Highlights From the 2017 Annual European MS Meeting · I would like to discuss a couple of posters about oral cladribine ... counts in patients with relapsing ... Highlights From

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Highlights From the 2017Annual European MS Meeting CME

Supported by an independent educational grant from EMD Serono


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Highlights From the 2017 Annual European MS Meeting CME

Target AudienceThis activity is intended for neurologists, primary care physicians, obstetricians, and gynecologists.

GoalThe goal of this activity is to relate newly released data from the annual European MS meeting to clinical practice.

Learning ObjectivesUpon completion of this activity, participants will have increased knowledge regarding the:

• Key data from recent clinical studies in MS

• Potential clinical applicability of clinical trial findings to improve the management of MS

• Identication of investigational therapies with improved efficacy and/or safety with regard to the management of MS

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Medscape, LLC staff have disclosed that they have no relevant financial relationships.

This article is a CME certified activity.To earn credit for this activity visit:


CME Released: 11/30/2017; Valid for credit through: 11/30/2018


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Disclosures

Moderator

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath Chair of Neurology, Barts and the London School of Medicine and Dentistry, London, United Kingdom

Disclosure: Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: AbbVie, Inc.; Bayer Schering Pharma; Biogen; Canbex Therapeutics Ltd; Eisai, Inc.; Elan Pharmaceuticals, Inc.; EMD Serono, Inc.; FivePrime Therapeutics; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; GW Pharmaceuticals; Ironwood Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer, Inc; Roche; sanofi-aventis; Synthon BV; Teva Pharmaceutical Industries Ltd; UCB Pharma, Inc.; Vertex Pharmaceuticals Incorporated.

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

Panelist

Anne Cross, MD Professor of Neurology; Head of Neuroimmunology, Washington University in St. Louis, St. Louis, Missouri, United States

Disclosure: Anne Cross, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AbbVie Inc.; Bayer HealthCare; Biogenc.; EMD Serono, Inc.; Genentech, Inc.; Novartis Pharmaceuticals Corporation.

Received grants for clinical research from: Genentech, Inc.

Dr Cross does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

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

Stephen Krieger, MD Associate Professor of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Disclosure: Stephen Krieger, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: ACADIA Pharmaceuticals, Inc.; Bayer HealthCare; Biogen; Celgene Corporation; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Mallinckrodt; MedDay; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA; TG Therapeutics, Inc. Served as a speaker or a member of a speakers bureau for: Biogen

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 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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Thomas Leist, MD, PhD Professor of Neurology; Director, Comprehensive MS Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States

Disclosure: Thomas Leist, MD, PhD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Biogen; EMD Serono, Inc.; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA

Served as a speaker or a member of a speakers bureau for: Biogen; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA

Received grants for clinical research from: Biogen; MedDay; Novartis Pharmaceuticals Corporation; Sun Pharmaceutical Industries Ltd.

Dr Leist 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 Leist does 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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Highlights From the 2017 European MS Meeting

IntroductionHighlights From the 2017 European MS Meeting

Gavin Giovannoni, MD, MBBCh, PhD, FCP (SA, Neurol), FRCP, FRCPath: Hello, I am Professor Gavin Giovannoni, Chair of Neurology at Barts and the London School of Medicine and Dentistry. Welcome to this program entitled MS Highlights from the 2017 European MS Meeting.

DisclaimerBecause this program will include a discussion of data that were presented in abstract form, these data should be considered preliminary until published in a peer-reviewed journal. We will also be discussing investigational agents that are not yet approved for use in the United States (US).


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PanelistsIn subsequent segments of this program, I will discuss some of the exciting new data with my colleagues Dr Cross, Dr Krieger, and Dr Leist.

A big body of work presented at the European meeting has been the impact of a new technological innovation in measuring neurofilament levels in the peripheral blood. You will hear more about this in another session. The important thing about neurofilaments is they are a nonspecific marker of neurodegeneration, and raised levels are prognostic. They can also be used as a treatment response. Most of the anti-inflammatory treatments dramatically reduce neurofilament levels over a 3- to 6-month period. I see peripheral blood neurofilament levels translating into clinical practice very, very quickly. That may become one of our treatment targets and would complement the magnetic resonance imaging (MRI) monitoring of patients as well.

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DMTs in MS

Investigational Disease-Modifying Therapies for MSJoining me now in our first session is Dr Anne Cross, Professor of Neurology, and Head of the Neuro-Immunology section at Washington University in St Louis to discuss some investigational disease-modifying therapies (DMT) for multiple sclerosis (MS). Welcome, Anne.

Anne H Cross, MD: Thank you, Dr Giovannoni. I would like to discuss a couple of posters about oral cladribine tablets. The reason I chose these is because this particular drug has been approved by the European Medicines Agency (EMA) in the last few months and will soon be put before the Food and Drug Administration (FDA) in the US. It is an up-and-coming, and potentially approved medication in the near future in the US.


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Long-Term Lymphocyte Counts in Patients With RRMS Treated With Cladribine Tablets, 3.5 mg/kgI am going to discuss a poster called, “Long-term lymphocyte counts in patients with relapsing-remitting MS (RRMS) treated with cladribine tablets at 3.5 mg/kg: total lymphocytes B and T cell subsets,” by Sorensen and the Danish MS Center and others.

Cladribine: Background[1,2]

The background for cladribine is that this is a chemotherapy that has been approved to treat hairy cell leukemia and B cell chronic leukemia for a number of years, decades actually. It was studied as a parenteral treatment for MS in the mid-1990s, but an original FDA application was withdrawn, and further studies on safety were considered necessary.

The drug was reformulated for oral use and in the 96-week CLARITY study, which involved well over 1300 patients and was published over 7 years ago in The New England Journal of Medicine in 2010, a positive effect vs placebo was seen in RRMS. However, the FDA rejected a new-drug application in 2011, due to concerns over safety, including a potential increased cancer rate and increased infections.

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Subsequently, there was a study comparing a large group of data from a number of clinical trials, including trials of cladribine but other drugs that are approved for MS. No increase in cancer rate was found compared to the other medications or to the placebo groups.

As one might expect for a drug that reduces lymphocyte proliferation, the most common serious adverse event (AE) in both the CLARITY study and another study, which was cut short in clinically isolated syndrome (CIS) called ORACLE, was lymphopenia.

Long-Term Lymphocyte Counts and Cladribine[3]

In a number of patients who had RRMS who received multiple courses of cladribine, in this study of over 600 patients in the abstract that I am going to talk about, the absolute lymphocyte counts were followed for over 5 years, and the B and T cell subsets, including CD4 and CD8 T cells, were followed for almost 5 years.


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Long-Term Lymphocyte Counts and Cladribine: Results[3]

It turned out that CD19 B cells were reduced and came back generally sooner than the T cells, coming back around 7.5 months. The nadirs were in the range of 12 weeks or so. The same thing for CD4 T cells, although they took longer to come back. Then for CD8 cells, which did fall, or trended to fall, they actually never did drop below threshold as a group. I thought that study was interesting because of the B cell population drop in particular.

Cladribine and Highly Active Disease

Radiologic Outcomes of Cladribine in Patients With MS and HAD: Background[4]

In the second study I am going to talk about, it turns out that this study was headed by Dr Giovannoni, and I did not even realize that when I chose this. This study was looking at radiologic outcomes in patients who had high-disease activity (HAD) with RRMS.

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Radiologic Outcomes of Cladribine in Patients with MS and HAD: Post Hoc Analysis[4]

And those patients were defined in a couple of ways.

The study was looking post hoc at MRI data from patients who were defined as HAD. It was based on either high relapse activity (HRA) of greater than 2 relapses, or 2 or more relapses in the prior year, and/or patients who were HRA plus treatment non-responders (TNR), ie, had 1 or more relapses plus MRI activity and had been taking DMT, so were not optimal responders to that.

Radiologic Outcomes of Cladribine in Patients with MS and HAD: Results[4]

These data were compared with the total population in the CLARITY study, which was the large RRMS study that was positive vs placebo. For the HRA subjects and also for those that were defined as HRA-TNR to their prior DMT, the relative risk reduction (RRR) for new gadolinium-enhancing T1 weighted lesions was just as high, if not higher, than for the total CLARITY population. Also new active T2 lesions and combined unique lesions, these were all just as good as for the total CLARITY population in this group of patients who had more aggressive MS.


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Concluding Remarks[3,4]

Dr Giovannoni: Could you summarize the key points in the 2 trials?

Dr Cross: For me, the first trial looking at the different subsets, in particular, CD4, CD8, and CD19 lymphocytes, I thought it was particularly noteworthy that both B cells and T cells, particularly CD4 T cells, were reduced and that B cells were reduced and perhaps have something to do with the mechanism of action of the drug. However, B cells returned first, just like they have with other drugs we have seen, and CD8 T cells were reduced least.

Dr Giovannoni: One of the things that I want to mention is that the B cells, when they do come back, do not overshoot, which is what we have seen with alemtuzumab. I personally think that may explain why we do not see secondary autoimmunity.

Dr Cross: I agree with you, totally. Then for the second abstract, the one on MRI endpoints, and I think that this one struck me as being of interest because, although we have 13 or more drugs in the US for RRMS, some of these are not particularly great for aggressive MS and this poster, although it was a post hoc analysis, suggests that oral cladribine may be a particularly good choice for patients with more aggressive MS. We need more drugs in that subtype.

Dr Giovannoni: One of the big advantages that is not captured in the abstracts is the ease of use of this drug, in the sense that you only have to take these tablets for 10 days in year 1 and 10 days in year 2, and it looks like the efficacy is long-term. Most of the patients remaining active up to 4 years.

Dr Cross: Yes. That certainly reduces the problem with nonadherence, or reduced adherence.

Dr Giovannoni: Thank you very much.

Dr Cross: Thank you.

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Biomarkers for Prognostication in Early MS

Biomarkers for Prognostication in Early MSDr Giovannoni: We are back again with Dr Anne Cross. This time our topic is Biomarkers for Prognostication in Early MS. Welcome back, Dr Cross.

Anne H. Cross, MD: Thank you, Professor Giovannoni.

Biomarkers in MS

Purpose of Biomarkers in MSDr Giovannoni: Why is the topic important?


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Dr Cross: For many reasons. Biomarkers, particularly biomarkers that may aid in prognostication, are greatly needed. They could improve our decision making early on in patients, which, at the current time, is mainly by trial and error, based on the clinician’s prior experience. They could help in treatment stratification, not only in terms of therapies for finding the perfect therapy for certain individual persons, but also stratification tools in clinical trials in the future.

Neurofilaments in MSNeurofilaments[5]

Dr Giovannoni: Before we get into specifics of the study, can you please provide a little background information on this biomarker neurofilament that you are going to be discussing? What is it, and how do we monitor it?

Dr Cross: Neurofilaments are highly specific to neurons, to the sub-bodies, and to the axons. They are essential for a number of things related to axonal growth and maintenance, as well as to nerve-conduction velocity. There are 3 types: there are the light, medium, and heavy chain. The light chain is the one that is being discussed and studied here.

Dr Giovannoni: Certain neurofilament light (NfL) labels at the time of the CIS appear to be associated with prognosis. Would you like to discuss the abstract that was presented?

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NfL Concentrations and CIS: Objectives and Methods[6]

Dr Cross: Yes, this one is entitled, “Serum NfL levels at the time of a clinically isolated syndrome are associated with long-term clinical and radiological outcome,” by Plavina and colleagues. The objective of this was to evaluate serum concentrations of NfL as a prognostic biomarker.

They used a very sensitive method called SIMOA, which is a single-molecule array done with electrochemiluminescence. They looked at over 300 patients from the CHAMPS and the CHAMPION studies, which were studies of interferon β1a intramuscular.

These were a large number of patients followed; they were compared in terms of vs placebo for conversion to clinically definite MS (CDMS), and they were also followed for up to 10 years in extension studies.


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NfL Concentrations and CIS: Results[6]

The results were highly significant in the sense that serum NfL levels being higher, predicted that patients would have, not only a higher T2 lesion burden at baseline, but also new T2 lesions in the coming 5 and 10 years. Also volumetric changes were worse in patients with higher serum NfL levels. To a lesser extent, NfL levels also predicted future numbers of relapses over 10 years, shorter time to CDMS over the following 10 years, and shorter time to reaching disability endpoints at 5 years.

Dr Giovannoni: What did the authors conclude about their findings, and could you try and put these into context for practicing neurologists?

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NfL Concentrations and CIS: Conclusions[6]

Dr Cross: They concluded that serum NfL may be a candidate biomarker for disease stratification in early MS. I believe these findings are very important because they derive, number 1, from a large number of subjects who are similar, patients with early MS or CIS.

Then these patients were followed rigorously for up to 10 years. They were followed in a highly internally consistent manner. The results were highly internally consistent, meaning that they were very believable in terms of predicting both MRI activity and clinical activity and disability accumulation.

Immunoglobulins in MS

Intrathecal Ig in MS: Background[7]

Dr Giovannoni: Let’s move on to the second study you have highlighted. I understand that you visited the poster by Gasperi and colleagues entitled, “Intrathecal immunoglobulin synthesis as a predictive marker for disability progression in multiple sclerosis.” Again would you mind providing some background on intrathecal immunoglobulin (Ig) synthesis?


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Dr Cross: It is well known that patients with MS have an elevated amount of Ig synthesis, not only IgG, which is generally the one that is measured by the laboratory, but also IgM and IgA. This occurs in over 90% of patients. It is usually measured as oligoclonal bands (OCB), but also as Ig levels and the Ig index, which is relative to the blood.

Intrathecal Ig in MS: Aim and Study Design[7]

The aim of this study was to investigate the association between Ig synthesis, as measured by an index relative to the blood, and disability progression over time. They looked at almost 400 patients in terms of these data and then followed the patients up for 2 years or more and looked at the association with progression.

Intrathecal Ig in MS: Results[7]

The results were that the presence of intrathecal Ig synthesis, IgG in particular, but also IgM and IgA, was associated with a higher risk of progression on the Expanded Disability Status Scale (EDSS) within these 2 years. It was much more pronounced in the data shown on the poster in those patients who had not received DMT. There was basically a shorter time to progression, and this was mainly driven by intrathecal IgG synthesis.

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Dr Giovannoni: Do you think this is going to make people do lumbar punctures more often?

Dr Cross: Perhaps. I think anything that can help prognosticate and stratify patients and help us determine what DMTs to start patients out on is worth a spinal tap. At least it would be if I had MS.

Dr Giovannoni: What are the overall takeaway messages from these 2 studies?

Overall Conclusions[6,7]

Dr Cross: For those of us in the US, given that we now have over 13 approved medications for DMT of RRMS, it is getting to be more and more important to stratify patients in terms of what to choose in the early stages of the disease. We are always trying to balance both efficacy and safety. If we have ways to determine which patients have a poorer prognosis, then it will help us determine which drugs to choose first, and hopefully the outcomes will be much better for those patients.

I also like the fact that both of these tests are going to be relatively easy to do, certainly looking at Ig levels in the spinal fluid is readily available right now to all clinicians in the US, so we can do this. Serum NfL levels, although they are still a research tool now, I think we are going to make it into the clinical world very quickly.

Dr Giovannoni: Thank you very much in joining us today.

Dr Cross: Thank you.


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What Is New in Progressive Forms of MS?

What Is New in Progressive Forms of MS?Dr Giovannoni: Joining me in this session, “What Is new in progressive forms of MS,” is Dr Stephen Krieger, Associate Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York. Welcome, Stephen.

Stephen Krieger, MD: Thank you.

Dr Giovannoni: Maybe you want to tell me about the posters you have selected and why?

Progression to SPMS

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Risk of SPMS: Methods[8]

Dr Krieger: Sure. The theme here is looking at progressive MS and the accumulation of disability and some of the uncertainty, in a sense, that we have in looking at that. The first presentation here is from Kalincik and the folks from Melbourne, looking at risks of secondary progressive MS (SPMS) in a large cohort from the MSBase group; this is over 6000 patients and over 30,000 visits.

What they looked for here was factors that could predict the conversion to SPMS. That is, of course, a somewhat arbitrary concept or construct, the idea that a patient at a certain point converts from relapsing to SPMS.

Risk of SPMS: Results[8]

What they found was that this conversion of phenotype was predicted by patients who had a more rapid accumulation of disability, higher EDSS scores, and longer disease duration. None of these are surprising, obviously.

I think what it tells us is something about the type of patient that we classify or think of as having SPMS. As we follow them along these lines, patients that were improving in their disability trajectory were less likely to be considered SPMS. That is sort of a validation of the methodology here, since we think of progressive MS as a gradual insidious worsening of disability.

One thing I thought was interesting was they did not find evidence that recent MRI disease activity predicted this conversion, nor did they find that presence of cord lesions predicted the conversion to secondary progressive MS. That is a little bit unexpected. Perhaps it is simply that cord lesions are so common that their mere presence or absence does not actually predict the development of a progressive course.

Dr Giovannoni: And the second abstract?


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Predicting MS Disease Progression From Placebo Arms[9]

Dr Krieger: Then we looked at a meta-analysis to look at disability accumulation. This was a study looking at some of the placebo arms in several of the randomized clinical trials that have been registration trials for our approved therapies.

Predicting MS Disease Progression From Placebo Arms: Statistical Methods, Definitions, and Baseline Factors[9]

This looks at RRMS patients treated with placebo to see, could we find factors that predict accumulation of disability in a relatively short term. This is unlike the first study, looking at long-term development of SPMS. This more looked at defining disease progression on a composite endpoint with EDSS changes and Multiple Sclerosis Functional Composite (MSFC) changes.

Here, they looked at all of the usual factors that we think of as being predictive: age, gender, relapse history, disease duration, presence of gadolinium-enhancing lesions. There are complex statistical models, which I cannot hope to describe myself.

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Predicting MS Disease Progression From Placebo Arms: Results[9]

They did not really find that any of these conferred a great predictive quality toward the development of disability in this group. It is somewhat humbling, if anything, that even with all of our factors, they really account for a small amount of the variance and disability accumulated from these cohorts.

Dr Giovannoni: I see the next abstract or presentation you picked was on misdiagnosis in primary progressive multiple sclerosis (PPMS).

Misdiagnosis of PPMS

PPMS Misdiagnosis in Europe and US: Background[10]

Dr Krieger: PPMS, at least with the approval of ocrelizumab in the US, has become a potentially treatable form of this disease. There is more of an emphasis on trying to recognize PPMS and make an astute diagnosis of it as early as possible.

It is also the form of the disease that lacks the characteristic calling card of the relapse. Therefore, historically, I think it has been a little bit more difficult to diagnose.


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PPMS Misdiagnosis in Europe and US: Methods[10]

Dr Krieger: This particular study looked at several hundred patients in both the European Union (EU) and the US who had developed PPMS and then looked to see whether they had been misdiagnosed initially.

PPMS Misdiagnosis in Europe and US: Results[10]

Dr Krieger: They found here that around 16% of the PPMS patients had been previously misdiagnosed in the EU, and 37% of them in the US.

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PPMS Misdiagnosis in 5EU and US: Conclusions[10]

Dr Krieger: It certainly points out that there is indeterminate diagnoses and the potential for misdiagnosis before PPMS declares itself. I think that, even as we are moving more toward a continuum of MS phenotype, the emphasis on accurate precise diagnosis in all the forms of MS remains very important with this being a treatable disease.

Dr Giovannoni: The points you are making are absolutely right. Another trend I noticed at the meeting was people are beginning to talk about 1 disease, not 2 or 3 diseases. This idea of having different types of phenotypes means different diseases is probably not going to hold for much longer.

I see the last abstract presentation you picked was on this brain reserve, cognitive reserve in progressive MS. Do you want to comment on that?


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Brain and Cognitive Reserve in Progressive MS

Brain Reserve and Cognitive Reserve in Progressive MS: Methods[11]

Dr Krieger: Absolutely. I picked this because this is both of interest to us, and some of this work was done in collaboration at Mount Sinai, and obviously of great interest to you and the Brain Reserve, Brain Health: Time Matters Initiative.

Here is an example of looking at brain reserve and cognitive reserve in progressive MS. By brain reserve here, we really mean brain volume, maximum lifetime brain growth; for cognitive reserve, they used educational level as a proxy for someone’s maximum cognitive functioning. What was interesting about this study is that it is looking at ways of trying to characterize the value of brain volume and the value of years of education (YOE) as being preventative in essence against the decline in progressive MS.

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Brain Reserve and Cognitive Reserve in Progressive MS: Results[11]

That is basically what they found, that controlling for a lot of the factors that you would think of as having prognostic importance, higher brain volume and higher cognitive reserve from YOE, independently protected against cognitive impairment in the context of progressive MS.

Dr Giovannoni: Another topic that was really highlighted at the meeting was the impact of comorbidities on progression, and I assume on cognition as well; the data will certainly emerge that comorbidities clip cognition due to MS. We are going to have to address MS holistically to make a difference in the long term.

I’d like to close and thank you very much for joining me today. Thank you.

Dr Krieger: Thank you.


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Exposure to DMTs Among Pregnant Women With MS

Pregnancy Rates in MS

Exposure to DMTs Among Pregnant Women With MSDr Giovannoni: Joining me now is Dr Thomas Leist, Professor of Neurology and Director of the Comprehensive MS Center at Jefferson University in Philadelphia. Welcome, Tom. Please tell us about the posters you visited over the past 2 days.

Thomas Leist, MD, PhD: Thank you.

BackgroundDr Leist: I looked at posters that were regarding pregnancy exposure in women with MS. The reason, obviously, why we are interested in this in MS is the fact that many of our newly diagnosed are women of childbearing age. We have numerous medications in the US, and medications range in their pregnancy ratings significantly.

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Pregnancy Incidence and Therapy Exposure in MS: Methods[12]

Dr Leist: The first one looks at the incidence of pregnancy and exposure from MSBase. It included 2 data periods: 2005 to 2010 and 2011 to 2016.

Pregnancy Incidence and Therapy Exposure in MS: Results[12]

Dr Leist: What is evident from this is that pregnancy is quite frequent. Most of the patients in the study were on the injectable agents, mostly interferons, but a small number of individuals were on agents such as azathioprine.

Most of the exposure while on treatment was relatively short, in the range of 30 to 50 days after conception or after becoming aware of pregnancy.


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Pregnancy and Alemtuzumab

Pregnancy Outcomes With Alemtuzumab: Background[13]

Dr Leist: The second study that I reviewed was the pregnancy outcome from alemtuzumab. This is a follow-up looking at the phase 3 protocols and the extension of the phase 3 protocols, as well as an open-label phase 4 study that followed approval of alemtuzumab, which is now available in over 60 countries.

This is interesting because alemtuzumab has a long-term biologic effect in the absence of detectability of the actual agent. This raises then the issue of a potential at-risk period around treatment.

Pregnancy Outcomes With Alemtuzumab: Results[13]

Dr Leist: In this study, there were a total of 218 pregnancies, with 147 live births that were observed, and here the information is obviously important, whether or not congenital abnormalities were observed. There was no increased risk of congenital abnormalities compared to expected. As always in these studies, it is interesting to see the spontaneous abortion rate, and, again, this was not significantly affected compared to what would be expected to normal pregnancies.

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So, it appears from this larger study, that if one uses the normal cautions, no pregnancy within 4 months of exposure with alemtuzumab, that to date there is no information regarding any teratogenetic signaling in these particular patients.

Dr Giovannoni: Do you want to continue with the final study?

Pregnancy and Cladribine

Pregnancy Outcomes With Cladribine: Background[14]

Dr Leist: The last study looks at the experience of pregnancies in the cladribine development. Here we have a small molecular entity that was specifically designed to target lymphocytes. Again, as was discussed with alemtuzumab, where there may be a biologic effect extending far beyond the actual presence of the agent, this is also the case in cladribine. We anticipated, during research, the biological effect of the agents that exceeds the times that the agent can actually be detected in the body.

At this point, and this is solely on the basis of theoretical consideration, there is a 6-month period during which one will consider a potential period following treatment that there could be a signal from the agent.

To date, there are about 8650 patient years of follow-up with cladribine during the development and in the postregistration trial follow-up period.


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Pregnancy Outcomes With Cladribine: Results[14]

Dr Leist: During this period, there were 44 pregnancies that occurred; there was a total of 18 live births that were observed in patients who were on cladribine. There was also a significantly large number of elective terminations of pregnancy, keeping in mind that, in certain countries, elective termination of pregnancy may be a way of doing fertility control. The number of spontaneous miscarriages while on cladribine was not increased, compared to that expected in the placebo or in the general population.

If we look at patients who were during the actual risk period, where we are concerned that the agent could be present, we had 16 pregnancies that occurred. They led to 3 live births, 10 elective terminations, 2 spontaneous miscarriages, and 1 medically indicated termination, which was due to an ectopic pregnancy. There were no fetal abnormalities observed in these live births, and no fetal abnormalities were reported otherwise.

There were also cases of pregnancy where the male partner was exposed to cladribine. Here we have 10 pregnancies that occurred, and for 9 of the 10 pregnancies we have an outcome, and these were healthy children. This is limited information on cladribine. Obviously, there is additional information needed, and this will be accumulated once this agent is in use.

Dr Giovannoni: Any concluding remarks to summarize the findings?

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Conclusions[12-14]

Dr Leist: We talked about the relatively large breadth of medical information that we accumulated around pregnancy. The initial study, the post hoc study from MSBase, informs us that pregnancies occur with quite high frequency in the younger MS populations. It is certainly something that is of importance. It also informs us that patients normally elect to discontinue medication. That is seen from the basis that the exposure of medication is relatively short.

The second 2 studies are for agents that have biologic effects that are present when the agent is actually eliminated from the organisms. We have more information with respect to the anti-CD52 treatment, which is encouraging at this point in time. The data that we have for cladribine are also encouraging. Obviously, we will need to follow this with the accumulating data that are collected in the mandatory registries.

Dr Giovannoni: Thank you, Dr Leist, for joining me today at the 2017 European MS Meeting.Thank you


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References1. Giovannoni G, Montalban X, Hicking C, Dangond F. Benefits of cladribine tablets on the achievement of no evidence of disease activity (NEDA) status in patients with multiple sclerosis: analysis of pooled double-blind data from the CLARITY and ONWARD studies. Mult Scler. 2016;22 (ECTRIMS):P641.

2. Pakpoor J, Disanto G, Altmann DR, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm. 2015;2:e158.

3. Soelberg-Sørenson P, Dangond F, Hicking C, Giovannini G. Long-term lymphocyte counts in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets 3.5 mg/kg: total lymphocytes, B and T cell subsets. ECTRIMS 2017; Paris, France. Poster P655.

4. Giovannini G, Rammohan K, Cook SD, et al. Effects of cladribine tablets on radiological outcomes in high disease activity (HDA) subgroups of patients with relapsing multiple sclerosis (RMS) in the CLARITY study. ECTRIMS 2017; Paris, France. Poster P1164.

5. Garcia ML, Lobsiger CS, Shah SB, et al. NF-M is an essential target for the myelin-directed “outside-in” signaling cascade that mediates radial axonal growth. J Cell Biol. 2003;163:1011-1020.

6. Plavina T, Singh CM, Sangurdekar D, et al. Serum neurofilament light levels at the time of a clinically isolated syndrome are associated with long-term clinical and radiological outcome. ECTRIMS 2017; Paris, France. Poster P629.

7. Gasperi C, Salmeri A, Antony G, et al. Intrathecal immunoglobulin synthesis as a predictive marker for disability progression in multiple sclerosis. ECTRIMS 2017; Paris, France. Poster P643.

8. Kalincik T, Fambiatos A, Jokubaitis VG. Risk of secondary progressive multiple sclerosis: a longitudinal study. ECTRIMS 2017; Paris, France. Poster P322.

9. Copetti M, Fontana A, Freudensprung U, et al. Predicting MS disease progression remains a significant challenge: results from advanced statistical models of RCT placebo arms. ECTRIMS 2017; Paris, France. Poster P324.

10. Shah-Manek B, DiBonaventura M, Brown H. Rates and predictors of misdiagnosis in primary progressive multiple sclerosis (PPMS) in Europe and the United States. ECTRIMS 2017; Paris, France. Poster P835.

11. Pepe A, Petracca M, Cocozza S, et al. Brain reserve and cognitive reserve in progressive multiple sclerosis: resilience against cognitive effects of neurodegeneration. ECTRIMS 2017; Paris, France. Poster P903.

12. Jokubaitis VG, Nguyen A-L, Kalincik T, et al. Pregnancy incidence and therapy exposure in relapsing forms of MS: a 12-year retrospective multicentre analysis. ECTRIMS 2017; Paris, France. Poster P353.

13. Rog D, Oh J, Chambers C, et al. Pregnancy outcomes in patients with RRMS treated with alemtuzumab from the clinical development program. ECTRIMS 2017; Paris, France. Poster P749.

14. Galazka A, Nolting A, Cook S, et al. Pregnancy outcomes during the clinical development programme of cladribine in multiple sclerosis (MS): an integrated analysis of safety for all exposed patients. ECTRIMS 2017; Paris, France. Poster A-858-0000-02723.


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Abbreviations AE = adverse eventAIR = annual incidence rateBPF = brain parenchymal fractionCDMS = clinically definite multiple sclerosisCI = confidence intervalCIS = clinically isolated syndromeCSF = cerebrospinal fluidDMT = disease-modifying therapyEDSS = Expanded Disability Status ScaleEMA = European Medicines Agency5EU = 5 European Union countries FDA = United States Food and Drug AdministrationGd = gadoliniumHAD = highly active disease9HPT = 9-Hole Peg TestHR = hazard ratioHRA = high relapse activityICV = intracranial volumeIDB = integrated clinical trial databaseIg = immunoglobulinIV = intravenousmAb = monoclonal antibodyMLBV = maximum lifetime brain volumeMRI = magnetic resonance imagingMS = multiple sclerosisMSFC-4 = 4-part Multiple Sclerosis Functional Composite NBV = normalized brain volumeNDA = new drug applicationNfH = neurofilament heavy chainNfL = neurofilament light chainOCB = oligoclonal bandOR = odds ratioPASAT = Paced Auditory Serial Addition TestPPMS = primary progressive multiple sclerosisRC = randomized clinicalRR = risk reductionRRMS = relapsing-remitting multiple sclerosisRRR = relative risk ratioSF-36 PCS and MCS = Short-Form-36 Physical Component Summary and Mental Component SummarySIMOA = single-molecule arraySPMS = secondary progressive multiple sclerosisT25FW = timed 25-foot walkT2LV = T2 lesion volumeTNR = treatment non-responderUS = United StatesVFT = Visual Function Testvs = versusYOE = years of education

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Highlights From the 2017 Annual European MS Meeting · I would like to discuss a couple of posters about oral cladribine ... counts in patients with relapsing ... Highlights From