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MS Highlights From the2017 Annual NeurologyMeeting CME

Supported by an independent educational grant from EMD Serono


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MS Highlights From the 2017 Annual Neurology Meeting CME

Target AudienceThis activity is intended for neurologists, primary care physicians, obstetricians & gynecologists and others who treat patients with MS.

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Disclosures

Faculty & Affiliations

Stephen Krieger, MDAssociate Professor of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York

Disclosure: Stephen Krieger, MD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: ACADIA Pharmaceuticals Inc.; Bayer HealthCare Pharmaceuticals; Biogen, Inc.; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Takeda Pharmaceuticals North America, Inc.; Teva Pharmaceuticals USAServed as a speaker or a member of a speakers bureau for: Biogen, Inc.

Dr Krieger does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Krieger does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Aaron Miller, MDProfessor of Neurology, Medical Director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis Icahn School of Medicine at Mount Sinai, New York, New York

Disclosure: Aaron Miller, MD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: Accordant; Acorda Therapeutics; Alkermes, Inc.; Biogen, Inc.; Celgene Corporation; Covidien; EMD Serono, Inc.; Genzyme Corporation; Mallinckrodt; Mapi-Pharma Ltd.; Novartis Pharmaceuticals Corporation; Roche; SanofiServed as a speaker or a member of a speakers bureau for: Biogen. Inc.; Genentech, Inc.; RocheReceived grants for clinical research from: Biogen, Inc.; Genentech, Inc.; Genzyme Corporation; Mallinckrodt; MedDay; Novartis Pharmaceuticals Corporation; Roche; Sanofi

Dr Miller does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Miller does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Augusto Miravalle, MDAssociate Professor of Neurology, Associate Chair of Education, Chief, Multiple Sclerosis Division, Department of Neurology,University of Florida, Gainesville, Florida

Disclosure: Augusto Miravalle, MD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: Genentech, Inc.;Received grants for clinical research from: Biogen, Inc.; Genentech, Inc.

Dr Miravalle does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Miravalle does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


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Robert Fox, MDStaff Neurologist, Mellen Center for Multiple Sclerosis, Vice Chair for Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio

Disclosure: Robert Fox, MD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: Actelion Pharmaceuticals, Ltd; Biogen, Inc.; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USAReceived grants for clinical research from: Novartis Pharmaceuticals Corporation

Dr Fox does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Fox does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Editor

Gena Dolson, MSScientific Director, Medscape, LLC

Disclosure: Gena Dolson, MS, has disclosed no relevant financial relationships.

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Stephen Krieger, MD: Hello. I am Stephen Krieger, Associate Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York. Welcome to this program titled, “MS Highlights from the 2017 Annual Neurology Meeting.” Today we will be discussing data on approved disease-modifying therapies (DMTs) in multiple sclerosis (MS). Joining me today is Dr Aaron Miller, Professor of Neurology and Medical Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis here at the Icahn School of Medicine at Mount Sinai in New York. Welcome Dr Miller.

Aaron Miller, MD: Hello Stephen, it is good to be with you.

Dr Krieger: We are going to discuss data presented in abstract form at the American Academy of Neurology (AAN) Annual Meeting. These data should be considered preliminary until published in peer-reviewed journals.

To begin, we have 15 approved DMTs for relapsing and progressive forms of MS. Ongoing studies, including postmarketing and extension studies, assess the continued efficacy and safety of these agents.

MS Highlights from the 2017 Annual Neurology Meeting: Approved DMTs


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I think it is worth beginning with progressive multifocal leukoencephalopathy (PML), which has been of course a major safety issue with natalizumab. We now recognize it as a safety issue with several of our other approved DMTs. Dr Miller, maybe you can tell us a bit about a study looking at patients at high risk for PML.

Dr Miller: This particular study looked at the switch of patients who had been doing well on natalizumab but seroconverted from JC virus-negative to positive.[1] This was a relatively small study of just 16 patients who were switched from natalizumab to alemtuzumab. Interestingly, there was a 2-month washout period, which is approximately when the biological effects of natalizumab should begin waning. Patients then received their first infusion of alemtuzumab. The good news was there was absolutely no clinical activity in any of the patients during that period of follow-up and only 1 patient had radiologic activity after 6 months.[1] This was not a surprising result, because alemtuzumab is an extremely effective drug and these patients had well-controlled MS when receiving natalizumab, but nonetheless it is reassuring.

It is not clear why the 2-month washout period was chosen. There may have been some potential safety concerns. The important thing is not to wait longer than 2 months because we know that patients who are off natalizumab for several months will likely have recurrence of disease activity, possibly to an excessive degree.

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Dr Krieger: That is great. Let’s turn from risk and switching to safety and early start of therapy. We can see some long-term results from REFLEX and REFLEXION, which looked at interferon beta-1a (IFNβ-1a) given subcutaneously early in the course of relapsing disease. We now have extension data over 5 years. What can we learn from those studies?

Dr Miller: The REFLEX trial was one of many trials in clinically isolated syndrome patients and it randomly assigned patients to receive either placebo or one of 2 doses of IFNβ-1a to see if one could delay the occurrence of clinically definite MS.[2]

This study, REFLEXION, was carried out to 60 months. Data from the first 2 years of the pivotal trial and the 5 years of this trial showed there was a higher rate of patients achieving no evidence of disease activity (NEDA) if they had been initially assigned to the interferon group. This was statistically significant for the 3-times-a-week dose.[2]

Dr Krieger: This further underscores the value of early treatment and also a great example of long-term safety and efficacy with one of our platform agents.


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We can turn to data on our most recently approved agent, ocrelizumab, which was approved for relapsing and progressive forms of the disease.

Dr Miller: This particular data set is from the phase 2 trial, not from the phase 3 trials. This was a trial that included roughly 55 patients in each of the arms; there were 2 different ocrelizumab dosing arms, an IFNβ-1a arm, and a placebo arm. In the phase 2 trial, magnetic resonance imaging (MRI) was the primary endpoint, occurring between 8 and 24 weeks after initiation of the drug.[3]

The authors analyzed MRI data at 4 and 8 weeks to see how early they can see evidence of benefit from ocrelizumab. They found that compared with IFNβ-1a at 4 weeks, there was a 62% reduction of the number of new gadolinium-enhancing lesions, and compared with placebo between 4 and 8 weeks, there was a 97% reduction.[3] They similarly found a greater reduction for new T2 lesions. From this, we can conclude that by 4 to 8 weeks there is a dramatic benefit of ocrelizumab, and in fact, there is a substantial benefit even in the first 4 weeks after initiation of therapy.[3]

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Dr Krieger: Thank you for that update. These data further underscore the efficacy of ocrelizumab on MRI outcomes in this disease. The data on appropriate and safe switching from one agent to another, as well as the data on the long-term safety and efficacy of agents that we have had approved for quite a number of years, are assuring and give us more information that we can use to personalize and optimize our treatment decisions. Thank you very much for joining me for this discussion.


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Dr. Krieger: Hello, I am Stephen Krieger. Joining me today is Dr Augusto Miravalle, Associate Professor of Neurology and Associate Chair of Education, and the Chief of the Multiple Sclerosis Division of the Department of Neurology at the University of Florida in Gainesville. Welcome, Dr Miravalle.

Augusto Miravalle, MD: Thank you, Stephen.

Dr Krieger: We are going to talk about imaging and other disease-related factors in MS.

MS Highlights From the 2017 Annual Neurology Meeting: Imaging and Disease Factors

Let us start by looking at a project on imaging of the spinal cord. We all recognize that spinal cord lesions are important, but this particular imaging study went one step further. What can you tell us about this one?

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Dr Miravalle: This is an important study because it highlights the relationship between gray matter atrophy, whether it is in the brain or the spinal cord, and clinical outcomes. In this study, the investigators looked at the presence of gray matter atrophy in the spinal cord using a new technique, 2D phase-sensitive inversion recovery.[4] They correlated that with clinical disability.

They concentrated on certain areas of the cervical and thoracic cord and they looked at the C2/C3 segment and the T9/T10 segment. Not surprisingly, there was some atrophy in the gray matter as expected. Perhaps the most important part of the study is that there was no correlation between gray matter atrophy and the presence of lesions or the presence of white matter atrophy in the cord, suggesting something similar to what we saw before with the brain.[4] Perhaps this process is independent from the presence of spinal cord disease as well as from the presence of T2 lesions.

In terms of clinical outcomes, they divided these patients with or without a prior history of spinal cord relapses or transverse myelitis. In patients who did not have prior history of relapses, the presence of cervical spinal cord gray matter atrophy explain up to 48% of the changes on Expanded Disability Status Scale (EDSS) score, again suggesting a strong correlation between the presence of gray matter atrophy in the cord and the presence of clinical disability.[4]

Dr Krieger: This is another example of what we are realizing, that the traditional white matter lesions are only part of the driver of disability in this disease.


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Let us turn to vitamin D. This particular project looks at even more personalized variability on the basis of race and ethnicity. What did we learn here?

Dr Miravalle: Actually, they tried to correlate 3 factors: the historical presence of exposure to ultraviolet radiation (UVR), the presence of multiple polymorphisms in the vitamin D-binding protein genes, and the presence of the 25-hydroxyvitamin D levels in a multiethnic population.[5]

Ultimately, the study suggests that there is a relationship between lifetime UVR exposure and a lower risk of MS, suggesting that individuals, regardless of race, who have increased exposure to UVR appear to have a lower risk of MS. That is particularly true in individuals who have at least 1 copy of the allele of rs7041, a vitamin D-binding protein gene.[5]

When you look at the levels of a 25-hydroxyvitamin D level and the risk of MS, there was an association suggesting a lower level of risk in individuals with higher levels of vitamin D, but only in whites. That association is not present in Hispanics and blacks.[5]

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Dr Krieger: There have been several new studies on the microbiome in MS. Tell us what you have seen in the one that we reviewed here.

Dr Miravalle: This study looked at patients with MS, relapsing and a secondary progressive disease as well as healthy controls. They divided these patients into 3 categories: patients who have active MS, meaning with active clinical disease; patients who are considered stable; and controls.[6] They looked at different stool samples and they measured recombinant DNA to try to profile different microbiomes. They found differences in the composition of the gut microbiota in individuals with active disease, suggesting that perhaps these different levels of different bacteria may influence, or at least be associated with, active disease vs stable disease.[6]

Dr Krieger: We talked at the beginning about spinal cord volume and gray matter area. Size does seem to matter in some regard in the nervous system and that concept extends into the concept of reserve. What did we learn here at AAN regarding reserve, structurally and functionally?


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Dr Miravalle: The concept of brain reserve, as you mentioned, is an important one. We are trying to understand the relationship with clinical outcomes and also how to measure reserve. This particular study developed an interesting way to include education. The way they defined a reserve score in the study is a combination of the intracranial volume (maximal lifetime brain growth) and an educational attainment score based on how many years of education patients had.[7]

They correlated both factors with clinical outcomes. Not surprisingly, they found that there was a direct relationship between higher reserve scores with lower accumulation of disability. This effect appears to be driven by the effect of education more than the effect of the intracranial volume.[7]

Dr Krieger: We hope to be able to quantify and personalize reserve in a truly predictive way in the future. At this point, however, I think we are still trying to understand the concept of reserve in terms of someone’s compensatory ability. This will be an interesting area to track in the next couple of years.

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Finally, here, in conclusion, we have talked about some novel imaging, novel concepts regarding vitamin D, and novel concepts regarding reserve against disability in this disease state. They are just examples of how we are focusing more and more on individual patient characteristics and how we assess and manage MS. I want to thank Dr Miravalle for a terrific conversation.


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Dr Krieger: Hello. I am Stephen Krieger. Today, we will be discussing progressive MS. Joining me today is Robert Fox, staff neurologist at the Mellen Center for Multiple Sclerosis and Vice Chair for Research of the Neurological Institute of the Cleveland Clinic. Welcome.

Robert Fox, MD: It is good to be here.

Dr Krieger: We know primary progressive MS affects around 10% to 15% of patients with MS.[8] Many patients who were diagnosed with relapsing disease develop secondary progressive MS over the course of their illness. There were data about many recent advances in the treatment of progressive MS presented at the 2017 AAN meeting. Maybe we can start with an abstract that was on many people’s minds, which is the results of the ORATORIO study of ocrelizumab in primary progressive MS.

MS Highlights From the 2017 Annual Neurology Meeting: Progressive MS

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Dr Fox: This abstract reports findings of a secondary analysis on the ORATORIO study. The investigators examined something similar to what is seen in relapsing MS. In relapsing MS, we looked at patients with no evidence of disease activity, no relapses, and no new lesions on magnetic resonance imaging (MRI).

For progressive MS, we also want to look at progressive disability. They coined a new concept, which is no evidence of progression or active disease (NEPAD).[9]

In the ORATORIO study, they found that 30% of the ocrelizumab-treated patients achieved NEPAD compared with only 9% of those on placebo.[9]

Dr Krieger: I think this is a nice way of extending the no evidence of disease concept into progressive MS.


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Dr Fox: What we do not know from the ORATORIO study is how effective the drug was over the course of the disease, over the various ages, and the various degrees of disability. What I would like to see is a breakdown of how effective the drug was in the older vs the younger patients, in the shorter disease duration vs the longer disease duration, and in patients with lower disability compared with higher disability.

Dr Krieger: I think those things are very important.

As we also think across the spectrum of our patients with progressive MS, it is worth looking at and changing subject here to think about secondary progressive MS (SPMS), also an important disease category for our patients over the course of their illness. There were data presented this past year on siponimod in SPMS. I think you were a part of those studies.

Dr Fox: Yes.

Dr Krieger: At the AAN meeting this year, we saw more detail on safety outcomes and other nuances of siponimod in SPMS. Maybe you can take us through some of those results.

Dr Fox: What was found is that the overall safety did not show much new compared with other sphingosine-1-phosphate (S1P) modulators like fingolimod, for example.[10] Serious treatment-emergent adverse events were seen in 18% of siponimod-treated patients and 15% of placebo-treated patients. These events were things that we would expect, like lymphopenia, liver function elevations, and bradyarrhythmia or slowing of the heart rate. Infections were seen equally between the 2 groups with the exception of herpes virus infections, which were seen a little bit more commonly in siponimod-treated patients.[10]

A new side effect that was not previously seen with S1P modulators is seizures. They were seen slightly more commonly in patients treated with siponimod. Another important safety concern with S1P modulators is malignancy. There was no evidence for an increased risk of malignancy in the siponimod-treated patients compared with placebo.[10]

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Dr Krieger: Another agent that has been studied in SPMS is natalizumab, which was studied in a large trial called ASCEND. At the AAN meeting this year, we saw several post hoc analyses of the ASCEND trial to try to get a more nuanced look at whether natalizumab may indeed have some effects on disability in a progressive MS population. Maybe you can take us through some of those.

Dr Fox: Sure. We often think in progressive MS about preventing decline, and that is important. We can also look at the smaller proportion of patients who demonstrate improvement in their function as measured by our disability scale, the Expanded Disability Status Scale (EDSS). This analysis looked at patients regarding the probability of disability improvement over 2 years. What they found is that the natalizumab-treated patients had a 40% increased probability of disability improvement compared with placebo.[11]

This was broken down into different endpoints. They had a multicomponent endpoint as well as 9-Hole Peg Test and timed 25-foot walk. All of these showed an improvement in the probability or in the increase in the probability of improvement with natalizumab compared with placebo.[11] I think this highlights that when we use strong anti-inflammatory therapy, even in progressive MS, we can see some improvement, particularly in patients who have active inflammation at the start of treatment.

Dr Krieger: Yes, I think this is a good example of knowing the right subgroup of patients, perhaps, to use a particular medication and to attempt to bring out the best possible outcomes for them.


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Well, this has been a terrific review and discussion of some of the work in progressive MS shown at this year’s meeting. In summary here, ocrelizumab has been the first approved therapy for PPMS. We saw interesting data here to further delineate some of the details of its efficacy, including the concept of NEPAD. We also saw some post hoc analyses and more nuanced analyses of trials of siponimod in secondary progressive MS and with natalizumab in secondary progressive MS as well, indicating that perhaps there really can be more dramatic benefit for those progressive patients who have an admixture of inflammatory disease. I want to thank Dr Fox for joining me on this call.

Dr Fox: It was my pleasure to be with you.

Dr Krieger: Thank you to all of you for listening.

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Dr Krieger: Hello, I am Stephen Krieger. Today, we will be discussing several investigational therapies in MS. Joining me again today is Dr Augusto Miravalle.

Dr Miravalle: Thank you, Stephen.

MS Highlights From the 2017 Annual Neurology Meeting: Investigational Therapies

Dr Krieger: One of the major unmet needs in MS is remyelinating therapies. Dr Miravalle, maybe you can tell us a bit about opicinumab and the SYNERGY trial.

Dr Miravalle: Opicinumab is a monoclonal antibody that blocks LINGO-1. By blocking that, you assume that is going to promote mechanisms of repair and remyelination. In this current study, patients received either placebo plus interferons or opicinumab plus interferons.[12] There were multiple doses used. The primary endpoint for this study was a combined endpoint looking at clinical outcomes as well as cognitive function, including 3-month confirmed improvement on the combination of all these outcomes, including EDSS, timed-25 foot walk, and 9-Hole Peg Test. Of all the patients enrolled, a total of 334 patients completed the study. Unfortunately, the endpoint was not met.[12]


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When you look at a subgroup analysis based on different doses, there was an inverted U-shaped curve without any clear correlation with higher doses as well.[12]

Dr Krieger: As you pointed out, the dose-response curve was complicated. I think there is probably still something to learn about how to optimize the dose of this agent to see if we can maximize its benefit as well as thinking about what the right outcomes should be for a remyelination trial. Obviously, improving patients from a disability perspective is the goal, but that may be hard to achieve in the context of a relatively short clinical trial.

Let us turn to a totally different strategy. This one was studied in a small SPMS project. This is an investigational molecule called MIS416. What can we say so far about this molecule in its relatively early stages of development for progressive MS?

Dr Miravalle: This molecule actually brings another side of the story: neuroprotection. It may or may not be linked to repair or remyelination. In this case, neuroprotection is accomplished by inducing reparative or growth factors that are known to preserve brain function.

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In this case, MIS416 showed improvement in animal models. This study actually is also based on an animal model that looked at pharmacodynamics and relationship between dose administration and the induction of certain growth factors, and indeed showed that the use of this medication induced a linear relationship with the modulation of these neuroprotective growth factors.[13] It is still too early to draw conclusions about its use in humans, but it is a promising molecule.

Dr Krieger: I think that is promising.

Let us look at the data. Cladribine was studied in a series of large clinical trials, but it was halted in its approval process because of some safety issues. Let us look back now at the cladribine data from 2 studies, the ORACLE study and the CLARITY study.

Dr Miravalle: The ORACLE study enrolled patients with clinically isolated syndrome to see whether the administration of cladribine would delay this conversion to clinically definite MS. They looked at those patients who actually converted during ORACLE study.[14] They followed them over time and compared the outcomes, including annualized relapse rate and gadolinium enhancement in patients who initially received cladribine plus IFNβ-1a subcutaneous vs the individuals who only received IFNβ-1a. There was a trend to suggest that individuals who received cladribine early on had improvement in those outcomes in the presence of annualized relapse rate, which was as low as 0.14.[14]


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The CLARITY study looked at individuals with high disease activity. In that case, individuals who received cladribine showed a higher efficacy vs placebo. This is a post hoc analysis in individuals with high relapse rate as well as a high evidence of inflammation.[15] This analysis showed an 82% reduction in the 6-month confirmed disability progression in individuals who were considered to have high disease activity, a 58% reduction in the annualized relapse rate vs placebo, and a 56% reduction in the risk of having a relapse.[15]

Dr Krieger: I think we see here from the ORACLE study the concept of the sustained efficacy of this agent used early in the disease and how, with its durable mechanism of action on the immune system, it may bring about quiescence of disease activity for a long time. From the CLARITY study in relapsing MS, a subgroup analysis might see whether patients with highly active disease will benefit the most. This was assess with substantial efficacy measures. What do we know about the safety issues with cladribine?

Dr Miravalle: As we know from previous studies, one of the risks of cladribine is the sustained lymphopenia as well as the risk of not only opportunistic infections but most importantly, malignancies. That is the main reason why the medication was not approved. Having this subgroup analysis might allow us to understand the role of this medication to try to identify which patients might be ideal candidates.

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Dr Krieger: I think these are great points. Dr Miravalle, again, I want to thank you for an insightful conversation about these topics. Thank you again for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. Thank you.


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References1. Bertolotto A, Capobianco M, Lo Re M, et al. High risk PML patients switching from natalizumab to alemtuzumab. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P2.407.2. Freedman MS, Comi G, Coyle PK, et al. Effect of early versus delayed scIIFN β-1a on radiological or clinical activity-free status in patients with clinically isolated syndrome: a post-hoc analysis of REFLEXION. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P6.358.3. Barkhof F, Kappos L, Bar-Or A, et al. Rapid onset of ocrelizumab suppression of brain MRI activity in relapsing-remitting multiple sclerosis. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Abstract S12.008.4. Schlaeger R, Papinutto N, Zhu A, et al. Atrophy of spinal cord gray matter is detectable at an early stage of multiple sclerosis. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Abstract S2.003.5. Langer-Gould A, Smith J, Lucas R, et al. Vitamin D-binding protein polymorphisms, 25-hydroxyvitamin D, sun exposure and risk of multiple sclerosis in blacks, Hispanics and whites. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P3.395.6. Nedelcu S, Contreras ALM, Eleftheriou E, et al. Variations in the gut microbiome in relapsing multiple sclerosis. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P3.398.7. Sumowski JF, Rocca MA, Leavitt VM, et al. Expending the Concept of Reserve from Cognitive to Physical Disability in Multiple Sclerosis. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P4.348.8. Mallucci G, Peruzzotti-Jametti L, Bernstock JD, et al. The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis. Prog Neurobiol. 2015;127-128:1-22.9. Wolinsky J, Montalban X, Kappos L, et al. Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P4.384.10. Fox R, Kappos L, Bar-Or A, et al. Safety and tolerability of siponimod in patients with secondary progressive multiple sclerosis. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Abstract S33.007.11. Giovannoni G, Stein D, Sellebjerg F, et al. Sustained disability improvement as assessed by a multicomponent endpoint in secondary progressive multiple sclerosis (SPMS) patients: a post hoc analysis from ASCEND. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P5.359.12. Mellion M, Edwards KR, Hupperts R, et al. Efficacy results from the phase 2b SYNERGY study: treatment of disabling multiple sclerosis with the Anti-LINGO-1 monoclonal antibody opicinumab. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Abstract S33.004.13. Girvan R, Pearson V, Hassanpour M, et al. Neuroprotective/neuroreparative activity of MIS416, a myeloid-directed innate immune therapeutic in phase 2B trial for the treatment of secondary progressive multiple sclerosis. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P5.333.14. Comi G, Leist T, Freedman MS, et al. Cladribine tablets in the ORACLE-MS study open-label maintenance period: analysis of efficacy in patients after conversion to clinically definite multiple sclerosis (CDMS). Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P6.349.15. Giovannoni G, Rammohan K, Cook S, et al. Efficacy of cladribine tablets 3.5 mg/kg in high disease activity (HDA) subgroups of patients with relapsing multiple sclerosis (RMS) in the CLARITY study. Presented at: American Academy of Neurology 2017 Annual Meeting; April 22-28, 2017; Boston, Massachusetts. Poster P6.360.

Dr Krieger: I think these are great points. Dr Miravalle, again, I want to thank you for an insightful conversation about these topics. Thank you again for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. Thank you.

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AbbreviationsAdd abbreviations below:9HPT = 9-Hole Peg Test25(OH)D = 25-hydroxyvitamin DAE = adverse eventARR = annualized relapse rateCDMS = clinically definite multiple sclerosisCDP = confirmed disability progressionCIS = clinically isolated syndromeDBP = vitamin D-binding protein geneDMT = disease-modifying therapyEDSS = Expanded Disability Status Scale EPO = erythropoietinFTT = finger-tapping testGA = glatiramer acetate Gd = gadoliniumHGF = human growth factorHRA = high relapse activityICV = intracranial volumeIFN = interferonIGF-1 = insulin-like growth factor-1 IM = intramuscularIV = intravenousJCV = JC virusLFT = liver function testMLBG = maximal lifetime brain growthMRI = magnetic resonance imagingMS = multiple sclerosisNEDA = no evidence of disease activityNEP = no evidence of progressionNEPAD = no evidence of progression or active diseaseNGF-β = nerve growth factor betaOLMP= open-label maintenance periodOR = odds ratioPASAT-3 = 3-Second Paced Auditory Serial Addition TestPML = progressive multifocal leukoencephalopathyPPMS = primary progressive multiple sclerosisPSIR = phase-sensitive inversion recoveryqw = every weekq4w = every 4 weeksRDBPC = randomized, double-blind, placebo-controlledRRMS = relapsing-remitting multiple sclerosisS1P = sphingosine-1-phosphateSC = subcutaneousSCI = spinal cord injurySPMS = secondary progressive multiple sclerosisT25FW = timed 25-foot walkTEAE = treatment-emergent adverse eventtiw = three times a weekTNR = treatment nonresponseUTI = urinary tract infectionUVR = ultraviolet radiationVEGF = vascular endothelial growth factor

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