A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis

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1 An Official Elsevier CME Medical Meeting Reporter AMA PRA Category 1 Credit : Joint ACTRIMS-ECTRIMS Meeting Reporter A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis Fred Lublin, MD Saunders Family Professor of Neurology Director, Corinne Goldsmith Dickinson Center for MS Icahn School of Medicine at Mount Sinai New York, New York Target Audience Neurologists and other healthcare professionals responsible for the diagnosis, treatment or management of patients with multiple sclerosis (MS). Program Overview This Elsevier Medical Meeting Reporter presents and summarizes important multiple sclerosis presentations and abstracts from the Joint Meeting of the American and European Committees for Treatment and Research of Multiple Sclerosis (ACTRIMS-ECTRIMS) hosted in Boston, Massachusetts. This meeting reporter focuses on the scientific and clinical updates that were presented by medical professionals, researchers, and MS advocates striving to contribute to the care of individuals suffering with this disease. Many of the critical unanswered questio ns related to optimal use of pharmacotherapuetics are being addressed in clinical trials. While virtually all of this data is eventually published, the latest results are inevitably presented first as scientific presentations and posters at the 2014 Joint ACTRIMS-ECTRIMS Meeting. This Elsevier Medical Meeting Reporter focuses on the pivotal sessions and key clinical data related to new treatment and standards of care of patients with multiple sclerosis to address physician knowledge in therapeutic selection and appropriate use of therapies. Educational Objectives Upon completion of this activity, participants will be able to: 1. Discuss current therapy options in multiple sclerosis, along with patient management strategies. 2. Evaluate clinical trial data and develop methods to incorporate emergent therapeutics into personalized treatment plans for patients with multiple sclerosis. Clyde Markowitz, MD Director, MS Center Associate Professor Department of Neurology University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania Stephen Krieger, MD Assistant Professor of Neurology Director, Neurology Residency Program Icahn School of Medicine at Mount Sinai New York, New York Co-provided by the Elsevier Office of Continuing Medical Education and AcademicCME academic CME

2 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting Disclosure of Conflicts of Interest It is the policy of the Elsevier Office of Continuing Medical Education that all faculty, instructors, and planners disclose real or apparent conflicts of interest relating to the topics of this educational activity. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: FACULTY RELATIONSHIP IDENTIFIED WITH: Fred Lublin, MD Consultant/Advisor: Acorda Therapeutics Inc.; Actelion Pharmaceuticals Ltd.; Biogen Idec; Bristol-Myers Squibb; Celgene Corporation; Coronado Bioscience; EMD Serono, Inc.; Forward Pharma; Genentech, Inc.; Genzyme Corporation; Johnson & Johnson; MedImmune, Inc.; Novartis Pharmaceuticals Corporation; Osmotica; Questcor Pharmaceuticals, Inc.; Receptos; Revalesio Corp; Roche; sanofi-aventis; Teva Pharmaceuticals, Ltd.; Xenoport, Inc. Employment Affiliation: Co-Chief Editor, Multiple Sclerosis and Related Disorders Grant/Research Support: Acorda Therapeutics, Inc.; Biogen Idec; Celgene Corporation; Genzyme Corporation; National Institutes of Health; National Multiple Sclerosis Society; Novartis Pharmaceuticals Corporation; sanofi-aventis; Teva Pharmaceuticals, Ltd. Clyde Markowitz, MD Consultant/Advisor: Acorda Therapeutics Inc.; Bayer HealthCare Pharmaceuticals; Biogen Idec; EMD Serono, Inc.; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Ono Pharmaceutical Co. Ltd.; Roche; sanofi-aventis; Teva Pharmaceuticals, Ltd Stephen Krieger, MD Consultant/Advisor: Acorda Therapeutics Inc.; Bayer HealthCare Pharmaceuticals; Biogen Idec; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Questcor Pharmaceuticals, Inc.; Teva Pharmaceuticals, Ltd NON-FACULTY Sandy Breslow; Jill McNair; Timothy Hayes, MD, PhD; Kristen Scollon; Emma Gilmartin; Jaimie Kelly and Bernard Abrams, MD hereby state that they or their spouse/life partner do not have any financial relationships to products or devices with any commercials interest related to the content of this activity of any amount during the past 12 months. To claim your CME certificate immediately, please complete the CME activity online at: RELEASE DATE November 5, 2014 EXPIRATION DATE November 4,

3 A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis Accreditation Statement The Elsevier Office of Continuing Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation Statement The Elsevier Office of Continuing Medical Education designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Financial Support This activity has been supported by an independent educational grant from Novartis Pharmaceuticals Corporation and Mallinckrodt Pharmaceuticals. Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Elsevier Office of Continuing Medical Education, AcademicCME, Novartis Pharmaceuticals Corporation and Mallinckrodt Pharmaceuticals do not recommend the use of any agent outside of the labeled indications. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. Method of Participation In order to claim credit, participants must complete the following: 1. Read the learning objectives, accreditation information, and faculty disclosures at the beginning of this activity. 2. Complete the Pre-Activity Questions. 3. Review the activity content. 4. Complete the Post-Activity Test Questions and Evaluation. 5. Physicians who receive a grade of 70% or better on the Post-Activity Test Questions and who complete the Evaluation will receive a CME certificate. 6. All other participants who receive a grade of 70% or better on the Post-Activity Test Questions and who complete the Evaluation will receive a certificate of participation. CME Inquiries/Special Needs For all CME inquiries or special needs, please contact 3

4 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting Pre-Activity Questions Answer sheet provided on page 21 Questions 1 and 2 should be answered on a scale of 1 to 5, with 1 meaning not confident and 5 meaning very confident. 1. Currently, how confident are you in your ability to apply emergent therapeutics into personalized treatment plans for patients with multiple sclerosis? 2. Currently, how confident are you in your ability to apply the most current safety and efficacy data to optimize the management of your patients with multiple sclerosis? 3. How is daclizumab, a monoclonal antibody therapy, different from other monoclonal antibodies currently available? a. Administered twice monthly b. Administered via once a month, subcutaneous self-injection c. Administered intramuscularly d. Can be taken only as a monotherapy 4. The phase 3 GLACIER study compared the safety of daily glatiramer acetate versus three-timesweekly administration at 40 mg instead of 20 mg. What decrease in injection site reactions was observed? a. 25% b. 50% c. 60% d. 75% 5. RCP1063 is an S1P1 modulator, similar to fingolimod but more receptor selective. What outcomes have been seen with this new treatment? a. Major cardiac issues observed b. No reduction in new T2 lesions c. 90% reduction in gadolinium-enhanced lesions d. 50% reduction in gadolinium-enhanced lesions 6. A 39-year-old patient with MS is transitioning from natalizumab to fingolimod. According to recent data presented at MS Boston 2014, which of the following is not a precaution that could be taken to ensure there is no occurrence of progressive multifocal leukoencephalopathy? a. Very little, if any, washout of natalizumab b. Six-month washout of natalizumab c. MRI base scans immediately after stopping natalizumab d. Check CSF for JC virus DNA 7. A 42-year-old patient with primary progressive MS has JC virus DNA present in her CSF. She wants to know what possible treatment options are currently in the development phase that would be an option for her. What do you tell her? a. The INFORMS trial with fingolimod b. ASCEND trial with natalizumab c. GALA trial with glatiramer acetate 8. What measure, that correlates with neurologic dysfunction and disability, could clinical trials start to incorporate in order to better determine NEDA (no evidence of disease activity)? a. Timed 25-foot walk b. Nine-hole peg test c. Expanded disability status score d. Brain atrophy measures 4

5 A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis Introduction The Joint Meeting of the American and European Committees for Treatment and Research of Multiple Sclerosis (ACTRIMS-ECTRIMS), MS Boston 2014, was held in Boston, Massachusetts, from September 10th to 13th, This monograph summarizes some of the many interesting presentations that took place and highlights areas of application to your clinical practice. Advances in treatments for relapsing MS, incidence and management of side effects, and considerations for the treatment of progressive MS are reviewed by Fred Lublin, MD, Saunders Family Professor of Neurology and Director of the Corinne Goldsmith Center for Multiple Sclerosis at the Icahn School of Medicine at Mount Sinai in New York; Clyde Markowitz, MD, Director of the MS Center and Associate Professor in the Department of Neurology at the University of Pennsylvania Perelman School of Medicine in Philadelphia; and Stephen Krieger, MD, Assistant Professor of Neurology and Director of the Neurology Residency Program at the Icahn School of Medicine at Mount Sinai in New York. Daclizumab Daclizumab is an investigational monoclonal antibody that targets the interleukin (IL)-2 receptor. Data from the DECIDE trial (NCT ) were presented and are discussed below. Clyde Markowitz, MD: The DECIDE trial was a head-to-head clinical trial of daclizumab administered as a once monthly subcutaneous injection and interferon beta-1a. Endpoints were evaluated over two years and included relapse rate reduction, MRI outcomes, safety measures, and disability progression. Data from the DECIDE trial showed a 45% reduction in relapse rate and a 27% reduction in disability progression at the six-month confirmed progression; statistically significant differences at three months were not confirmed. There was approximately a 60% reduction in gadolinium-enhanced lesions. Overall, the data are appealing. Safety issues requiring monitoring included liver enzyme abnormalities, which are worrisome, and injection site reactions, which were somewhat worse than what has been observed with the interferons. Daclizumab is another potential treatment option going forward, if it gets approved. 1 We will have to determine how we use this compound; that is, as monotherapy or in combination with other agents. For example, we have done trials with interferon in combination with daclizumab, and the data suggested that the combination was reasonably efficacious and safe. So, it has potential as combination therapy or as monotherapy. Stephen Krieger, MD: Daclizumab is different from the available monoclonal antibodies in a number of ways. One thing to emphasize is that DECIDE was a head-to-head trial with interferon beta-1a. So, rather than being combined with interferon in this trial, it was compared head-to-head. Consequently, those reductions in relapse rate, MRI lesions, and even the six-month disability outcomes, are very impressive, given that daclizumab was compared directly with interferon, not placebo. It is also different from other monoclonal antibody therapies in that it is a self-injection. All of our other monoclonal antibody therapies require infusions. Daclizumab is an injection that is administered by the patient or caregiver at home. A once-a-month dosing schedule raises the idea of combination therapy, perhaps with an agent that is given more frequently, and this would be just a once-a-month addition. However, we have to consider the potential side effects and adverse events that may be associated with various combinations before we pursue them. 1 Fred Lublin, MD: Once a month subcutaneous administration is attractive. The other nice thing for many studies moving forward is that the head-to-head data against once-weekly interferon provides an idea how the agent could be positioned. FIGURE 1 1 5

6 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting Peginterferon beta-1a (Plegridy) Peginterferon beta-1a, which is a pegylated form of interferon, was approved for the treatment of patients with relapsing forms of MS in August It is administered as a subcutaneous injection every two weeks. 2 Dr. Markowitz: We will likely start to use more of this recently approved compound, as compared with standard interferon beta-1a, which is given once a week. We seem to be moving away from injectable therapies to some degree, but as the frequency of injection decreases, I think they become more attractive. 2 Dr. Lublin: Peginterferon beta-1a is a good example to discuss because it is administered subcutaneously instead of intramuscularly, and it is given every two weeks. We are, perhaps, not getting away from injections, but extending their use by making them a little more convenient. In the case of the pegylated interferon, it s just that administration is every two weeks. It may be necessary to devise a clever way to alert patients that it is time for their next injection. Every week is easy to remember; so it will be interesting to see if there is a good way to help patients remember their injections every two weeks. Regardless, the data presented on this compound were good. 2 Dr. Markowitz: Absolutely. The data were good, with no new safety signals. Overall, the two-year disability data that were presented were good. 2 FIGURE 2 2 Glatiramer acetate Data from the phase 3 GALA study (NCT ) and the phase 3 GLACIER study (NCT ) were presented and are discussed below. Dr. Lublin: The GALA study compared three-timesweekly administration of a double dose of glatiramer acetate with the standard daily dose. Again, I have a feeling that that trend of less frequent administration is going to continue with the injectables, especially because of the safety record. With the newer drugs, a lot of patients say, Well how long has that drug been out there? 3 Dr. Markowitz: Data from the GLACIER study, which compared the safety of daily glatiramer acetate versus three-times-weekly administration at 40 mg instead of 20 mg, were presented as well. The less frequent administration schedule was associated with a significant 50% reduction in injection site reactions clearly the schedule involves fewer injections, so fewer injection site reactions are expected. In addition, this dose was well tolerated, and no new safety signals were noted. 3 Dr. Krieger: That study, in my opinion, provides some real-world data about side effects and adverse events with the new formulation of glatiramer acetate. So, for patients who are on the daily formulation who will ask whether the injections will be as tolerable with the new formulation, we now have some actual data that we can share with our patients. We can reassure them that it is a less frequent injection, but they should not expect more severe injection site reactions or changes to the skin that would be concerning based on those data. 3 FIGURE 3 3 6

7 A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis Dr. Markowitz: Some data were also presented regarding a generic glatiramer acetate. Dr. Lublin: Cost has become a big issue with new drugs. Not just in MS, but in other areas. We have had to deal with it more recently because we ve had more agents and more people being treated, and we ve been getting a lot of push-back from insurance companies. Dr. Krieger: The cost of medicines for MS has increased more rapidly than the cost of medicines overall. MS medicines and MS treatments comprise a disproportionately large amount of the overall health care costs, considering that we re taking care of a pretty small disease state compared with diseases like cardiovascular disease. Consequently, potentially less expensive medicines could be beneficial. This is the first time that we ve seen any data for any generic in this entire field. This is one of the notable things that came out of this 2014 meeting: this is the first time we ve seen data for a generic formulation. Data for this particular generic glatiramer acetate, given as a once-daily injection the old formulation this study was done to look for MRI outcomes, which was suggested as a way to gauge the biologic outcomes of this formulation. What they showed, with a reference arm to placebo, was a reduction in MRI outcomes for brand glatiramer acetate and generic glatiramer acetate; both reduced the MRI outcomes to the same degree really matched against placebo. That goes a long way to show at least noninferiority of this generic formulation. Now, it s not clear whether this is going to come to market, whether we as clinicians will have any control over whether our patients get the generic or brand drug. At least we re starting to get a sense of what the data look like for this generic. Several other companies may also be producing generic glatiramer acetate. The main concern is that just because we ve seen the data for this one, it doesn t necessarily mean that it will translate across all of the generic formulations of glatiramer acetate, and we may not know which one our patient is getting if it gets approved. 4 FIGURE 4 4 Dr. Lublin: Interferons and monoclonal antibody therapies are all biologics. One cannot just look at their composition and conclude that they have activity. Their tertiary structure and conformational issues must be taken into consideration. However, glatiramer acetate is a complicated molecule, too. It is not a diuretic, and it is not like molecules such as dimethyl fumarate (DMF), which would be easy to duplicate. Glatiramer acetate is a random chain copolymer, and every batch is actually a little bit different; even though its production is standardized, it cannot be completely standardized. So, would you use generic glatiramer acetate if you didn t have some evidence of clinical activity? Dr. Markowitz: That is an important point, because this trial design included purely an MRI outcome, although clinical measures were captured. It was only a nine-month study. Dr. Krieger: Sort of like a phase 2 trial. Dr. Markowitz: Yes, exactly. When you look at the data, there was no real difference between the placebo group and the two arms of the study in terms of the clinical outcomes, such as relapse rates. So how do we know whether the drug is going to be good for clinical outcomes? All of the pivotal studies of various agents are at least two-year trials designed to assess these outcome measures. I m a little reluctant at this point, until I see some clinical data, to make this decision. I m hopeful that the FDA will require clinical data before granting approval. The European Union requires only MRI data to demonstrate some equivalency. It s like a two-edged sword if the FDA accepts these MRI data, then MRI data should 7

8 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting be accepted as an outcome measure for every trial going forward. Dr. Lublin: This trial was designed for the European Medicinal Authority (EMA), and they put forth a guidance requiring a demonstration of equivalence. An equivalence study was done with boundaries for which generic glatiramer acetate was compared with the other agents, and I think it was within a 15% margin. The EMA also required a placebo tracking arm to ensure that both formulations were active. So, they took the nine-month MRI, which was based on the Canadian and European glatiramer acetate study from 15 years ago. This is their result. 4 They succeeded in achieving what the EMA required. Is this not enough information? Dr. Markowitz: No. Dr. Krieger: No, it s not enough information. I think that Dr. Markowitz s point that neither the generic nor the brand glatiramer acetate showed an effect on relapses departs from all of the data we have for glatiramer acetate over the last 20 years. It makes it hard to interpret this trial in that context. In addition, to your point, we still don t have clinical data for this generic. So that concerns me as well. Dr. Markowitz: Nine months is too short. Dr. Lublin: Okay, so two out of three physicians do not consider these data sufficient. I do, because I think they show a biologic effect. It is a strong MRI effect, which I think is satisfactory in terms of predicting or indicating biologic activity. One of you raised a very good point that if the FDA were to accept this, then would that mean that they would go ahead and look at MRI activity in general? We ll come back to that when we talk about advanced metrics for outcomes to give us better assessments in clinical trials. FIGURE 5 4 RCP1063 Results of a phase 2/3 trial of the sphingosine-1- phosphate receptor 1 (S1P1) modulator, RCP1063, were also presented. 5 Dr. Markowitz: RCP1063 is like fingolimod, although fingolimod is less selective in terms of which receptors it interacts with, and now because of aspects of the adverse event profile of fingolimod, with cardiac, pulmonary, and maybe even some ophthalmologic issues, we re looking for something more selective. RCP1063 is more selective. In the phase 2/3 trial, it was compared with placebo at two different doses. The data presented were very robust with regard to the effects on MRI, clinical metrics, relapse rate, etc. The outcome was primarily MRI outcomes, and a 90% reduction in gadoliniumenhanced lesions was observed. There was an 80% 90% reduction in new T2 lesions, and no major cardiac issues were noted. The safety profile looks very impressive. So, we may end up with several other agents that are also targeting more specifically one of the subtypes of receptors, which may reduce some of the concerns from a cardiac standpoint. 5 Dr. Lublin: So, there are at least three, maybe four, others S1P1-3 or-5? The major issue here is whether the efficacy signal will be better. This would be interesting, not easy to do, but interesting. Perhaps more importantly, better safety and better tolerability in the sense of perhaps not having to go through as many hoops to get started with S1P1. 8

9 A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis Dr. Krieger: The burden of proof that the more selective S1P1 modulators are safer than fingolimod is pretty high because the adverse events that we think about with fingolimod are rare. There is a great deal of monitoring that we have to do to ensure we catch them if they happen, but they are rare events. So, in this trial, with roughly 250 patients, it is excellent that that sort of safety signal was not seen. With a rare event like this, in this particular trial, I m not sure it s scaled enough to help us estimate the risk of rare events. But, the trial is clearly going to move forward to the phase 3 portion based on the efficacy data, and subsequent studies should give us a much better idea of safety. Dr. Lublin: It would be nice to get rid of six-hour monitoring. Dr. Krieger: Yes. Dr. Markowitz: Absolutely. FIGURE 6 5 Steroids An interesting question that has been studied for quite some time is, can oral high-dose steroids be substituted for the IV steroids used for acute relapse? A study from France relating to this issue was discussed. Dr. Krieger: This question has been debated for a long time. We use a standard three to five day IV course, but this was extrapolated from the Optic Neuritis Treatment Trial (ONTT). Many other studies have used different doses and dose frequencies, but this study looked at a noninferiority design of three days of high-dose oral steroids of 1000 mg per day, so this is not to be confused with a low-dose prednisone pack-type of steroid treatment, but rather a 1000 mg steroid given orally for three days versus the more traditional 1000 mg IV steroid given for three days. This was an acute relapse study, so patients had to be enrolled promptly upon relapse, which is one of the challenges of doing a study like this. Results indicated noninferiority for the oral regimen compared with the IV regimen based on the speed of relapse recovery. Although this was a relatively small study, these are good data, and these are hard projects to do because of the challenges of recruitment and timing. Thus, it is unlikely that it will be replicated in larger studies; we re not going to see phase 3 trials designed to look at this question. 6 Dr. Lublin: These trials are hard to do. The design included a window of up to 15 days, but the longer it takes to enroll patients, the greater the potential for bias to achieve noninferiority because that means no difference. There was no control to ensure that the treatment was actually making a difference. The results only indicate that the two therapies are similar. I think they carried this out well. Dr. Markowitz: Safety is our primary concern. Administration of 1000 mg into the stomach raises concerns about all of the effects that steroids have on changing the stomach lining, gastrointestinal bleeding, etc. But no new safety signals were observed, and the treatment was reasonably well tolerated. We all have these issues of how we are going to treat our patients with these steroids should they receive them at home? Should they receive them in the office? Should they receive them in the hospital? Over the last several years, we have encountered some patients who just do not have IV access. They must receive their medication in an oral form, and on some occasions, we have prepared methylprednisolone sodium succinate in a blender and then given it to the patient to drink because that could work as well. It is not an ideal situation because it does not taste very good. But the concern then is, how are you going to deliver the number of pills required? The dose is 1000 mg, and most of the prednisone tablets are 20 mg, which requires the patient to take 50 pills per day. 6 Dr. Lublin: This was not as much of an issue in France because in Europe they have 100 mg tablets, but many parts of the world do not. This issue was raised during the question-and-answer session. Having 100 mg is not so bad, but 50 pills would be quite a bit. Actually, the 50 pills get you 1000 mg, but that is not the equivalent oral dose of 1000 mg IV. 6 9

10 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting Dr. Markowitz: Right, it requires 1250 mg. Dr. Lublin: We were using 1400 mg when we were trying to study this, unsuccessfully, but nevertheless, somewhere between 1250 and 1400 mg because of absorptive difficulties. Dr. Markowitz: Right. But, I think it gives us the option; we don t need to be concerned that we re not giving the same efficacy. Thinking you need to give IV, but you don t. FIGURE 7 6 Progressive multifocal leukoencephalopathy (PML) Dr. Lublin: PML is a complication of treatment with natalizumab, with over 500 cases reported to date. The issue is whether any of the other immunomodulators or immunosuppressants produce PML in patients with MS. The immunosuppressants produce PML in other patient populations. At this meeting, PML was discussed in the context of switching from natalizumab to another drug, such as fingolimod. Dr. Krieger: We have not attributed PML to any of our other modern disease-modifying agents. For instance, with DMF, which was approved in March 2013, around 90,000 patients have received that drug postmarketing, and no PML cases have emerged. The occurrence of PML in patients receiving DMF is something that has been watched closely because there have been approximately five PML cases with other fumarate derivatives in other disease states, mostly in patients with psoriasis in Germany. I don t know that we really understand the causality in terms of whether that was a consequence of other immunosuppressants that those patients had been taking, whether it was a consequence of the fumarate derivative, or the extent to which the underlying systemic autoimmune disease was in and of itself a risk factor. 7 Dr. Markowitz: Detailed data were presented on patients who had transitioned to fingolimod after natalizumab. There was a study of 11 patients, 10 who had previously been on natalizumab and one who had not. Interestingly, the shortest transition duration was three weeks, but there were no good follow-up MRIs or cerebrospinal fluid (CSF) analyses to provide information about whether the patients had PML and they just switched over. I think the longest transition duration was six months. What I think is really interesting is that, in all of the data that we have on fingolimod, we have not seen any cases of PML in patients who did not have prior exposure to natalizumab. One patient had some very, very aggressive brain MRI activity, with about 10 clinical attacks within that year, and that patient had been on fingolimod for about seven months, but had received prior treatment with azathioprine and steroids, so there are other factors involved. The patient did have an neuromyelitis optica (NMO) positive blood test, and a low copy number of John Cunningham (JC) virus in the CSF. This was a very unusual case. It is not clear that it was related to fingolimod because of all of the confounding factors. I think it s a pretty good comfort that we haven t seen any PML in fingolimodtreated patients independent of natalizumab. FIGURE

11 A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis Dr. Krieger: I agree that is a comfort. What is perhaps a little discomforting about the presentation with 10 cases of PML emerging while the patients were switched from natalizumab to fingolimod is that we need to make sure that we are still being vigilant in thinking about PML, even after natalizumab has been discontinued. It is particularly important in the context of the new way we recommend and understand the best way to switch a patient from natalizumab to a subsequent agent, which is to really have very little, if any, washout at all. I think the old thinking had been to let natalizumab wash out for several months. 8 Dr. Markowitz: The prescribing information recommends six months of washout prior to initiating another therapy. Dr. Krieger: That is not done anymore. I think we need to remain vigilant when our post-natalizumab patients are on their next drug, be it fingolimod or any other, that the risk for natalizumab-associated PML does not immediately vanish with that transition. This came up in Dr. Bruce Cree s, from the University of California San Francisco, presentation regarding post-natalizumab rebound and how to make these transitions. There is a consistent message that allowing a long washout opens the door to relapse, recurrence of disease, severe MS disease in some cases, regardless of whether we call it rebound. With that transition being very short, the consideration for PML has to be paramount for at least several months. 8 Dr. Lublin: These data are important. People used to argue about the rebound a plethora of studies support the idea of rebound, beyond just return to baseline activity, but actually truly rebound. It has become more of a concern than dual immunosuppression. I think that s guiding the trend of starting earlier and earlier. Because when they waited three months, nothing seemed to help avoid the rebound. So, we have moved the initiation of the subsequent drug to sooner after discontinuation of natalizumab. However, then you must be careful that you re not missing a case of latent PML that was just starting to brew. It is important to be vigilant. 8 Dr. Markowitz: And how do we manage that? That s really the question. Most MS-neurologists feel that you need to have some baseline MRI scans after stopping natalizumab, right when you re starting up your new drug, to make sure that there s nothing there that is suggestive of PML. Some people are even making a recommendation to look at the CSF. Dr. Lublin: I m not entirely sure what you do with the information. Dr. Markowitz: Right, because you re going to ask the question, Do they have JC virus DNA in their CSF by polymerase chain reaction (PCR)? before you start. We know from some of the studies that were looking at the original population of patients who ended up stopping the trial because of PML that there were a couple of cases in there that had JC virus DNA in their CSF. Dr. Krieger: There was another presentation here at ACTRIMS-ECTRIMS showing the same thing. JC virus DNA in the CSF is not the same thing as PML it isn t always PML. Certainly one would have to be concerned about it though, if you found it in that kind of setting. 9 Dr. Lublin: Gene Major s lab at the National Institutes of Health (NIH) also had a poster showing that individuals who have recovered from PML continued to have JC virus copies in their CSF for long periods of time. The meaning of that observation was not clear because the patients were no longer sick, and the results were independent of whether they had immune reconstitution inflammatory syndrome (IRIS). We think of IRIS as a way of clearing the virus, but it doesn t clear it completely. 10 Dr. Markowitz: Another thing that was interesting was the question about DMF and the cases in patients with psoriasis treated with fumaric acid esters. We have no specific guidance on how to monitor patients for lymphocyte counts, but there was some suggestion that the patients who ended up going on to develop PML had very low lymphocyte counts. So, how do we manage our patients who are currently on DMF, and at what frequency should we be looking at their lymphocyte count, and at what level do we actually make a change or have a thought that we might need to suspend the treatment temporarily? 11 Dr. Lublin: Ralf Gold from Germany, who has had a lot of experience with both fumaric acid and PML, recommended that they not drop below 500 cells/μl. Dr. Markowitz: This is an interesting issue because I ve been monitoring our patients, and we do have some who go below 500 cells/μl. Dr. Lublin: We tolerate a lower number with fingolimod. Dr. Markowitz: Correct. 11

12 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting Dr. Krieger: But that is based on the mechanism of action of fingolimod. We expect lower numbers because the cells are sequestered. Dr. Lublin: That s true; DMF is a little different. Dr. Lublin: The mechanism of action is what makes it so difficult to transition a patient from natalizumab to fingolimod because both drugs are sequesterers rather than immunosuppressants or cytotoxic agents. So, cells are still potentially there, just sort of removed. FIGURE 9 9,10 Stem cells Data on stem cells were presented, relative to the potential of stem cells to repair the nervous system. Dr. Lublin: Animal studies support that stem cells not hemotoxic bone marrow transplantation, but autologous stem cells regardless of where they are derived (in this case, bone marrow), hold the promise of both turning off the immune response and enhancing repair. I use the term enhancing repair because it is unclear whether they are repairing themselves or providing a permissive milieu that allows for intrinsic repair. 12 Dr. Krieger: The notion that mesenchymal stem cells can have an immunomodulatory and reparative role, even without having to enter and graft into the central nervous system, raises a whole new set of possibilities as to how these cells can be used. Jeff Cohen s project looked at 25 patients. This was really a safety study, a small project, obviously, but a proof-of-concept and safety study with autologous-derived stem cells. From a technical perspective, the investigators were able to acquire the cells, grow them in sufficient numbers, establish their validity, and transfuse them. I think that was successful in 24 out of the 25 patients, which is terrific. No major safety signal emerged, certainly no untoward immune consequences, and no opportunistic infections were noted. Unfortunately, they did not see any efficacy outcomes, but the trial was not designed to show efficacy, so I don t view that as an impediment for further development of mesenchymal stem cells. This is being done in a variety of labs and contexts. This was a very nice project to show how this work can be done and scaled up for larger efficacy studies. 13 Dr. Markowitz: Absolutely. Our patients who want stem cells will travel across the planet to get them, and these are in situations that might put them at risk for all sorts of things that are not necessarily regulated. So, we need data, and we need good studies to really look at this. This was the first really solid study that addressed this with mesenchymal stem cells. I hope we go forward with it. Dr. Lublin: There were some hints there, so that would be good. One also could come away with the concern that we may be throwing out the stem cell strategy if we re looking for only anti-inflammatory effects, which is all that you would see in a short-term study like this. I think that would be a mistake. I don t think we need stem cells for their anti-inflammatory effects; we need them for repair. Dr. Markowitz: At least we now know that the study can be done; the procedural aspects are taken care of. Dr. Lublin: There was a nice session on some of the underlying mechanisms of repair, specifically remyelination. One study evaluated epigenetic control of myelin formation and myelin repair, 14 and another assessed the other underlying mechanisms of all of the dendrocyte precursors and upregulation of myelin-producing cells from a couple of different laboratories

13 A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis FIGURE and it is using a composite imaging-based endpoint, with both standard MRI metrics, MRI measures of brain volume, as well as optical coherence tomography (OCT), and novel imaging techniques. This study is, of course, going to show us if ibudilast is effective on those endpoints, but it will also enable analysis of which of those metrics, alone or in combination, is the best gauge for progressive disease. So, I think that trial is one to look at because it encompasses a lot of where the field is going. 16 FIGURE Progressive MS Dr. Lublin: One big area of interest amongst our community members is how to tackle the problem of treating progressive MS/secondary progressive MS. We have talked about all of these disease-modifying agents that we have, but they are all intended for relapsing forms of MS, and we have yet to see a successful trial in progressive MS, with one exception in phase 2 that we ll discuss. But, there s a lot going on. Dr. Krieger: There is clearly a great unmet need in MS, and at this point, anyone who cares for people with MS. We have plenty to offer patients with relapsing disease too many things to discuss in the time we have (in a single office visit). However, there are few options that have great data for patients with severely progressive disease. Agents to address that need are being pursued by almost every company investigating a molecule for MS. There are a number of ongoing trials. Some of the challenges are to try to figure out the best outcomes to use. How we can study an agent without evaluating relapse rates or new T2 and gadolinium-enhanced lesions which are not the best outcomes for the progressive forms of the disease? So, as interesting as the molecules are, it is important to determine how we re going to design these studies to have composite endpoints that will give us a more nuanced sense of whether we re preventing disability. One example is an ongoing trial, the SPRINT-MS trial, which is a phase 2 trial looking at ibudilast. This study is novel in a couple of ways. It is looking at a combined population of patients with primary and secondary progressive MS, Dr. Lublin: Jeremy Chataway published data on a phase 2 study of simvastatin for progressive MS, with change in brain volume over two years as an outcome measure, which provided at least some proof-of-principle. 17 Dr. Markowitz: One of the things that I think we as a community must determine is how long we should be doing our clinical trials to be looking at progressive disease. We know that when we do an MRI, and MRI in MS can be pretty accurate, you can count the number of new lesions, and in the relapsing form of the disease, you can count the number of relapses that you re having. But in the progressive form of the disease, you don t see progression in over six months to a year for the most part, so you really need several years before you can actually determine whether this is going to be an effective therapy. The trials that we ve done to date in primary and secondary progressive MS were pretty short studies. We don t know yet whether the effects and we ve learned a little from the pathology of what we re seeing with this disease of whatever is happening in the progressive disease in the first couple of years will show up 13

14 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting clinically for three to five years. So, if we re going to do a clinical trial in progressive disease, we have to make sure that we are going to be studying those patients for whatever period of time you say, three years, at four, five, and six years, and see if you had a difference because data suggest that this is what we may be missing. It s not that the drugs don t work, it s that we haven t figured out a way to study them. Dr. Krieger: Part of the issue with the need for these long trials, which of course, you also want to expedite to get answers for these forms of the disease is not just the length, but the sensitivity or the nuance of our outcome measures. If we have more nuanced outcome measures to show progression sooner, we might not have to wait for the more overt signs of progression that we see in our clinical practice, and really those assessed by the traditional measure of disability, the expanded disability status score (EDSS). We all know that the EDSS can be insensitive to a lot of the ways that our patients progress. For example, the currently ongoing secondary progressive MS trial for natalizumab, the ASCEND trial (NCT ), is based on EDSS outcomes as well as more functional clinical scales, like the timed 25-foot walk and the nine-hole peg test, which is a measure of upper extremity function. That might allow us to see nuances in how these patients are changing, right in the range where the EDSS might not be so sensitive, in that three, four, five, six range, which is really hard to pull out in someone who is progressing in a relatively short period of time. That trial will look at that with a combined clinical endpoint, and results will be available sooner than results from some of these other trials that we re talking about with combined novel imaging endpoints. 18 FIGURE Dr. Lublin: Data from the INFORMS study of fingolimod will be reported later this year (NCT ). INFORMS was a trial in patients with primary progressive MS that used composite outcomes: EDSS, timed 25-foot walk, and the nine-hole peg test. That will also provide useful information. I don t think we can wait or do a study for five years. I think we have to do better in a shorter period of time. It s a practical matter. I think what you re saying is correct we need to know that information. But, I just don t know if it will happen. So, we have to hope that some of these other studies will guide us. We re really sort of setting the standards that we ll use moving forward. 19 The fingolimod study is attractive because fingolimod crosses the blood-brain barrier and gets into the CNS. But we do have other monoclonal antibodies, natalizumab, and ocrelizumab. So, presumably immunomodulators that will also be reporting results for primary progressive or secondary progressive disease, but not until next year. Some of these studies are event driven, so you don t necessarily have a time frame, you just have to observe a certain number of events to be able to achieve enough power to conclude that there is a difference between groups. That may help us, if we choose to do this properly. 19 Dr. Krieger: I think that s an important point that you bring up about the INFORMS trial, the fingolimod trial in primary progressive MS. That trial will likely report the soonest, so we should all await the publication of these data. Fingolimod is already an FDA-approved drug, so if the results are positive, presumably we ll be able to utilize fingolimod for primary progressive MS patients in a relatively expeditious way based on the safety profile

15 A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis Dr. Lublin: If something worked in primary progressive, would you use it in secondary progressive? Dr. Markowitz: Absolutely. No question about it. Dr. Krieger: Yes. There was a presentation exploring the question of whether we should really say that primary progressive and secondary progressive are different diseases. The ultimate conclusion was that there is probably a spectrum, and we don t have true biologic determinants to conclude that one is different from the other. I agree with that. Dr. Lublin: Progressive disease is progressive disease. I think that in the future, that s how we ll be choosing whether it s progressive with activity or progressive without activity. But we want progressive progressing. FIGURE Dr. Markowitz: Absolutely. Dr. Krieger: It is a moving target because it continues to be defined differently. One of the standard definitions is no new relapses during the course of a trial, no new disability, and then no new lesions no enlarging or T1 gadolinium-enhanced lesions. Given that, it s probably not a complete measure if someone is truly disease activity-free, so other versions of this with added layers of outcomes were discussed at this meeting. Dr. Markowitz: Should brain atrophy be used as an endpoint? We do not have much data from our clinical trials with brain atrophy we have some, from some of the studies. Moving forward, I think a lot of our clinical trials will start to incorporate brain atrophy measurements because it could have a very good correlation with neurologic dysfunction and disability, and that is ultimately what we re trying to deal with. Dr. Krieger: One of the discussions involved the fourth layer of disease activity. We need a fourth layer, so brain atrophy could be added. FIGURE We talked about outcome measures, and there is one that we re developing from the CombiRx trial that assessed the value of subtraction MRI early on, within the first six months of the study, and it did a good job of predicting both later MRI change and later clinical change. The other metric that people are paying attention to is the disease activity-free state or no evidence of disease activity, and how we can use that better in answering questions. When we are already getting to a point where the annualized relapse rate is very low, it is going to be hard to do better. 20 Dr. Krieger: No evidence of disease activity, or NEDA, is a new acronym that was often discussed at this meeting. Some might argue that it is wishful thinking that most of our medicines cannot yet afford us NEDA in most of our patients; but, that is certainly the goal. Dr. Lublin: Maria Pia Sormani gave us the biostatistical basis for the confidence limits of the brain volume loss, and when it was greater than a standard deviation away, that that would be considered abnormal, controlling for parameters such as age, disease, and baseline activity. 20 Ludwig Kappos showed how this would work and that the best studies to look at this are the fingolimod FREEDOMS trials because they have the best brain volume data of the published 15

16 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting trials. It was recorded throughout the trials, for six and 12 months and going out into their extension periods. So, we don t have this confounder that some people called pseudo-atrophy and other people call worsening of effect. So, it made for a very nice example for studying this fourth layer. I thought it was an intriguing way to look at the disease. It is a way to bring in a different dimension than just anti-inflammatory effects. 21 Dr. Krieger: Right, and of course that s going to have a dovetail effect with the move toward looking at progressive MS, because brain atrophy and loss of brain volume seem to be a direct manifestation of ongoing disability and progressive disease. Conclusion Dr. Lublin: MS Boston 2014 was a busy meeting, which shows us that a lot of good work is going on. Let s discuss the takeaways. Dr. Markowitz: We have several agents that provided some new data from clinical trials. We have some data from the daclizumab arena, which looked promising. Even some of the agents that we re already using such as glatiramer acetate had informative data regarding tolerability issues and the three-times weekly regimen. I think that the big issue that is on a lot of neurologists minds is how do we manage patients with PML and JC virus data. I think all of that really gives us some anxiety, but as we learn more, we can feel a little more comfortable. We get better at figuring out which patients are appropriate for which treatment. Some of the new agents, such as the S1P1 molecule, looked exciting. We even talked about stem cells, which is an area that we really need to expand on, and we re starting to get to the point where we re starting to ask the right questions, study the right population, develop the right kind of studies for this. Dr. Krieger: At this meeting, we got to see some of the shifting of the gaze toward a higher standard of efficacy with NEDA and the move toward treating and having effective treatments for progressive disease. Looking ahead, the next trial that is likely to provide data for us is the INFORMS trial of fingolimod in primary progressive MS. So, that really brings together a number of things that we ve been talking about here. For ocrelizumab, the other anti-b-cell monoclonal antibody, a relapsing remitting and a primary progressive trial are ongoing. The relapsing remitting trial will soon provide data as well. So, I think those are the next two that we are going to see. From an approval perspective, we just saw the approval of pegylated interferon-1a, so that will become available and start to influence how we re using that in the coming months. We may see the approval of alemtuzumab. The FDA is looking at this again. We didn t discuss it in detail today, all of the data on alemtuzumab had been previously presented, but that may come to FDA approval in the United States as well. It has already been approved in some 30 countries outside of the US. In summary, I think that in the coming months, we have a couple of possible approvals, data from a couple of important trials, and then shifting the gaze forward, we re really looking at treatment and trials for progressive disease. Dr. Lublin: We have much to look forward to MS is a very active scientific and therapeutic area. FIGURE 15 16

17 A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis References 1. Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs Interferon ß-1a in RRMS patients. Presented at: 2014 Joint ACTRIMS- ECTRIMS Meeting; September 2014; Boston, MA. FC Calabresi p, Kieseier B, Arnold D, et al. Clinical efficacy of peginterferon beta-1a in relapsing-remitting multiple sclerosis: 2-year data from the phase 3 ADVANCE study. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. FC Wolinsky J, Dietrich D, Borresen T, et al. GLACIER: openlabel, randomized safety/tolerability study of glatiramer acetate 40mg/mL three times weekly versus 20mg/mL daily in RRMS. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. FC Cohen J, Belova A, Selmaj K, et al. Generic glatiramer acetate is equivalent to copaxone on efficacy and safety: results of the randomized double-blind GATE trial in multiple sclerosis. Presented at: 2014 Joint ACTRIMS- ECTRIMS Meeting; September 2014; Boston, MA. FC Han M. Immune cell trafficking to the CNS, mechanisms and therapeutic implications. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. TC Le Page E, Veillard D, Laplaud VD, et al. Efficacy and safety of oral versus intravenous high-dose methylprednisolone in multiple sclerosis relapses, a randomized double blind trial (COPOUSEP). Presented at: 2014 Joint ACTRIMS- ECTRIMS Meeting; September 2014; Boston, MA. PS Putzki N, Clifford DB, Bischof D, Moore A, Weinshenker BG, Freedman MS. Characteristics of PML cases in multiple sclerosis patients switching to fingolimod from natalizumab. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. FC Cree B. Rebound after natalizumab discontinuation. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. PS Wiendl H, Schwab N, Schneider-Hohendorf T, Breuer J, Posevitz-Fejfar A. JCV index and L-selectin for natalizumabassociated PML risk stratification. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. PS Herbert J, Ryerson L, Kister I, et al. Establishment of a global registry for multiple sclerosis patients on extended dose natalizumab dosing. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. Poster Gill A, et al. Crit Rev Immunol. 2013; 33(4): Peruzzotti-Jametti L, Mallucci G, Tannahill G, et al. Injection of next-generation directly-induced neural stem cells (inscs) induces recovery in a chronic mouse model of multiple sclerosis. Presented at: 2014 Joint ACTRIMS- ECTRIMS Meeting; September 2014; Boston, MA. PS Cohen J, Imrey PB, PLanchon SM, et al. Phase I trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. PS P Casaccia. Epigenome-wide studies: what can we learn from them? Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. HT C Lubetzki. Remyelination in the adult central nervous system: mechanisms and perspectives. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. HT Fox, R. A Phase 2 Randomized, Double-blind, Placebocontrolled Study to Evaluate the Safety, Tolerability and Activity of Ibudilast (MN-166) in Subjects With Progressive Multiple Sclerosis. Presented at: 2014 Joint ACTRIMS- ECTRIMS Meeting; September 2014; Boston, MA. 17. Chataway J. PS8.2. Update on completed and ongoing neuroprotection and repair trials. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. PS Giovannoni G. New Treatment Targets for MS. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. SS Kappos L, Radue EW, Freedman MS, et al. Inclusion of brain volume loss in a revised measure of multiple sclerosis disease-activity freedom: the effect of fingolimod. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. FC Freeman L, Lalys F, Staewen TD, et al. Early on-treatment T2 and T1 subtraction MRI predicts imaging and clinical outcomes in the CombiRx cohort. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. PS Sormani MP, Kappos L, Radue EW, et al. Defining brain volume cut-offs to predict disability progression in MS: an analysis of a large cohort of relapsing-remitting MS patients. Presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; September 2014; Boston, MA. PS

18 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting Post-Activity Test Questions Answer sheet provided on page 21 To participate: 1. Log on to Or 2. Tear out, complete and return both sides of the following page. Record answers on page 21. See the top of page 21 for detailed instructions to receive CME credit. 1. How is daclizumab, a monoclonal antibody therapy, different from other monoclonal antibodies currently available? a. Administered twice monthly b. Administered via once a month, subcutaneous self-injection c. Administered intramuscularly d. Can be taken only as a monotherapy 2. The phase 3 GLACIER study compared the safety of daily glatiramer acetate versus three-times-weekly administration at 40 mg instead of 20 mg. What decrease in injection site reactions was observed? a. 25% b. 50% c. 60% d. 75% 3. RCP1063 is an S1P1 modulator, similar to fingolimod but more receptor selective. What outcomes have been seen with this new treatment? a. Major cardiac issues observed b. No reduction in new T2 lesions c. 90% reduction in gadolinium-enhanced lesions d. 50% reduction in gadolinium-enhanced lesions 4. A 39-year-old patient with MS is transitioning from natalizumab to fingolimod. According to recent data presented at MS Boston 2014, which of the following is not a precaution that could be taken to ensure there is no occurrence of progressive multifocal leukoencephalopathy? a. Very little, if any, washout of natalizumab b. Six-month washout of natalizumab c. MRI base scans immediately after stop natalizumab d. Check CSF for JC virus DNA 5. A 42-year-old patient with primary progressive MS has JC virus DNA present in her CSF. She wants to know what possible treatment options are currently in the development phase that would be an option for her. What do you tell her? a. The INFORMS trial with fingolimod b. ASCEND trial with natalizumab c. GALA trial with glatiramer acetate 6. What measure, that correlates with neurologic dysfunction and disability, could clinical trials start to incorporate in order to better determine NEDA (no evidence of disease activity)? a. Timed 25-foot walk b. Nine-hole peg test c. Expanded disability status score d. Brain atrophy measures 20

19 CME Test Answer Sheet and Evaluation Form 2014 Joint ACTRIMS-ECTRIMS Meeting Reporter A Scientific and Clinical Update on Current and Emergent Therapeutics within Multiple Sclerosis Instructions for CME Credit Complete evaluation online: or evaluation to or Fax to or Mail form to: EOCME, Department , 65 East Butler Avenue, Suite 102, New Britain, PA AMA PRA Category 1 Credit : 1.0 RELEASE DATE November 5, 2014 EXPIRATION DATE November 4, 2015 You must receive a grade of 70% or better on the Post-Activity Test Questions and complete both sides of this form to receive credit for this activity. Title/ MD DO I am a licensed Degree: NP PA Physician in the Yes RN Other: United States: No Please select the number of years you have been in practice: Physician Specialty First Name Last Name Professional Address City State Zip Professional I attest that I spent hours/ minutes of AMA PRA Category 1 Credit(s) hours. Maximum credit hours available are 1.0. Pre-Activity Questions Answer Key (Please fill-in answers) ➂ a b c d 4. a b c d 5. a b c d 6. a b c d 7. a b c 8. a b c d Post-Activity Test Questions Answer Key (Please fill-in answers) 1. a b c d 2. a b c d 3. a b c d 4. a b c d 5. a b c 6. a b c d 21

20 An Official Elsevier Medical Meeting Reporter from 2014 Joint ACTRIMS-ECTRIMS Meeting PLEASE RATE THIS CME ACTIVITY EXTENT TO WHICH LEARNING OBJECTIVES WERE MET Overall Evaluation Very Poor Poor Fair Good Excellent Content Usefulness Quality How many patients do you see with MS each week? N/A: I don t see any patients Discuss current therapy options in multiple sclerosis, along with patient management strategies. Strongly Strongly Disagree Disagree Neutral Agree Agree Evaluate clinical trial data and develop methods to incorporate emergent therapeutics into personalized treatment plans for patients with multiple sclerosis. Strongly Strongly Disagree Disagree Neutral Agree Agree As a result of participating in this activity, I will consider current efficacy and safety data on novel therapies and long-term safety data for existing therapies when managing individualized treatment plans for patients with MS. The following questions should be answered on a scale of 1 to 5, with 1 meaning NOT at all confident and 5 meaning EXTREMELY confident. After participating in this activity, how confident are you in your ability to apply emergent therapeutics into personalized treatment plans for patients with multiple sclerosis? After participating in this activity, how confident are you in your ability to apply the most current safety and efficacy data to optimize the management of your patients with multiple sclerosis? Do you feel the activity was fair balanced and free of commercial bias? If no, please explain: What topics would you like to see in future CME activities? Do you wish to be notified by when new educational programs are offered by Elsevier? Please take a moment to reflect on your current and planned use of the practice strategies discussed in this activity. You will not be graded on your responses. On the left side of this table, indicate how often you CURRENTLY use each of the following clinical practice strategies for your patients with multiple sclerosis. Then, on the right side, indicate how often you NOW PLAN to use these same strategies based on your participation in this CME activity. Your Current Use Your Planned Use Never Not often Sometimes Often Always N/A Clinical Practice Strategies Never Not often Sometimes Often Always N/A a. Consider appropriately switching therapeutic options, such as natalizumab to fingolimod, to maximize patient outcomes b. Utilize long-term outcomes from recent clinical trials when developing individualized treatment plans for patients with multiple sclerosis c. Discuss current therapeutic options to improve adherence for patients with multiple sclerosis 22

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