MS Highlights From the 2016 Annual Neurology...

MS Highlights From the 2016 Annual Neurology Meeting Supported by an independent educational grant from EMD Serono.

http://www.medscape.org/interview/ms-data

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MS Highlights From the 2016 Annual Neurology Meeting

Target AudienceThis activity is intended for neurologists, primary care physicians, and OB/GYNs.

GoalThe goal of this activity is to understand clinical data on multiple sclerosis (MS) presented at the 2016 American Academy of Neurology meeting and how they may be applied to clinical practice.

Learning Objectives• Summarize key data from recent clinical studies in MS

• Assess how clinical trial findings can be applied in practice to improve the management of patients with MS

• Identify investigational therapies with improved efficacy or safety with regard to the management of relapsing-remitting or progressive MS

Credits AvailablePhysicians - maximum of 0.75 AMA PRA Category 1 Credit(s)™

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

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

www.medscape.org/roundtable/ms-nurses

CME Released: May 27, 2016; Valid for credit through May 27, 2017


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Authors and DisclosuresAuthors

Stephen Krieger, MD

Associate Professor of Neurology; Director, Neurology Residency Program, 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: Acorda Therapeutics; Bayer HealthCare Pharmaceuticals; Biogen Idec Inc.; Genentech, Inc.; Genzyme Corporation; Mallinckrodt; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA

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.

Mark S. Freedman, MSc, MD

Professor of Neurology, University of Ottawa; Senior Scientist, The Ottawa Hospital Research Institute; Director, Multiple Sclerosis Research Unit, Ottawa Hospital General Campus, Ottawa, Ontario, Canada

Disclosure: Mark S. Freedman, MSc, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Actelion Pharmaceuticals, Ltd; Bayer HealthCare; Biogen; Chugai Pharma USA, LLC; EMD Serono, Inc.; Genzyme Corporation; F. Hoffmann-La Roche Ltd; Merck Serono; Novartis Pharmaceuticals Corporation; Opexa Therapeutics, Inc.; Sanofi; Teva Canada Limited

Served as a speaker or a member of a speakers bureau for: Genzyme Corporation

Dr Freedman 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 Freedman 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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James D. Bowen, MD

Medical Director, Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, Washington

Disclosure: James D. Bowen, MD, has disclosed the following relevant financial relationships:

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

Served as a speaker or a member of a speakers bureau for: Acorda Therapeutics; Biogen; EMD Serono, Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc; Teva Neuroscience, Inc.

Received grants for clinical research from: Acorda Therapeutics; Alexion Pharmaceuticals, Inc.; Allergan, Inc.; Biogen; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; Novartis Pharmaceuticals Corporation; Opexa Therapeutics, Inc.; Osmotica Pharmaceutical Corp.; Roche; Sanofi; XenoPort, Inc.Owns stock, stock options, or bonds from: Amgen Inc.

Received honoraria from: Acorda Therapeutics; Biogen; EMD Serono, Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc; Teva Neuroscience, Inc.

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

Scott Newsome, DO

Assistant Professor of Neurology; Director, Neurology Outpatient Services and Neurology Infusion Center, John Hopkins University School of Medicine, Baltimore, Maryland

Participation by Dr Newsome in this activity does not constitute or imply endorsement by the Johns Hopkins University or the Johns Hopkins Hospital and Health System.

Disclosure: Scott Newsome, DO, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Biogen; Genzyme Corporation; Novartis Pharmaceuticals CorporationReceived grants for clinical research from: Biogen; Novartis Pharmaceuticals Corporation

Dr Newsome 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 Newsome 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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Becky J. Parks, MD

Associate Professor of Neurology; Co-Director, Comprehensive Multiple Sclerosis Center, Washington University School of Medicine, St. Louis, Missouri

Disclosure: Becky J. Parks, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Biogen; Mallinckrodt; Novartis Pharmaceuticals Corporation

Received grants for clinical research from: Novartis Pharmaceuticals Corporation

Owns stock, stock options, or bonds from: Biogen

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

Robert J. Fox, MD

Staff Neurologist, Mellen Center for Multiple Sclerosis; Vice-Chair for Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio

Disclosure: Robert J. Fox, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Actelion Pharmaceuticals, Ltd; Biogen; Genentech, Inc.; Mallinckrodt; MedDay; Novartis Pharmaceuticals Corporation; Teva Neuroscience, Inc.; XenoPort, Inc.

Received grants for clinical research from: Novartis Pharmaceuticals Corporation

Dr Fox 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 Fox 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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EditorsGena Dolson, MSScientific Director, Medscape, LLC

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

Stacey J.P. Ullman, MHSScientific Director, Medscape, LLC

Disclosure: Stacey J.P. Ullman, MHS, has disclosed no relevant financial relationships.

Christin L. MeltonFreelance Writer, Kendall Park, New Jersey

Disclosure: Christin L. Melton has disclosed no relevant financial relationships.

Christina LoguidiceFreelance Writer, Kendall Park, New Jersey

Disclosure: Christina Loguidice has disclosed no relevant financial relationships.

CME Reviewer/Nurse PlannerAmy Bernard, MS, BSN, RN-BCLead Nurse Planner, Medscape, LLC

Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.

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The American Academy of Neurology (AAN) 2016 annual meeting included numerous scientific presentations addressing all aspects of multiple sclerosis (MS), including basic science, reports on investigational therapies, and results of phase 3 and postmarketing extension trials. This activity focuses on new clinical trial data and how these data may inform clinical practice, imaging and biomarkers, and the clinical utility of “no evidence of disease activity” (NEDA) as a treatment endpoint.

Stephen Krieger, MD: Hello, I am Dr Stephen Krieger, associate professor of neurology at the Icahn School of Medicine at Mount Sinai. Today we will be covering MS highlights from the 2016 annual meeting of the AAN looking at established and switching therapies for MS. Joining me today is Dr Mark Freedman, professor of neurology and director of the Multiple Sclerosis Research Unit at the Ottawa Hospital General Campus. Welcome, Dr Freedman.

Mark Freedman, MD: Thank you, Stephen.


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Dr Krieger: This program will include discussion of off-label treatments and investigational agents not approved by the US Food and Drug Administration (FDA) for use in the United States and data from abstracts presented at AAN. All these data should be considered preliminary until they are published in peer-reviewed journals. An array of disease-modifying therapies (DMTs) are used to treat MS. It is important to recognize that some patients may have inadequate responses and will need to switch therapies. Data from the 2016 AAN meeting offer additional insights regarding the efficacy of our medicines and regarding strategies for using established therapies or switching therapies. To begin, let’s talk about alemtuzumab data from the ongoing CARE-MS studies.

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Dr Freedman: Alemtuzumab is a new molecule that has an interesting regimen. Although all our other therapies are meant to be given on an ongoing basis, the trial protocol for alemtuzumab is unusual because it includes 2 treatment courses spaced 1 year apart, followed by a wait-and-see approach. Just how durable are the responses over the ensuing years? As extension data continue to be reported — with the caveat that not everybody from the original trial is enrolled in the extension study — they provide information about alemtuzumab’s durability.

The 2 studies are CARE-MS I, which focused on treatment-naive patients and compared high-dose interferon(IFN)-beta-1a vs alemtuzumab; and CARE-MS II, which is the only study that looked at true breakthrough patients (those who did not have an optimal response to first-line therapy).

Dr Krieger: In essence, was the CARE-MS II core study a switch study?

Dr Freedman: Absolutely. Patients were switched to either high-dose IFN-beta-1a for 2 years or to the 2 courses of alemtuzumab.[1]


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At the end of the 2-year core study, the IFN patients were switched to alemtuzumab in the extension study. The data presented at AAN are for IFN patients who initially received alemtuzumab in the extension study.

Dr Krieger: What is a big takeaway from the extension study about the durability of alemtuzumab’s efficacy?

Dr Freedman: There are many ways to talk about durability. The most recent and the one everybody probably likes the best is the NEDA story. NEDA basically means patients have absolutely no detectable evidence of disease activity. They have no attacks, no magnetic resonance imaging (MRI) activity, and no apparent evidence of worsening disability.

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In the extension study, the NEDA numbers continued to go down the longer patients were followed. The NEDA rate in the extension study was lower for the IFN cohort from CARE-MS II than for the IFN cohort from CARE-MS I,[1,2] but that was expected because CARE-MS II patients had more advanced MS than CARE-MS I patients. They also had MS longer and had already demonstrated that they were resistant to a medication. From the standpoint of alemtuzumab’s durability, the NEDA numbers in the extension study are quite high. They are in the 70% range for the CARE-MS I population and are more than 50% — almost two-thirds even -- for the CARE-MS II population. That is pretty good when you consider that the NEDA rate with the older therapies 5, 6, or 7 years ago would probably be less than 20%.

The NEDA percentages were for patients who did not require additional treatment after their second course of alemtuzumab in the extension study. As MS progresses, some patients will experience disease activity, and the investigators in the trial had the option to apply another treatment. Clinicians who treat patients with MS are more and more interested in prophylactic treatments. We are trying to prevent attacks that could lead to disability. Might we eventually find evidence from these studies as to when that occurs? If we do find most patients start to have reactivation at a certain point, we might consider being proactive and give another 3-day course of alemtuzumab.

Dr Krieger: I think the extension trial will give us more information about how to use alemtuzumab in the best possible way in the coming years. There was an Italian-led study that looked at patterns of maintaining or switching therapy in about 1000 patients.[3] What did you think of those data?


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Dr Freedman: Data were collected from 15 centers in Italy over a few years, during a time when new therapies — particularly oral treatments — became available.[3] Data showed people switched for various reasons. About one-third of people switched for convenience, many because they did not like the injectables and not because of “suboptimal response.” Most switches, however, were because the investigator or treating neurologist felt the patient was having a suboptimal response and it was time to move on to another therapy. They escalated to other therapies that are perceived to be stronger, such as fingolimod or natalizumab.

Dr Krieger: Right, about two-thirds of the patients were switched for suboptimal response. That seems to speak to a lower threshold for changing a patient’s medicine than we might have seen before the introduction of these newer therapies.

Dr Freedman: I cannot agree more, and that is the idea behind NEDA. Our tolerance of disease activity has really dropped from 2 decades ago, when we were willing to accept low-level disease. Now, more people are striving for NEDA. Now that we have a bigger tool chest, patients are reaching for different drugs, looking for a different mechanism, and trying to control the disease.

Dr Krieger: Let’s look at an investigational therapy that has shown good efficacy in this regard. Cladribine has been studied in several phase 3 trials, and I believe you presented some extension data here at the meeting. This is an agent that may move forward toward an approval process.

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Dr Freedman: The companies probably made the wrong move in 2011 when they decided not to pursue approval of cladribine for MS. Parenteral cladribine has been used for years off-label, and some people may have forgotten that an oral form of the drug was heavily tested in trials. There were several presentations at the AAN meeting of data that were left in limbo when the manufacturers decided not to try to market oral cladribine.

The CLARITY trial was a big phase 3 study, and the CLARITY extension study was the only study, believe it or not, that looked at therapy durability.[4] The study examined whether a couple of years of cladribine was enough and what would happen if you stopped the drug for 2 years or longer. The CLARITY extension randomly assigned the cohort of patients who received cladribine in the CLARITY core trial to cladribine or placebo and then crossed patients from the core trial’s placebo cohort over to cladribine. What would happen to those patients who stayed on cladribine vs those who stopped the drug? Again, this speaks to endurance.


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We also had the ORACLE study, which provided the strongest data we have seen to date in patients with clinically isolated syndrome (CIS).[5] From a numbers standpoint, cladribine had almost twice the efficacy of any other drug we have seen. I think cladribine will make a resurgence.

Dr Krieger: Fair enough. It might add to our armamentarium and help us accomplish many of the treatment goals we have talked about today. Mark, congratulations on the presentation and thank you for joining me for this discussion. And to the audience, thank you for joining us today. Please proceed to the next segment in the series on results from the 2016 AAN annual meeting.

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Stephen C Krieger, MD: Hello, I am Dr Steven Krieger, and joining me today at the 2016 AAN meeting is Dr Jim Bowen, medical director of the Multiple Sclerosis Center at the Swedish Neuroscience Institute in Seattle.

Today we will be discussing MS highlights from the meeting, focusing on investigational therapies. Dr Bowen, tell us about the data that you found impactful or instructive regarding cladribine.

Dr Bowen: One of the studies is the CLARITY extension.[4] Just to remind people, the 2-year CLARITY study compared placebo with 3.5 mg/kg and 5.25 mg/kg cladribine.[6] The CLARITY extension followed patients for an additional 2.5 years. Patients who were previously on placebo were added to the 3.5-mg/kg arm, whereas those originally receiving cladribine were re-randomized to cladribine 3.5 mg/kg or placebo for 2 years. Adverse events (AEs) led to discontinuation of treatment in 11% of patients. Patients who were switched to placebo in the extension had fewer AEs. A common AE with cladribine was lymphopenia, with grade 3 or 4 events seen in 37% to 41% of patients.


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Dr Krieger: This is not terribly surprising given the mechanism of action of this medicine. Is that right?

Dr Bowen: Right. It is essentially a chemotherapy, so you would expect this to happen. The most common serious AEs in all groups were infections, gastrointestinal (GI) disorders, and a total of malignancies.

Dr Krieger: Was there any new safety signal with malignancies?

Dr Bowen: Nothing new that we know of.

The other cladribine study was ONWARD, which included patients who had RRMS despite being on IFN.[7] Patients were kept on IFN and then randomized to receive either placebo or cladribine as an add-on (total dose, 3.5 mg/kg). Approximately 14% of patients had secondary progressive MS (SPMS). The mean number of qualifying relapses was lower in the group that received cladribine. The annual relapse rate was 0.12 in the combined treatment arm and 0.32 in the IFN-only group.

Dr Krieger: That is a very low annualized relapse rate.

Dr Krieger: How about the MRI outcomes? Did they bear out the decrease in relapses?

Dr Bowen: Yes. The mean numbers of new T1-gadolinium-enhancing lesions and of new or enlarging T2 lesions were also reduced in the cladribine group.

Dr Krieger: The ONWARD study and the CLARITY study were both completed years ago. In a sense, we now have long-term experience with these medicines in the trial setting. How might that inform the development plans for cladribine moving forward?

Dr Bowen: The European Medicines Agency (EMA) and the FDA both initially declined to approve cladribine, but the manufacturers are resubmitting an application for approval to the EMA. The hope is that development of cladribine will move forward and it will eventually be approved.

Dr Krieger: Sure, especially when you consider that since these trials were completed, the FDA has approved several medicines that have their own complexities, such as fingolimod and alemtuzumab. These are medicines that have changed our sense of risk and benefit a little when it comes to treating MS.

Dr Bowen: Right. I think we are more willing to accept some risk now when treating patients who have active disease.

Dr Krieger: The success of fingolimod in treating MS has led to the subsequent development of other sphingosine-1-phosphate (S1P)-receptor molecules. One of these is ozanimod. Can you tell us about the data presented at the AAN meeting from the ozanimod clinical trial?

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Dr Bowen: The RADIANCE study randomly assigned 252 patients to placebo, 0.5 mg ozanimod, or 1 mg ozanimod.[8] The most common treatment-emergent adverse events were nasopharyngitis, headache, and urinary tract infections. The researchers titrated the dose when patients initiated ozanimod in the study, which seemed to address the issue of bradycardia. There is a natural circadian rhythm to cardiac rates, and ozanimod blunted that mildly, but otherwise it did not really lead to a drop in pulse rate.

Dr Krieger: What did the efficacy of ozanimod look like?

Dr Bowen: The RADIANCE extension study was 48 weeks.[9] Patients in the ozanimod arm continued their assigned dose, and patients who were taking placebo were re-randomized between the 2 treatment arms. Outcomes for patients who maintained their previous dose of ozanimod during the extension study were similar to their outcomes in the original study. In both treatment groups, the unadjusted annualized relapse rate decreased by about half from the end of the parent study at week 24 to the end of the extension study at week 72. The rates dropped from 0.43 to 0.26 in the 0.5 mg group and from 0.26 to 0.15 in the 1 mg group.

Dr Krieger: These are very good efficacy data, especially for a phase 2 trial with only a couple of hundred patients.


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Dr Bowen: The investigators also looked at NEDA rates and saw no evidence of worsening disease; 44% of the 0.5 mg group and 63% of the 1 mg group met NEDA. Findings for patients who switched from placebo to ozanimod mirrored findings for patients who took the drug in the parent study. The annualized relapse rate again dropped by about half, from 0.50 at week 24 of the parent study to 0.26 in the low-dose group and 0.16 in the high-dose group at week 72 of the extension study.

Dr Krieger: This is a nice dose-response type curve, in terms of the drug’s efficacy. In our final moments, what was the main takeaway from the study of biotin in progressive MS?

Dr Bowen: This study surprised us. Biotin is a coenzyme for carboxylase enzymes, and acetyl-CoA carboxylase is the rate-limiting step in myelin synthesis, which is why the investigators looked at biotin. There were 2 previous studies, a phase 1 study of 23 patients that showed that 91% of them improved and 22% got better on the Expanded Disability Status Scale (EDSS).[10] There was also a previous phase 3 study that showed a significant proportion of patients improving.[11] The study being presented at this year’s meeting was a small, single-center study with 29 patients that examined biotin in 3 groups: patients with relapsing disease that was well-controlled but who still had progressive disability; patients with SPMS who were not on treatment; and patients with primary progressive MS (PPMS).[12] The biotin was well tolerated. Two patients stopped biotin after 1 or 2 months because of a perceived lack of benefit.

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Dr Krieger: This was a single center effort to, in a sense, replicate in a real world setting the type of results that have been seen in earlier clinical trials. There at least seems to be a hint that it might have helped.

Dr Bowen: Yes, in the relapsing group, 3 patients showed some improvement in their tandem gait, but not in their EDSS. In the SPMS group, 5 patients showed mild improvement in energy levels, hip flexor strength, and dysmetria. In the PPMS group, 3 patients had slight improvement in energy, visual acuity, or leg strength, but again no change in EDSS.

Dr Krieger: I think it warrants future study but is something that we can already talk to our patients about.

Dr Bowen: Yes, they can get it over the counter.

Dr Krieger: Jim, thank you so much for joining me for this discussion and, to the audience, thank you for joining us today. Please proceed to the next segment in the series for further topics in MS from the 2016 AAN meeting.


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Stephen C Krieger, MD: Hello, I am Dr Stephen Krieger. Joining me today at the 2016 AAN meeting is Dr Scott Newsome, assistant professor of neurology at The Johns Hopkins University School of Medicine.

In this program, we are going to cover MS highlights at the meeting, turning our attention to NEDA, which has become an important area of discussion in MS research and treatment and is an outcome that we look for in our clinical trials.[13] Studies presented at the AAN meeting examined the importance and relevance of NEDA.

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Dr Newsome, thank you for joining me. Let us talk about NEDA in the CARE-MS series of trials, which compared alemtuzumab with active comparator IFN-beta-1a given 3 times a week.[14,15] What can you tell us about the NEDA outcomes from the 4-year extension of the CARE-MS I study?[15]

Dr Newsome: First, when we think about NEDA in clinical trials, we have to think about what the comparator arm is doing in relation to the drug being tested. It is challenging to look across trials and compare NEDA for each individual trial. Nevertheless, it is a good thing to cross-compare trials occasionally. The 4-year extension of CARE-MS I showed that 50% of individuals in the core study achieved NEDA at year 2.[14,15] A large majority of these individuals went on to achieve NEDA in subsequent years — up to 5 years — which shows the durability and sustainability of alemtuzumab vs the IFN product used in this study.


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Dr Krieger: CARE-MS I was the trial of alemtuzumab in treatment-naive patients. The CARE-MS II study, which had a similar design, enrolled patients who had breakthrough disease on another agent.[16] In essence, it was a more refractory or highly active disease cohort. How did these patients do with regard to the high-bar outcome of NEDA in the 4-year extension?[17]

Dr Newsome: Before even having the study results for CARE-MS II, one would surmise that NEDA at year 2 — the end of the core study — would be lower because a more refractory group of patients was enrolled. And, in fact, that is what was seen. About 36% of alemtuzumab-treated patients recruited for the extension study from CARE-MS II had achieved NEDA at year 2 and required no further treatment during the 4-year extension.[17] Similar to patients achieving NEDA at year 2 in the core study, a good majority continued to demonstrate NEDA at years 3, 4, and 5 of the extension study. Therefore, at least with regard to CARE-MS I and II, it appears that individuals who achieved NEDA early on had sustained NEDA in subsequent years. I think this finding can be helpful for clinicians. If you see someone in a clinical trial who does not have any evidence of inflammatory activity on MRI or clinical examination within the first 2 years of the trial, it gives you some confidence to continue that patient on the medication vs someone who is showing inflammatory activity within that timeframe. In the latter case, one has to consider that this might not be the best drug for that person moving forward.

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Dr Krieger: Maintaining NEDA cannot be achieved in the majority of our patients, but it does speak to the idea that an early responder to a particular type of therapy may be more likely to continue to respond to that therapy.

This finding was also observed in the REFLEXION study, in which patients with clinically isolated syndrome (CIS) received subcutaneous IFN-beta-1a once a week or 3 times a week.[18] This is one of our older medications that is still widely used. What did the NEDA data look like in REFLEXION?

Dr Newsome: This study showed that a greater proportion of individuals randomized to the more frequently administered IFN achieved NEDA and maintained that response up to 5 years post-randomization than patients receiving less frequent or delayed dosing of IFN. This indicates to me that the older injectable therapies that we have, which have very well established safety profiles, do impact the disease on an inflammatory level and could be continued for many people.

Dr Krieger: This brings us to a set of trials that look at a new medicine that is going to be reviewed for potential approval and may come to fruition this coming year. This agent is ocrelizumab, an infused monoclonal antibody. Tell us a little about the NEDA data for ocrelizumab from the OPERA I and II studies.[19]


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Dr Newsome: The data from these 2 studies were very exciting and may lead to approval of this drug for MS. These studies compared ocrelizumab with active comparator IFN-beta-1a, not placebo, and found that ocrelizumab-treated patients achieved NEDA in a much more robust fashion than patients receiving IFN.[19] At week 24 in both studies, ≥96% of ocrelizumab-treated patients had no new or enlarging T2 lesions vs 61% to 71% of the IFN-treated patients. Based on these findings, ocrelizumab appears to have a much more robust effect on the inflammatory phase of MS than does IFN. If this medication and others in the pipeline are ultimately approved, I think they will be a good addition to our current armamentarium.

Dr Krieger: I agree. That number — 96% free of new and enhancing lesions -- is very impressive. Additionally, almost 48% of ocrelizumab-treated patients in both studies achieved NEDA at 2 years, which is also impressive.[19] These data help give us a sense of what we might be able to achieve in coming years in terms of shutting down evidence of inflammatory disease activity.

This has been a terrific, quick review of the NEDA data we have seen here at the 2016 AAN meeting. Dr Newsome, thank you very much for joining me in this discussion and, to our audience, thank you for joining us and listening in today. Please proceed on to the next segment in this series.

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Stephen C. Krieger, MD: Hello, I am Dr Stephen Krieger. Joining me today is Dr Becky Parks, associate professor of neurology and co-director of the Comprehensive Multiple Sclerosis Center at the Washington University School of Medicine in St. Louis, Missouri. Dr Parks, welcome. We are going to be discussing MS highlights from the 2016 annual meeting of the AAN, focusing on new MRI and biomarker information in MS that may help guide how we think about imaging and biomarkers in the management of this disease. Dr Parks, tell us about data presented on microRNA (miRNA), which is something most of us probably do not use and have not heard much about before.

Dr Parks: Some of the most intriguing information presented came from the Harvard Group, in a continuation of their studies on miRNA in brain atrophy.[20] To break this down, they found that miRNAs correlate with T2 and T1 lesion load as well as with measures of atrophy, including gray matter atrophy and overall brain parenchymal fraction. One intriguing finding was a negative correlation between miRNA and brain atrophy. They found that as miRNA measures increased, brain volume decreased.

Dr Krieger: This could give us some biological insight into lesion formation and perhaps into the neurodegenerative aspects of MS.


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Dr Parks: Yes. In fact, I think if these findings about miRNA are validated in larger populations of MS patients, there is a potential role for using these measures both in clinical trials as a biomarker of drug efficacy and then in clinical decision making.

Dr Krieger: That is great. In our field, personalizing care — being able to get a sense of who will respond to what modality of therapy and even being able to prognosticate more meaningfully for patients — is obviously a huge unmet need.

The CLARITY study of cladribine has garnered some renewed interest. What can you tell us about the context of MRI outcomes in CLARITY and their use for prognosticating?

Dr Parks: Basically, the original study demonstrated reductions in the relapse rate and in MRI measures of disease activity in patients treated with cladribine vs placebo.[21] Cladribine also slowed progression of disability vs placebo. In the extension study, patients randomized to placebo in CLARITY crossed over to cladribine and patients treated with cladribine were re-randomized to cladribine or placebo.[22] The patients treated with cladribine in the extension study fared better on measures of MRI than patients given placebo.

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An interesting finding was that the overall development of new lesions was low in all groups, suggesting that patients assigned to placebo in the extension study derived a durable benefit from their 2 years of cladribine therapy in the core study.

Dr Krieger: In essence, it is sort of a double-crossover design.

Dr Parks: Yes, it was a very interesting study design.

Dr Krieger: More than 80% of the cladribine-treated patients had no new gadolinium-enhancing lesions, which is a good measure of the drug’s effect on disease activity. Gadolinium-enhanced lesions are sort of a classic MRI biomarker of inflammatory disease.

Although we recognize brain atrophy as a sign of progression or neurodegeneration, brain atrophy is hard to measure in practice.[23,24] For instance, our center measures brain atrophy with the naked eye; we do not have quantified metrics for it. Perhaps other ways to quantify atrophy could give us insight into the course of disease and disability. A large study looked at optical coherence tomography and retinal atrophy.[25] What can you tell us about those findings, from a predictive perspective?


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Dr Parks: This was a great study. As you pointed out, it was a large study. The investigators enrolled almost 900 patients, who were followed for up to 5 years. They were looking at whether the thickness of retinal nerve fiber layers correlated with disability at 5 years. The bottom line is that MS patients who had reduced thickness of the retinal nerve fiber layer in eyes that were not affected by optic neuritis had a 58% greater risk of disability progression at 5 years. Specific cutoffs were used that had statistical significance as predictors of disability. These are important findings. Optical coherence tomography is a fairly accessible tool and could easily be deployed in a clinical setting.

Dr Krieger: Optical coherence tomography is noninvasive and relatively inexpensive, and thickness of the retinal nerve fiber layer can be quantified in clinical practice perhaps more easily than brain atrophy, which is usually the measure we use for neurodegeneration.

Dr Parks: Right, and brain atrophy is more difficult to measure and there are controversies regarding the meaning of the measurements.

Dr Krieger: The data we talked about shed light on blood tests and imaging biomarkers in relation to outcomes from clinical trials. They may eventually guide how we think about efficacy and help us personalize some of our decisions. I am grateful to you, Becky, for joining us in this discussion. I also want to thank the audience for joining us today. Please proceed to the next segment in this series for more information on MS from the AAN 2016 annual meeting.

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Stephen C. Krieger, MD: Hello, I am Dr Stephen Krieger, and we are continuing our discussion of meeting highlights from the AAN annual meeting talking about MS. Joining me today is Dr Robert Fox, staff neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. We will be discussing data presented on progressive MS. There have been a number of clinical trials that focused on progressive MS in the past couple of years, and a good deal of data presented at AAN looked at progressive disease.

Let’s start by talking about the ASCEND trial of natalizumab in secondary progressive MS.

Dr Fox: Sure. The ASCEND trial looked at natalizumab in patients with later-stage disease: secondary progressive MS following a relapsing-remitting course.[26]


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Overall, the trial did not find that treatment with natalizumab slowed MS progression. A subset analysis found that natalizumab had a positive effect on upper limb function that was unrelated to the decrease in relapses. What do we make of that? In general, it suggests that natalizumab can decrease active inflammation and perhaps some of the resulting injury -- as measured by arm function — in patients with SPMS. Overall, however, patients with SPMS will continue to have gradual insidious progression even in the setting of a highly effective anti-inflammatory therapy like natalizumab.

Dr Krieger: This was particularly true for the EDSS measurements, which prioritize gait. The EDSS and the Timed 25-Foot Walk (T25FW) showed patients had progressive dysfunction in gait. It was disappointing that natalizumab did not prevent ambulatory disability.

Dr Fox: That is true. It highlights that progression likely initiates years earlier, when the injury developed. Now, the positive benefit natalizumab had on arm function may be driven by the possibility that arm dysfunction in progressive MS is a later phenomenon. Thus, treatment with natalizumab can help prevent progression in arm dysfunction.

Dr Krieger: Part of the emphasis on progressive disease has involved looking back at clinical trials of relapsing MS that included patients with progressive MS. The clinical trial campaign for teriflunomide included quite a few clinical trials, and several of these enrolled patients with progressive forms of the disease.

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Dr Fox: Right. Together, the TOWER and TEMSO trials enrolled 122 patients with SPMS or progressive relapsing MS.[27] Because patients had to have active inflammation to get into the trials, the patients with progressive MS were at an earlier stage of disease. When investigators looked at the subgroup of patients with relatively early progressive MS, they found that during the first 5 years of teriflunomide therapy, only 20% of patients had confirmed disability progression for 12 weeks or longer; and during the next 4 years of treatment, none of the patients had sustained disability progression. It is very encouraging that over 9 years, only 20% of patients had sustained disability progression. Although this was a small group of only 122 patients and a post hoc analysis, it is nevertheless encouraging that even after MS has evolved into secondary progressive or progressive disease, we can still see a benefit from treating active inflammation if we catch these patients early.

Dr Krieger: The recognition that there is overlap between disease activity (the inflammatory component) and progressive disease has informed the design of other trials, such as the ORATORIO trial. The ORATORIO study investigated ocrelizumab, a B-cell depleting agent, in PPMS.[28] Although the study looked at a PPMS population, it had some interesting nuances regarding the admixture of inflammatory disease.


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Dr Fox: Overall, ORATORIO was a positive study and showed that ocrelizumab could slow the overall progression of disability. It also slowed the rates of T25FW progression and brain atrophy. Not surprisingly, given that ocrelizumab is a strong anti-inflammatory, it was also associated with a reduction in new lesions and less progression of T2 lesion volume. However, a subset analysis for the one-quarter of patients with gadolinium-enhancing lesions at baseline or active inflammation as measured by MRI found that they accounted for the majority of benefit seen with ocrelizumab across the whole study. To put it in another way, the 75% of patients who did not have gadolinium-enhancing lesions at baseline saw a much lower magnitude of benefit, as measured by disability progression. The findings again highlight that these anti-inflammatory therapies can be quite effective when patients have active inflammation, but it is much tougher for them to show benefit in patients who have no active inflammation.

Dr Krieger: That is also part of the story behind the INFORMS trial of fingolimod in PPMS that was published last year.[29] This was another study in which fewer patients had active disease, and it was a negative study. What data on brain atrophy in the INFORMS study were presented at the AAN meeting?

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Dr Fox: The analysis presented at the AAN meeting focused on brain volume as a predictor of disability to understand what attributes at baseline predicted disability progression or even bigger problems.[30] The investigators grouped patients into 3 categories, depending on whether they had a low, medium, or high amount of brain atrophy as measured by normalized brain volume.

The study showed that patients with a low amount of atrophy had the lowest risk of worsening disability, and those with a high amount of atrophy had the highest risk of worsening disability. Also, a higher amount of atrophy at baseline correlated with higher T2 lesion volume at baseline. This all fits together: those with more injury as measured by T2 lesion volume and brain atrophy were at the greatest risk for disability progression. Although fingolimod did not show an overall benefit, it did show a reduction in new lesions and fewer relapses.[29]


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These results again emphasize that the earlier we treat PPMS patients who have active inflammation, the more likely we are to see a benefit. Once the amount of injury, such as brain atrophy, increases, it becomes harder to treat this form of MS.

Dr Krieger: Robert, thank you so much for joining me for this discussion; and to the audience, thank you for participating in this activity. Please continue on to the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.

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Safety and tolerability of cladribine tablets in patients with relapsing-remitting multiple sclerosis (RRMS): final results from the 120-week phase 3b extension trial to the CLARITY study. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.095.5. Leist TP, Comi G, Cree BA, et al; oral cladribine for early MS (ORACLE MS) Study Group. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014;13:257-267.6. Giovannoni G, Comi G, Cook S, et al; CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416-426.7. Montalban X, Cohen B, Leist T, et al. Efficacy of cladribine tablets as add-on to IFN-beta therapy in patients with active relapsing MS: final results from the phase II ONWARD study. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.029.8. Frohna P, Olson A, Cravets M, et al. Clinical safety of the novel, selective S1P receptor modulator, ozanimod, from phase 2 trials in relapsing multiple sclerosis (RADIANCE) and moderate to severe ulcerative colitis (TOUCHSTONE). Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P2.092.9. Selmaj K, Cohen J, Arnold D, et al. Results from the 48-week blinded extension of RADIANCE: a randomized, double-blind, placebo- controlled phase 2 trial of oral ozanimod in relapsing multiple sclerosis. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.023. 10. Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015;4:159-169.11. Tourbah A, Lebrun-Frenay C, Edan G, et al. MD1003 (high doses of biotin) in progressive multiple sclerosis: subgroup analyses of the MS-SPI trial. Mult Scler J. 2015;23:S233.12. Birnbaum G, Stulc J, Snyder T. High dose biotin as treatment for progressive multiple sclerosis. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.039.13. Stangel M, Penner IK, Kallmann BA, Lukas C, Kieseier BC. Towards the implementation of ‘no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord. 2015;8:3-13.14. Cohen JA, Coles AJ, Arnold DL, et al; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing- remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380:1819-1828.15. Giovannoni G, Arnold D, Cohen J, et al. Long-term responders from the CARE-MS I study: no evidence of disease activity for 4 years following 2 courses of alemtuzumab and no further treatment. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.054.16. Coles AJ, Twyman CL, Arnold DL, et al; CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380:1829-1839.17. Wiendl H, Arnold D, Cohen J, et al. No evidence of disease activity for 4 years following 2 courses of alemtuzumab and no further treatment: long-term responders from the CARE-MS II study. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.059.18. Coyle P, Comi G, Freedman M, Chen L, Marhardt K, Kappos L. Effect of early versus delayed subcutaneous interferon (scIFN) β-1a to achieve no evidence of disease activity (NEDA) in patients with clinically isolated syndrome (CIS): a post-hoc analysis of REFLEXION. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.111.19. Traboulsee AL, Arnold DL, Bar-Or A, et al. Ocrelizumab no evidence of disease activity (NEDA) status at 96 weeks in patients with relapsing multiple sclerosis: analysis of the phase iii double-blind, double-dummy, interferon beta-1a-controlled OPERA I and OPERA II studies. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster PL02.004.20. Gandhi R, Healy B, Regev K, et al. Serum microRNAs are related to brain MRI lesions and atrophy in patients with multiple sclerosis. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P4.140.21. Rammohan K, Giovannoni G, Comi G, et al. Cladribine tablets for relapsing–remitting multiple sclerosis: efficacy across patient subgroups from the phase III CLARITY study. Mult Scler Relat Disord. 2012;1:49-54.22. Comi G, Giovannoni G, Cook S, et al. Magnetic resonance imaging (MRI) outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets: results from the 120-week phase IIIb extension of the CLARITY study. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P2.114.23. Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain. 2002;125:1676-1695.24. Riley C, Azevedo C, Bailey M, Pelletier D. Clinical applications of imaging disease burden in multiple sclerosis. Expert Rev Neurother. 2012;12:323-333.25. Martinez-Lapiscina E, Arnow S, Wilson J, et al. Retinal atrophy measured by optical coherence tomography predicts disability progression in multiple sclerosis. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster S45.007. 26. Steiner D, Arnold DL, Freedman MS, et al. Natalizumab versus placebo in patients with secondary progressive multiple sclerosis (SPMS): results from ASCEND, a multicenter, double-blind, placebo-controlled, randomized phase 3 clinical trial. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P009.27. Nelson F, Lebrun-Frenay C, Camu W, et al. Outcomes in patients with progressive MS: analysis of teriflunomide long-term extension data. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.038.28. Montalban X, Hemmer B, Rammohan K, et al. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis: results of the phase III double-blind, placebo-controlled ORATORIO study. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster S49.001.


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29. Lublin F, Miller DH, Freedman MS, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387:1075-1084.30. Wolinsky J, Haring D, Sormani MP, et al. Brain volume as a predictor of disability in primary progressive multiple sclerosis: evidence from the INFORMS trial. Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster S51.007. AbbreviationsAAN = American Academy of NeurologyAE = adverse eventARR = annualized relapse rateBPF = brain parenchymal fractionsCDP = clinical disease progressionCIS = clinically isolated syndromeCU = combined uniqueDMT = disease-modifying therapyEDSS = Expanded Disability Status ScaleEMA = European Medicines AgencyFDA = US Food and Drug AdministrationGA = glatiramer acetateGd = gadoliniumGI = gastrointestinalGMF = gray matter fractionsHR = hazard ratioIFN = interferonIL-10 = interleukin 10IV = intravenousmiRNA = microRNAMRI = magnetic resonance imagingMS = multiple sclerosisMV = macular volumeNBV = normalized brain volumeNEDA = no evidence of disease activityOCT = optical coherence tomographyON = optic neuritisPPMS = primary progressive multiple sclerosispRNFL = peripapillary retinal nerve fiber layer pts = patientsQOL = quality of lifeRRMS = relapsing-remitting multiple sclerosisSC = subcutaneousS1P = sphingosine-1-phosphate SPMS = secondary progressive multiple sclerosisT25FW = Timed 25-Foot WalkUC = ulcerative colitis

Releated LinksPredicting Clinical Outcomes in the Treatment of MS http://www.medscape.org/viewarticle/861198

Neurology Exchange: Integrating New DMD Therapies Into the MS Treatment Landscape http://www.medscape.org/viewarticle/861194

Neurology Exchange: Individualizing Therapy and Optimizing Treatments in MS http://www.medscape.org/viewarticle/861193

Clinically Challenging Case Simulations in MS: Addressing Breakthrough Disease http://www.medscape.org/viewarticle/852635

Multiple Sclerosis Leadership Summit: Scientific Advances and Clinical Updates in MS Treatment & Care http://www.medscape.org/viewarticle/857953

http://www.medscape.org/viewarticle/861198







MS Highlights From the 2016 Annual Neurology...

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