expert perspectives on new data in multiple sclerosis from...

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Expert Perspectives on New Data in Multiple Sclerosis From the 2018 European MS Meeting CME


Supported by an independent educational grant from EMD Serono.

www.medscape.org/viewarticle/905441



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

GoalThe goal of this activity is to educate clinicians about practical issues and pregnancy in multiple sclerosis (MS), as well as clinical trial data on investigational and long-term disease-modifying therapies for relapsing MS.

Learning ObjectivesUpon completion of this activity, participants will:

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• Key data from clinical trials for the management of MS

• Key data relating to the use of biomarkers to aid in the recognition and assessment of progression in MS

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Disclosures

Moderator

Stephen Krieger, MD Associate Professor of NeurologyDirector Neurology Residency program Icahn School of Medicine at Mount SinaiNew York, New York

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

Served as an advisor or consultant for: Bayer HealthCare; Biogen Idec Inc.; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Mallinckrodt Pharmaceuticals; MedDay Pharmaceuticals; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA; TG Therapeutics

Served as a speaker or a member of a speakers bureau for: Biogen Idec Inc.

Panelists

Patricia K. Coyle, MD Professor and Vice Chair of NeurologyDirector MS Comprehensive Care CenterStony Brook University Medical CenterStony Brook, New York

Disclosure: Patricia K. Coyle, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Accordant Health Services, LLC; Bayer AG; Biogen Idec Inc.; Celgene Corporation; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Roche; Sanofi; Teva Pharmaceuticals USA

Received grants for clinical research from: Actelion Pharmaceuticals, Ltd; Alkermes, Inc.; Biogen Idec Inc.; Genentech, Inc.; MedDay; NINDS; Novartis Pharmaceuticals Corporation; Roche

Thomas P. Leist, MD, PhD Professor Thomas Jefferson UniversityPhiladelphia, Pennsylvania

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

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

Served as a speaker or a member of a speakers bureau for: Actelion Pharmaceuticals, Ltd; Biogen Idec Inc.; Celgene Corporation; Teva Pharmaceuticals USA

Received grants for clinical research from: Actelion Pharmaceuticals, Ltd; Biogen Idec Inc.; Chugai Pharmaceutical Co.; Novartis Pharmaceuticals Corporation



Steering Committee

Chair

Stephen Krieger, MDAssociate Professor of NeurologyDirectorNeurology Residency ProgramIcahn School of Medicine at Mount SinaiNew York, New York

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

Served as an advisor or consultant for: Bayer HealthCare; Biogen Idec Inc.; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Mallinckrodt Pharmaceuticals; MedDay Pharmaceuticals; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA; TG Therapeutics

Served as a speaker or a member of a speakers bureau for: Biogen Idec Inc.

Members

Patricia K. Coyle, MDProfessor and Vice Chair of NeurologyDirector MS Comprehensive Care CenterStony Brook University Medical CenterStony Brook, New York

Disclosure: Patricia K. Coyle, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Accordant Health Services, LLC; Bayer AG; Biogen Idec Inc.; Celgene Corporation; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Roche; Sanofi; Teva Pharmaceuticals USA

Received grants for clinical research from: Actelion Pharmaceuticals, Ltd; Alkermes, Inc.; Biogen Idec Inc.; Genentech, Inc.; MedDay; NINDS; Novartis Pharmaceuticals Corporation; Roche

Anne H. Cross, MDProfessor of NeurologyWashington University School of MedicineSt. Louis, Missouri

Disclosure: Anne H. Cross, MD, has disclosed the following relevant financial relationships:

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

Received grants for clinical research from: Genentech, Inc.



Gavin Giovannoni, MBBCh, PhDProfessor and Chair of NeurologyBarts and The London School of Medicine and DentistryLondon, United Kingdom

Disclosure: Gavin Giovannoni, MBBCh, PHD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: AbbVie Inc.; Bayer HealthCare; Biogen; Canbex Therapeutics Ltd.; Eisai Inc.; Elan; Five Prime Therapeutics; Genzyme Corporation; Genentech, Inc.; GlaxoSmithKline; GW Pharma; Ironwood Pharmaceuticals, Inc.; Merck & Co., Inc.; Merck Serono; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Roche Holding AG; Sanofi-Aventis; Synthon; Teva Pharmaceuticals USA; Vertex Pharmaceuticals Incorporated

Thomas P. Leist, MD, PhDProfessor of NeurologyThomas Jefferson UniversityPhiladelphia, Pennsylvania

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

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

Served as a speaker or a member of a speakers bureau for: Actelion Pharmaceuticals, Ltd; Biogen Idec Inc.; Celgene Corporation; Teva Pharmaceuticals USA

Received grants for clinical research from: Actelion Pharmaceuticals, Ltd; Biogen Idec Inc.; Chugai Pharmaceutical Co.; Novartis Pharmaceuticals Corporation

Claire Riley, MDAssistant Professor of NeurologyMedical DirectorColumbia MS CenterColumbia University Irving Medical CenterNew York, New York

Disclosure: Claire Riley, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Celgene Corporation; Teva Pharmaceuticals USA

Editors

Catherine Friederich MurrayScientific Director, Medscape, LLCDisclosure: Catherine Friederich Murray has disclosed no relevant financial relationships.

Renata Feldman, PharmD, RPhAssociate Scientific Director, Medscape, LLCDisclosure: Renata Feldman, PharmD, RPh, has disclosed no relevant financial relationships.

CME Reviewer

Nafeez Zawahir, MDCME Clinical Director, Medscape, LLCDisclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.



Program Introduction

Stephen Krieger, MD: Hello. I am Dr Stephen Krieger, Associate Professor of Neurology and Director of the Neurology Residency Program at the Icahn School of Medicine at Mount Sinai in New York. Welcome to this program entitled Expert Perspectives on New Data in Multiple Sclerosis (MS) from the 2018 European MS Meeting.

Panelists

Joining me today are Dr Patricia Coyle, Professor and Vice Chair for Clinical Affairs of Neurology and Director of the MS Comprehensive Care Center at Stony Brook University in Stony Brook, New York, and Dr Thomas Leist, Professor of Neurology at Thomas Jefferson University in Philadelphia. Welcome.



DisclaimerThis 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. This meeting brought, I think, additional complexity and nuance to many different topics in MS, diagnosis, care, and management, and we are going to review some of them here today.

Pregnancy and MS

Stephen Krieger, MD: Hello. I am Dr Stephen Krieger from Mount Sinai in New York. Welcome to this segment of the program titled Pregnancy and MS. Joining me now is Dr Patricia Coyle from Stony Brook University Medical Center in Stony Brook, New York. Welcome Dr Coyle.

Patricia Coyle, MD: Thank you, Stephen.



Knowledge Gap: Teratogenic Risks of DMTs[1]

Dr Krieger: A recent work by Rasmussen and colleagues has looked at how patients with MS do not often have adequate knowledge to make informed decisions about family planning or teratogenic risks with our disease-modifying therapies (DMTs) for MS. It is important for us as clinicians to have these conversations with our patients. Why do not we talk about some of the family planning and pregnancy-related data from this recent meeting?

Dr Coyle: That was a pretty major topic. There were a number of papers and presentations pertinent to pregnancy.



Reproductive Decision Making in MS[2]

One of them was a questionnaire that was sent out by the New York State MS Consortium to close to 1650 MS individuals. They had a pretty good response rate of about 38%. They had 137 or 21.9% of patients who did not become pregnant, and 15% said it was because of their disease. That is unfortunate. That is a little bit scary because we really had no data that pregnancy is something negative for the major form of MS, relapsing MS.



Reproductive Decision Making in MS (cont) [2]

They also saw that married women and those that had less than a college education were more likely to become pregnant as opposed to women who were unmarried and had lower educational levels. I supposed that is not really surprising. I think it indicates the level of impact of these issues on choices, important lifestyle choices. There were a number of presentations from Denmark in their very large countrywide Danish registry.



Reproductive History in a Danish Nationwide Study[3]

There were a number of presentations from Denmark in their very large countrywide Danish registry. They had more than 9000 individuals with MS, and they matched them 1 to 4 with a reference control cohort. They found absolutely no difference between the MS group and the match control group in a rate of elective abortions, spontaneous abortions, or ectopic pregnancies. It is very reassuring and confirms earlier data.

Dr Krieger: It helps us with the specific point raised in the first study that women may avoid pregnancy without real reason to do so.

Dr Coyle: Absolutely. They also recorded that the women and men with MS had fewer children compared with the controls, and that is a very interesting feature.



Pregnancy Outcomes With Teriflunomide[4]

They also had to report on pregnancy exposures with teriflunomide. That is one of the orals that is a particular concern, as you know because it is teratogenic in animal models. A relatively small group, but they looked at 13 women with MS who became women and 18 men with MS who were taking teriflunomide and their spouse became pregnant. That is of interest because teriflunomide can enter semen less than 1% of blood levels, but this has been a theoretic concern that a man taking teriflunomide might inoculate his non-MS partner.

Dr Krieger: This is the only one of our medicines where we have to counsel men for family planning purposes also.

Dr Coyle: That is absolutely correct. They really found no bad issues whatsoever. My own concept would be just check the teriflunomide blood level in the non-MS female.



Ocrelizumab and Pregnancy Outcomes[5]

Obviously, they also had some pregnancy data with regard to the newest DMT, ocrelizumab, the humanized anti-CD20. The numbers remained very small, actually, no bad signal whatsoever.



Concluding Remarks

The interesting thing was at the very end of this European meeting, when they were giving the clinical highlights, they had one of the speakers synapse all the data on pregnancy presented here. What she said was that it is pretty apparent that concerns about pregnancy with our MS DMTs are somewhat overblown if you just read the label. That none of the MS DMTs to date have been proven to be teratogenic in humans. That we have enough human exposures with glatiramer acetate (GA) and the interferon betas to actually continue to use them up to pregnancy and even beyond if you wished.

We need to continue to collect data. That if a woman decided she was not going to breastfeed and was going to resume a DMT, that should be done within 7 to 14 days of giving birth, but that there was no reason not to encourage MS women to breastfeed. If they did, make it exclusive. They reported that very few of the postpartum relapses resulted in disability. They also made an interesting comment about natalizumab, which is often used in very active MS individuals and may in the minority have a rebound. Often in Europe, they will continue to use natalizumab in the patient until about the mid part of pregnancy of the second trimester. I thought that was a very interesting background summary.

Dr Krieger: It is and it gets that really the issues that I think we need to discuss with women and many cases, men with MS as they are planning their treatment strategy and family planning. Issues such as washout periods, which are getting shorter and shorter and perhaps nonexistent as we get more and more reassuring data.

Then, on the other end in the postpartum period, try to minimize the washout from pregnancy in essence. With the increased risk of relapse during that period and the quick resumption of DMTs in those circumstances.

I think in the aggregate, it is all pretty reassuring data, but then the mandate is on us to convey this in a meaningful way to our patients and try to address the knowledge gaps that the Rasmussen study and other studies have shown on this topic.

Dr Coyle: Absolutely. We need to continue to collect data with pregnancy exposures. We need really to try to enter them into registry which all of the drugs have.

Dr Krieger: Right. Terrific. Thank you so much, Dr Coyle.

Dr Coyle: Thank you, Stephen.



Clinical Trial Data for Investigational Disease-Modifying Therapies for Relapsing MS

Stephen Krieger, MD: Hello. I am Dr Stephen Krieger from Mount Sinai in New York. Joining me now to discuss clinical trial data for investigational disease-modifying therapies for relapsing MS is Dr Thomas Leist of Jefferson University. Welcome, Dr Leist.

Thomas Leist, MD: Thank you for having me, Dr Krieger.

Ublituximab[6]

The first one that I would like to review is ublituximab. This is a glycoengineered anti-B cell antibody that has a higher affinity. This raises the potential opportunity to deplete CD20 positive cells more effectively and perhaps in a shorter period of time.



Ublituximab in RRMS[6]

This is also a phase 2 study looking at 48 patients divided into different dosing groups. The primary goal was to find a dose that carried forward into the phase 3 development.

The idea was to potentially get to a point where one can have 1-hour infusions. Ultimately, what the investigators found is that 150 milligrams infused over 4 hours at the beginning and then followed by 450 milligrams given over 1 hour at week 2 then week 24 depleted B cells to 99% as measured with CD19.

What was also important here to show, even though it is a small number of patients, that there was a reduction of T2 lesions, and there was an attenuation of gadolinium-enhanced lesions in the trial. There was also an early signal for a reduction of the relapse rate or for a very low relapse rate.

We also have early data on relapses. There was a low relapse rate in the treated patients.

What was not presented at this meeting are the data surrounding the depletion of B cells and the higher affinity effect that this antibody has, whether or not, for example, antibody levels will be strongly reduced and with other agents. This is obviously something from a safety point of view that we will need information on. We will stay tuned and see how this develops over the next years.



Bruton Tyrosine Kinase Inhibitor[7]

The second group of agents that I thought were interesting are the protein tyrosine kinase inhibitors. The first effect is on inhibiting B cells, and the second effect is inhibiting macrophages. It has 2 effects, both on the adaptive and on the innate immune system. This effect is transient, so there is not a depletion of such cells as with the last agent that I discussed.

Evobrutinib: Phase 2, 48-Week Study[8]

Evorutinib is the first agent of its class where we have now some information from a 48-week phase 2 study. This particular agent was studied at 3 doses, 25 milligrams, 75 milligrams, and 75 milligrams twice a day. A primary readout was gadolinium-enhancing lesions at 12, 16, 20, and 24 weeks cumulatively. The study was positive in terms of that both of the higher doses of the agent reduced gadolinium enhancement.



Evobrutinib: Safety Data[8]

There was a higher safety signal in the higher dose, so it will now be important to see how this is carried forward into the phase 3 development.

This is representative of a new class of agents that will be keeping us busy in terms of data over the next few years in MS.



Cladribine: Post-Hoc Analysis of CLARITY Data[9]

Dr Krieger: Let me ask you this also. One of the other agents that has been studied extensively is oral cladribine. It is investigational, but also we have had some long-term experience with it. Can you tell us some of the updates on the data for oral cladribine as we are thinking about that as potentially being in our armamentarium in the United States?

Dr Leist: One of the questions that one has is there an age limitation of patients who could potentially benefit from oral cladribine. An important point to consider here is that the data that we have come from clinical trials that enrolled a certain age range of patients, so 55 was the upper age. For this particular study, there was an attempt to look at patients less than 45 years old and patients more than 45 years old.

This is interesting, because in the United States, the average patient with multiple sclerosis is about in the mid-40s. It is certainly of interest if whether an agent can benefit both patients below this age line and patients above this age line.



Cladribine: Post-Hoc Analysis of CLARITY Data (cont) [9]

What was shown by the investigators is that patients both in the below 45 and in the above 45 age group had comparable treatment effect with cladribine. Keep in mind obviously that the patients who went into these clinical trials were patients who had disease activity before going into the clinical trial. These are patients with documented inflammatory disease activity.

Dr Krieger: That might distinguish this from data from practice that suggested that in general, our DMTs may use up their usefulness over a certain age, in the 50s. It is interesting to see with a data cut above and below 45 that the efficacy with cladribine seem to be maintained.

Dr Leist: I think that is a very important point that you are making. In a clinical trial, we select patients who have recent disease activity or a recent disease event. That makes it only partially comparable to studies that are outside of the clinical trial environment.

Dr Krieger: This is a terrific review of several of the investigational agents that were being looked out here at the European MS conference. Thank you for taking us through it.

Dr Leist: Thank you.



Practical Issues in Multiple Sclerosis

Stephen Krieger, MD: Hello. I am Dr Stephen Krieger from Mount Sinai in New York. Welcome to this segment of the program titled Practical Issues in Multiple Sclerosis. Joining me again is Dr Patricia Coyle from Stony Brook University Medical Center in Stony Brook, New York. Welcome back.

Patricia Coyle, MD: Thank you, Stephen.

Dr Krieger: This has a busy meeting, this European MS conference, a lot of topics. I think one of the challenges is to find the ones that are going to have meaningful practical impact into how we manage and take care of MS. What struck you?



DMT Treatment Timing in RRMS[10]

Dr Coyle: I think one of the interesting studies was based on the MS-based global registry, which is a large registry of MS patients worldwide. They were really trying to address the issue of what is the optimum time of treatment after the presentation of relapsing MS after somebody presents with a clinically isolated syndrome (CIS), high risk. What is the optimum timing to get them on a DMT if there is this window of opportunity to really say it is early?

I was struck by the fact that they came up within 6 months of the CIS. That echoes exactly rheumatoid arthritis and the American College of Rheumatology, where they defined early treatment as within 3 to 6 months of the presentation. I think we now have our walking papers. We need to have our CIS patients on a DMT within 6 months of their presentation.

Dr Krieger: I think that also echoes in a practical cohort what we have seen from our CIS trials, which always suggest that early treatment as opposed to delayed treatment, has a long-term therapeutic benefit preventing relapses, preventing disabilities. To see that in the MS-based cohort puts in real-world terms what we know from our trials. You are right. That is our mandate.



Predictors of Risk for Progression to SPMS[11]

Dr Coyle: That is a key feature, early treatment. They had another very interesting study that looked at early MS and whether there were predictors for more rapid transition to secondary progressive disease, relapsing to secondary progressive disease. Obviously, that is something we are very worried about because that is a disabling feature of MS that we do not really have good treatment for.

What they discovered with that cortical lesions on the baseline brain magnetic resonance imaging (MRI) were a warning sign that that patient was more likely to move into a secondary progressive stage faster. It was much better not to have any cortical lesions. The other thing they found was an early high clinical attack rate, having several relapses. The cortical lesions interest me, because we have recently focused on that with the 2017 revised criteria. They are not so easy to see. You can talk about doing double inversion recovery.

I do not think we think about cortical lesions that much, but I think we have to. For me, this is going to bring me to my neuroradiologist to say, we need to start to see cortical lesions. How can we do this routinely?

Dr Krieger: It is one of these things that in some ways hides in plain sight. We have been looking at MRI scans all these years not focusing on cortical lesions. As you said, they have been promoted into the 2017 McDonald Criteria for how we diagnose this disease. They are an important prognostic feature. We know lesion localization matters, and obviously, location of lesions in the spinal cord or brain stem drives progressive motor impairment.

Cortical lesions may drive the progression towards secondary progressive multiple sclerosis (SPMS) as well. You are absolutely right. We have to look for them and get our radiologists to look for them.



Comorbidities and MS[12]

Dr Coyle: Another interesting paper addressed the issue of comorbid conditions in MS. I know there has been a real emphasis on that. It is very important to treat, because comorbidity can really make features of MS worse, for example, vascular risk factors increasing the likelihood of developing disability.



Acute Myocardial Infarction and MS[13]

I was very surprised to see a major epidemiologic study from Canada that reported that the rate of myocardial infarctions (MIs) was higher in individuals with MS than in matched controls, with hazard ratios in the range of 1.6 to 1.7.

Personally, that has not been my experience. I think I am going to need to look at it a little bit further. Certainly, if that is a comorbid condition that is increased, then I think we need to be aware of that, particularly in our middle-aged patients with MS. We know that the presentation of MI may not be the same in women. We need to be particularly concerned about that. What do you think about that?

Dr Krieger: It has not been my experience either, but these large cohort studies I think can reveal things that one person’s clinical practice might not, and Ruth Ann Marie’s work I think looks at that in really meticulous detail. As you said, I think it has implications for how we think about some of our medicines, which can have cardiovascular side effects, or we need to be cognizant of underlying cardiac risk when choosing those medicines.

I also think it might dovetail with the movement towards dietary modification in MS towards a more heart-healthy diet. Presumably, that will have positive effects on MS, because of brain health. It may have positive effects on our patients because of cardiac health as well.



sNfL[14]

Dr Coyle: That is a very good point, Stephen. The final comment I wanted to make is that there were a number of presentations on neurofilament light protein and its measurement, particularly in the blood. People are really getting more and more excited about this as a prognostic marker, but there were a lot of presentations where they looked at it for treatment response, where they documented that the blood levels went down.



Implementing sNfL Testing Into Practice[15]

I thought the most thoughtful presentation came from the Hopkins group, where they basically made the point that there is a commercial kit that you can do, the very ultra-low levels, the single molecule array (SIMOA) technique to measure neurofilament light protein as an axon injury marker in blood. They knew what the significant cutoff was there.

There are also a lot of home-brewed assays, particularly in some of the big labs in Europe, where they have been publishing extensively. They used their own reagents a little bit, and their cutoff is different. They were making the point that for this to be truly transported to clinical usage as a biomarker, we need 1 assay. We need everybody to have agreed to 1 assay with defined significant cutoffs. I think there were corporate players that are trying to develop this on a large scale where it would not be a super expensive test. You need something that is easy to get if this is going to be a valuable biomarker where everybody is doing the same assay with the same cutoffs defined as meaningful. I think that is something to look forward to in the future.

Dr Krieger: I think that is quite right. That is our 2019 outlook, perhaps, for what a new biomarker and a blood biomarker may really be in MS. Perhaps, if we are back next year, it will be in the clinical practice and we can see how we can use this practically in real world management. Dr Coyle, thank you again.

Dr Coyle: Thank you, Stephen.



Long-Term Use of Disease-Modifying Therapies for Relapsing MS

Stephen Krieger, MD: Hello. I am Dr Stephen Krieger from Mount Sinai in New York. Joining me again to discuss long-term use of disease-modifying therapies for relapsing MS is Dr Thomas Leist of Jefferson University. Welcome back, Dr Leist.

Thomas Leist, MD: Hello.



Natalizumab, JCV, and PML[16]

Dr Krieger: The long-term use of medicines is really characterized by a balance of risk and efficacy. Perhaps, the best example of that in our field is the use of natalizumab, the surveillance for the JC virus, and the risks for progressive multifocal leukoencephalopathy (PML). One of the strategies that has been employed and being studied now is extended interval dosing of natalizumab to try to mitigate that risk. Why do you not take us through some of that work and those concepts, Dr Leist?

Dr Leist: Thank you.



Natalizumab: EID and Efficacy[17]

Natalizumab is provided in a fixed dose, 300 milligrams This has raised the issue of whether dose-extension could be a way of addressing the risk. At this particular meeting there were several studies that addressed the efficacy of extended dosing, whether extended dosing is associated with PML, and persistence or receptor occupancy of natalizumab in the patients who had extended dosing.

The first study looked at extended dosing in patients who had already been more than 24 months on natalizumab. This author showed consistent efficacy, but showed a reduction of the patients who remained relapse-free over the period of time in the study. This raises the issue and will justify further studies whether or not extended dosing is actually giving the patient the same clinical benefit.

The criticism of this study was that the extended dosing was not at a fixed interval, so there may be patients mixed in that were perhaps longer than the biologic half-life of the agent. From that point of view, this certainly needs additional work.



Natalizumab: EID and PML Risk[18]

A second study that I would like to discuss is whether extended dosing is associated with a lower risk for PML. Of 56 cases of PML, five of these cases were observed in patients on extended dosing. Again, we do not know exactly what the extended dosing means. We also do not know how quickly after switch over from the extended dosing they could actually see that the PML occur.

All of these patients had a high index. I think this is important to keep in mind. This study also tells us something else, because 3 of the patients had non undetectable JC virus by polymerase chain reaction (PCR), we all need to be aware that in many patients with PML actually, we need to use high-resolution PCRs that are not the normal JC PCRs that are available in our electronic medical records.



Saturation of CD49d With Natalizumab in EID[19]

Another point was that natalizumab binds VLA-4 or CD49d. saturation of CD49d needs to be maintained. At this meeting presented, one of papers looked actually at extended dosing and VLA-4 occupancy. In patients who had greater than 4-week infusion cycles, the receptor occupancy of CD49d was maintained at levels that are generally consistent with a treatment effect.

This is encouraging, but it also indicates whether we may need to personalize this monitoring in these patients with CD49d, because it is possible that patients who are a little bit heavier may potentially have a higher drop out of the receptor occupancy.



Alemtuzumab: Long-Term Safety and Efficacy Data[20]

Dr Krieger: In general, I think the management of safety with natalizumab has been a real changed point for our field as we have more and more efficacious agents that bring certain risks to bear for our patients. The other medicine I think that was a step in that direction was alemtuzumab, We are finally seeing some larger and long-term data from real-world use .What have we seen there?

Dr Leist: One of the studies looked within the Swedish registry of patients which had received 2 treatment cycles. These patients had a significant benefit not only in the Expanded Disability Status Scale (EDSS), but also in patient-reported outcomes and cognitive measures. That is encouraging to see. Obviously, we need to keep in mind that this is an agent that needs long-term monitoring, because we do have the autoimmune risks. For the appropriate patients, it certainly gives additional hope and potential intervention to be looked at.



Efficacy of Treatment: Prospective 2-Year Study of Fingolimod and GA[21]

Dr Krieger: Now that we have had oral medicines approved for the better part of the decade, We are seeing more head-to-head comparisons in the long term. What can you tell us there?

Dr Leist: Patients in clinical trials are obviously selected for disease activity, and then they are enrolled in a clinical study. A little bit more unusual is comparing patients who are in the community and are stable on a given agent and tend to ask the question, are the older agents necessarily worse in a stable patient or are they not worse in a patient. Do we have to change patients to one of the newer agents or is a stable patient on, let us call it, the legacy medications, actually still adequately served?

This is a small study that I would like to point out. It only includes a little bit more than 80 patients. These are patients who were stable. Here, we are looking at T2 lesions. We look at the other MRI outcomes, but we also look at cognitive testing in these individuals and patient-reported outcomes.

These are patients who are specifically selected for their stability. One of the important points over here was that in the follow-up period no difference in the behavior of the patients on glatiramer acetate or on fingolimod. From that point of view, what this indicates is that patients who with proper ascertainment remained stable on a treatment may still be served with that particular treatment.

This study also indicates that actually, letting patients continue their medications that they are doing well on would potentially be advised.

Dr Krieger: I think this has been a very nice review of some of the longer-term data from legacy medications, as you said, and some of those that are more modern. Yet, we still have the advantage of long-term data for them. I appreciate you going through this data from the European MS conference. Thank you again, Dr Leist.



Thank you

We have covered an array of topics in MS diagnosis, care, and management from the European MS conference here in 2018. I hope you have enjoyed the program. Thank you for participating in the activity. Please continue on to answer the questions that follow and complete the evaluation.



AbbreviationsAE = adverse eventAMI = acute myocardial infarction ARR = annualized relapse rateBTK = Bruton tyrosine kinase BTKI = Bruton tyrosine kinase inhibitorCD49d = alpha4 integrin CI = confidence intervalCLVT = California Verbal Learning Test CU = combined unique DM = diabetes mellitusDMT = disease modifying therapyEDSS = Expanded Disability Status ScaleEID = extended interval dosing EQ-5D = EuroQol-5DIRR = infusion-related reactionGA = glatiramer acetateGd+ = gadolinium-enhancingHTN = hypertensionIMSE-3 = Immunomodulation and Multiple Sclerosis Epidemiology Study 3mAb= monoclonal antibodyMRI = magnetic resonance imagingMS = multiple sclerosis MSIS-29 = Multiple Sclerosis Impact ScaleMSSS = Multiple Sclerosis Severity ScaleNEDA = no evidence of disease activity PASAT = Paced Auditory Serial Addition TestPML= progressive multifocal leukoencephalopathyRA = rheumatoid arthritisRRMS = relapsing-remitting multiple sclerosis SAE = serious adverse eventSDMT = Symbol Digit Modalities Test SES = socioeconomic statusSID = standard interval dosing SIMOA = single molecule array SLE = systemic lupus erythematosussNfL= serum neurofilament light chain SPMS = secondary progressive multiple sclerosisTEAE = treatment-emergent adverse event



References

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