As timeallows, we will consider the different mechanisms of the actions of these drugs, current knowledge of their likely safety and efficacy,and how they may fit into our therapeutic armamentarium over the next five years ‐ assuming that they are able to make it throughthe registration process unscathed.

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Jerry WolinskyDepartment of Neurology, The University of Texas, Health Science Center at Houston, Houston, Texas, USA

Our future health depends on today’s medical experts minds, therefore, the SeronoSymposia International Foundation (SSIF), in partnership with the European NeurologicalSociety (ENS), has decided to establish a prestigious award to recognize and rewardexcellence in medical education.

The Serono Symposia International Foundation (SSIF) is seeking candidates amongmedical experts who are continuing to drive medical education forward through theirresearch and dedication in the field of neurology.

The criteria for candidate application cover a wide range of skills and attributes that SSIFis looking for in a potential candidate and winner of the SSIF award.

The Award Committee composed of Members of the SSIF Scientific Committee and Boardof Directors Members and ENS Members will assess the candidate’s professionaldedication and leadership to continuining medical education.

If you are a physician and/or scientist from 35 to 50 years old working in:• degenerative dementias and/or• multiple sclerosis and/or• neurodegenerative disease entailing movement disorders and/or• Parkinson’s disease

The SSIF Award will be a great opportunity for you!

Find out more and apply to the SSIF award on www.ssifaward.org

The winner of the SSIF award will receive Euro 10,000, less any taxes deductable, and will become a member of the SSIF advisory committee.

Applications are open for submission from May 28, 2011 until December 31, 2011.

SSIF awardRewarding scientific excellencein medical education

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