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Clinical Perspectives on Key Data Presented at ECTRIMS 2010 CME/CE

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This article is a CME/CE-certified activity. To earn credit for this activity visit: medscape.com/advances-in/ectrims2010

ReleaseDate:10/20/2010Validforcreditthrough10/20/2011

TargetAudienceThis activity is intended for neurologists, multiple sclerosis (MS) specialists, primary care practitioners, MS nurse specialists, advanced practice clinicians, managed care personnel, and clinicians who care for patients with MS.

GoalThe goal of this activity is to discuss recent conference data related to the treatment of MS.

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AuthorsandDisclosures

AuthorsHoward L. Zwibel, MDFounding Director (Emeritus), Neuroscience Consultants Comprehensive Care Multiple Sclerosis Center, Coral Gables, Florida

Disclosure: Howard L. Zwibel, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Acorda Therapeutics, Inc.; Teva Neuroscience, Inc.

Served as a speaker or a member of a speakers bureau for: Acorda Therapeutics; Teva Neuroscience, Inc.

Dr. Zwibel does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the US Food and Drug Administration (FDA) for use in the United States.

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

Timothy L. Vollmer, MDProfessor, Department of Neurology; Director, Neuroscience Clinical Research, University of Colorado School of Medicine, Aurora, Colorado

Disclosure: Timothy L. Vollmer, MD, has disclosed the following relevant financial relationships:

Received grants for clinical research from: Acorda Therapeutics, Inc.; Barrow Neurological Foundation; Biogen Idec Inc.; BioMS Medical Corporation/Medwell Capital; Biosite, Inc.; Daiichi Sankyo, Inc.; Eli Lilly and Company; EMD Serono Inc.; Genentech, Inc.; Genzyme Corporation; Merck Serono; National Institutes of Health; National Multiple Sclerosis Society; Novartis Pharmaceuticals Corporation; Ono Pharmaceuticals; PDL BioPharma, Inc.; Pfizer Inc.; Rocky Mountain Multiple Sclerosis Society; sanofi-aventis; Teva Pharmaceuticals USA; Translational Genomics Research Institute

Served as an advisor or consultant for: Biogen Idec Inc.; Daiichi Sankyo, Inc.; Eisai Inc.; Eli Lilly and Company; GlaxoSmithKline; Guidepoint Global LLC; IMPAX Laboratories, Inc.; Novartis Pharmaceuticals Corporation; PRIME Education, Inc.; Projects in Knowledge Inc.; sanofi-aventis; Schering-Plough Corporation; Teva Pharmaceuticals USA; XenoPort, Inc.

Served on the scientific boards of: Biogen Idec Inc.; Consortium of Multiple Sclerosis Centers; Elan Pharmaceuticals, Inc.; EMD Serono, Inc.; GlaxoSmithKline; IMPAX; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA

Served as a speaker or a member of a speakers bureau for: Athena Neurosciences, Inc.; Biogen Idec Inc.; Buffalo Neuroimaging Analysis Center; Buffalo Neurological Ins.; Consortium of MS Centers; EMD Serono, Inc.; MedscapeCME; National Multiple Sclerosis Society; New York University; Ono Pharmaceuticals; Teva Neuroscience, Inc.; University of Texas; Xenoport, Inc.

Served as an expert witness for: Genentech, Inc. vs. Biogen Idec Inc.

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

Suhayl Dhib-Jalbut, MDProfessor and Chairman, Department of Neurology, UMDNJ - Robert Wood Johnson Medical School, New Brunswick, New Jersey

Disclosure: Suhayl Dhib-Jalbut, MD, has disclosed the following relevant financial relationships:

Received grants for clinical research from: Bayer HealthCare Pharmaceuticals; EMD Serono, Inc.; Teva Neuroscience, Inc.; Served as an advisor or consultant for: Bayer HealthCare Pharmaceuticals; Biogen Idec Inc.; EMD Serono, Inc.; Teva Neuroscience, Inc.

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

Massimo Filippi, MDProfessor, Department of Neuroscience; Director, Neuroimaging Research Unit, Scientific Institute and University Hospital, San Raffaele, Milan, Italy

Disclosure: Massimo Filippi, MD, has disclosed the following relevant financial relationships:

Received grants for clinical research from: Bayer Schering Pharma; Biogen-Dompe AG; Fondazione Italiana Sclerosi Multipla (FISM); Fondazione Mariani; Genmab A/S; Merck Serono; Teva Pharmaceutical Industries Ltd.Served as an advisor or consultant for: Bayer Schering Pharma; Biogen-Dompe AG; Genmab A/S; Merck Serono; Pepgen Corporation; Teva Pharmaceutical Industries Ltd.

Served as a speaker or a member of a speakers bureau for: Bayer Schering Pharma; Biogen-Dompe AG; Genmab A/S; Merck Se-rono; Teva Pharmaceutical Industries Ltd.

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

Fred D. Lublin, MDSaunders Family Professor of Neurology, Mount Sinai School of Medicine; Director, Corinne Goldsmith Dickinson Center for MS, Mount Sinai Medical Center, New York, NY

Disclosure: Fred D. Lublin, MD, has disclosed the following relevant financial relationships:

Owns stock, stock options, or bonds from: Cognition Pharmaceuticals, Inc.

Received honoraria from: EMD Serono, Inc.; Pfizer Inc.; Teva Neuroscience, Inc.

Received grants for clinical research from: Acorda Therapeutics, Inc.; Biogen Idec Inc.; Genentech, Inc.; Genzyme Corporation; National Institutes of Health; National Multiple Sclerosis Society; Novartis Pharmaceuticals Corporation; sanofi-aventis; Teva Neuroscience, Inc.

Served as an advisor or consultant for: Abbott Laboratories; Acorda Therapeutics, Inc.; Actelion Pharmaceuticals, Ltd.; Allozyne; Avanir; Bayer HealthCare Pharmaceuticals; Biogen Idec Inc.; BioMS Medical Corporation; Celgene Corporation; EMD Serono, Inc.; Genentech, Inc.; Genmab, Inc.; MediciNova, Inc.; MorphoSys; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Questcor Pharmaceuticals, Inc.; Roche; sanofi-aventis; Teva Neuroscience, Inc.

Served as a speaker or a member of a speakers bureau for: EMD Serono, Inc.; Pfizer Inc.; Teva Neuroscience, Inc.

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


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

EditorsAnne Roc, PhDScientific Director, Medscape LLC

Disclosure: Anne Roc, PhD, has disclosed no relevant financial relationships.

PeerReviewerBrian Steingo, MDDirector, Fort Lauderdale MS Center, Sunrise Medical Group, Pompano Beach, Florida

Disclosure: Brian Steingo, MD, has disclosed the following relevant financial relationships:Received grants for clinical research from: National Multiple Sclerosis Society

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

Served as a speaker or a member of a speakers bureau for: Biogen Idec Inc.; EMD Serono, Inc.; Teva Neuroscience, Inc.

CMEReviewer/NursePlannerLaurie E. Scudder, DNP, NPAccreditation Coordinator, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC

Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

AnExpertInterviewonRisksandBenefitsofNewTreatmentsinMSCME/CEHoward L. Zwibel, MD; Timothy L. Vollmer, MDPosted: 10/20/2010

Howard L. Zwibel, MD: Hello. I’m Dr. Howard Zwibel. I am the founding Director Emeritus of the Neuroscience Consultants Comprehensive Care Multiple Sclerosis (MS) Center in Coral Gables, Florida. It is my pleasure to welcome you to this series of video interviews titled Clinical Perspectives on Key Research at ECTRIMS 2010. I’m conducting these directly from Gothenburg, Sweden, during the 26th Congress of the European Committee on Treatment and Research on MS, better known as ECTRIMS.

It’s my pleasure today to be speaking with my colleague, Dr. Timothy Vollmer, Professor of Neurology and Director of Neurological Clinical Research at the University of Colorado School of Medicine in Aurora, Colorado.

The goal of this activity is to identify and evaluate therapeutic implications of novel conference data related to MS therapies. This interview will focus on reports at ECTRIMS related to risks and benefits of newer medications and their effects on the immune system.

Before we begin, I want to note at this point that during this activity we may discuss data on a number of different agents, some of which have not yet been approved by the FDA [US Food and Drug Administration].

Tim, 2 posters have been presented, one on gray matter atrophy by first author, Sarah Morrow,[1] and the other on white matter integrity by John DeLuca.[2] Can you tell us a little bit about cognitive reserve and the implication of these studies with regard to managing MS?

Timothy L. Vollmer, MD: Howard, I think this concept of cognitive reserve as applied to MS is a very important concept, and it’s one that’s evolving fairly rapidly right now. It’s a concept that’s primarily been developed in the field of Alzheimer’s disease and refers to the observations that patients who are physically and intellectually active have an increased capacity to tolerate injury to the brain. In other words, for Alzheimer’s patients who have more education, it takes them longer before they actually begin to manifest dementia.

It’s been applied to MS recently by Dr. John Deluca and others. Recent research has shown that being physically and intellectually active can actually decrease the chance of disability and delay the onset of disability. This concept comes from the flexibility that the cortex has to rewire and reorganize itself after injury. As a result, it’s possible that this process of cognitive reserve actually masks early changes in MS.

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These 2 papers address this in MS. The first paper by Dr. Morrow looked at loss of volume of gray matter structures in the deep parts of the brain in patients with clinically isolated syndrome, both adults and children. What they showed was that despite the fact that patients looked like they were stable and doing well, the brain was actually shrinking, and the major part of the brain that was shrinking was the gray matter, not the white matter.[1]

Dr. Deluca’s paper looked at the effect of cognitive retraining and what’s going on in the brain. They reported that if you put patients with mild disability through a cognitive retraining program, you can actually see changes in the brain that are a reflection of that retraining. Although the initial research in his lab showed changes in gray matter volumes and processes going on in the gray matter as measured by functional MRI, this new paper shows that [cognitive retraining] can also affect and improve nerve fibers that are going through the corpus callosum. The corpus callosum becomes more normal, [which we can see] by looking at various measures of MRI.

Dr. Zwibel: Thank you, Tim. This is clearly an area that you presented eloquently that has been under-discussed in the MS world.What did you find most interesting at ECTRIMS with regard to the treatment effects of new and emerging therapies?

Dr. Vollmer: The first thing that impressed me was that papers reported the consequences of discontinuing natalizumab in patients. There has been concern for some time that there might be a rebound effect in patients with MS who are treated with natalizumab when natalizumab is stopped. There were at least 4 papers presented at the ECTRIMS meeting here that reported exactly that phenomenon.[3-6]

The consequences of this rebound effect are quite significant. Dr. Cree from University of California, San Francisco, reported on a series of patients who had natalizumab discontinued for various reasons, including a desire to get pregnant or to switch to other medications, and he showed that about 33% of those patients will have a relapse and that their MRIs become very active.[3] In fact, the average number of gadolinium-enhancing lesions on the MRI was over 6, which is unusual in MS, as you know.

In addition, the consequence of this rebound effect was clinically important. Their mean EDSS [Expanded Disability Status Scale] with his group went from [2.9] to 4. This is an issue that I think clinicians dealing with natalizumab as a treatment for MS have got to pay attention to. It means that we have to find ways to stop natalizumab and still avoid this rebound effect, and that’s an area that’s still under investigation.I think that the second major development here is this evolving concept that the goal of immunologic therapy in MS is to achieve a disease activity-free state. This means that patients are not having relapses, they’re not progressing, their MRIs are not changing, and they’re not having new gadolinium events. That’s a shift from our earlier thinking about therapies, which were primarily to slow the progression of MS. Now the goal is to stabilize patients. Even further, there are a number of papers reporting that, with natalizumab, the goal might be to improve function.[7-9] Areas that have been shown to improve [with natalizumab] include cognitive, motor, and visual function. Even employment status improved over time on natalizumab. We may be moving our therapeutic goal from simply trying to stop the disease to actually improving patients, particularly as some new therapies enter the marketplace.

Dr. Zwibel: This is something our patients would look forward to.

Dr. Vollmer: Yes. Also at the meeting there have been reports on treating children with MS with natalizumab and it’s been reported that it’s safe and effective, and I think that’s an important opportunity, given that we all see children, unfortunately, who have MS.[10]

Finally, there were similar concerns of a potential rebound effect (that I discussed earlier with natalizumab) with fingolimod, which has recently been approved in the United States, as you know. There’s a study from the Cleveland Clinic on patients who were discontinued from fingolimod.[11] MS did reactivate on average about 6 months after discontinuation of fingolimod, but there did not appear to be any rebound effect. These are, I think, papers that can have an impact the day-to-day management of patients.

Dr. Zwibel: Thank you for bringing us up-to-date in those areas. What have you learned at this meeting with regard to the effects of new and emerging therapies on the immune system?

Dr. Vollmer: Well, there are a few things. Again, I’m fairly clinically oriented in this discussion today. I was looking at papers that were discussing immunologic findings in patients on therapies that might have clinical relevance.

The first one was a paper that looked at levels of soluble vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) in the blood of patients treated with natalizumab.[12] These are molecules that are involved in the trafficking of immune cells from the blood into the brain. They are shed from the endothelium under certain conditions and they’re elevated in patients who have active inflammation. [The authors] showed that patients treated with natalizumab had over time a decrease in the level of these soluble molecules in the blood. That suggested that these may be valuable biomarkers. For example, they might be available for us to use to determine treatment effect with natalizumab, and possibly other medications as well.

Another paper looked at the immunologic consequences of treatment with fingolimod.[13] [There were] some interesting observations when they were looking at lymphocytes in the cerebral spinal fluid. One was that the ratio of CD4 cells to CD8 cells


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has shifted from about a 3:1 ratio to a 1:1 ratio. That suggests a shift in immunoregulation in the brain of patients treated with fingolimod. In addition, they showed a decrease in activated microglia as well as an increase in natural killer cells. These suggest that fingolimod may be acting directly in the brain, and its benefit may come from that direct effect. From earlier research not reported [at ECTRIMS 2010], we know that fingolimod has [been found ] in the central nervous system. This is of interest to us in thinking about ways to potentially dose the drug to increase the benefit for patients with MS, while decreasing its peripheral effects and minimizing risks associated with the drug.

Finally, laquinimod is an oral agent that’s in clinical studies at this point. Its mechanism of action is not well understood, but 2 reports at this meeting are of interest. One study showed an increase in BDNF or brain-derived neurotrophic factor production by certain lymphocytes [with laquinimod treatment], and that suggests that laquinimod may be working through a neuroprotective effect.[14] In addition, another study indicated that laquinimod treatment results in a shift [in function] of B cells toward a regulatory function.[15] That’s a new area in immunology. We’ve always thought about T cells being regulatory. There’s evidence that B cells can also downregulate autoimmunity in the central nervous system and it’s possible that part of laquinimod’s effect is by that mechanism.

Dr. Zwibel: Thank you again for that answer. Next, I would like to ask you about the session on risks and benefits of new therapies in MS. What do you think are the practical take-aways from this session?

Dr. Vollmer: A series of our colleagues presented on different molecules at this session. Dr. Edan[16] talked about the cytotoxic therapy, such as mitoxantrone, cyclophosphamide, azathioprine, etc. His major points were that the cytotoxic drugs are probably not good long-term strategies for the management of MS because of increasing risks and safety issues. He suggested that cytotoxic agents in the future for MS treatment are probably best as induction therapies or possibly as add-on therapies in lower doses.

Dr. Polman[17] reviewed treatment [of MS with] sphingosine 1-phosphate receptor agonists, with fingolimod as the first drug approved in this class. He discussed the possibility that they may have a neuroprotective effect, as I mentioned earlier, and then went over the safety profile. He points out that this class of drugs affects receptors that are widely distributed in the body. As a result, they will have effects on the retina in terms of macular edema, in the heart in terms of bradycardia, and [they may] possibly induce atrial ventricular conduction block, and in the lungs [these drugs may] lead to bronchoconstriction. They also result in mild immunosuppression, and there is a mild increase in risk for infection. In addition to an increased risk for infections, it’s possible that the infections might be more severe as a result of being treated with these drugs.

His main suggestion was that future research may develop agents that are more selective for the sphingosine 1-phosphate recep-tor, which is more selectively expressed in the immune system, and decrease the activation of other receptors, particularly 3, 4, and 5, which are currently activated by fingolimod. In the future, we may look to developing fingolimod-like drugs that are more selective that would be of benefit.

Dr. Vermersch[18] presented on natalizumab, and the main discussion was on the risk for primary multifocal leukoencephalopathy (PML). Currently, there are [68] cases reported. So far, 29% of patients diagnosed with PML after treatment with natalizumab have died; [this rate] is unfortunately not going down. In addition, he emphasized that outcomes from PML were really determined by how early the diagnosis was made. If the diagnosis was made when there was minimal involvement in the brain, then the out-comes were actually pretty good. He emphasized that in the management of patients treated with natalizumab, we really need to develop ways to monitor [risk for PML] more closely and detect the disease earlier.

Finally, I think there was one very interesting report by Dr. Kappos[19] on a phase 2 trial of ocrelizumab in MS. Ocrelizumab is an anti-CD20 molecule antibody that kills B lymphocytes. It’s very similar to rituximab, which has been studied in MS before. This was a study of 220 patients in 4 arms: 2 different doses of ocrelizumab [600 mg and 1200 mg], placebo, and an interferon beta-1a-treated group. The study showed an 89% reduction in MRI disease activity and 80% relative reduction in risk for relapse [with the 600 mg dose] compared with placebo, and [both doses of ocrelizumab] were shown to be superior to the interferon beta. The safety profile was actually pretty good, and it was well tolerated. However, there was one serious adverse event related to the development of a thrombotic microangiopathy in one patient, and that occurred about 12 weeks after treatment with ocrelizumab and presumably was due to that treatment. I think [ocrelizumab is] a promising therapy that might eventually be in the clinics. The study indicates that it’s probably going to be comparative with other agents in terms of safety, but there will be significant issues that we will have to monitor, similar to current agents.

Dr. Zwibel: Thank you, and the viewers thank you for keeping us up-to-date with this very latest of information. I’m going to change gears just a little bit, Tim, and ask you this question: what role can nurses and advanced practice clinicians play with regard to newer therapies in MS? What challenges may they encounter if their patients go on these newer therapies?

Dr. Vollmer: I think they play a key role. As I mentioned, with the newer therapies, we have known potentially serious risks [associated] with them. I don’t want to imply they’re necessarily riskier than other therapies we’ve had in the past. That’s another discussion. But we know about potentially serious complications, which can be anticipated and monitored for. For example, with natalizumab, as I mentioned, it’s really important that they are well aware of the earliest signs and symptoms of PML. Those may include, as you know, memory problems or early confusion. [Clinicians should] discuss these with their patients and their families.

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Educate the family members on what to look for, because oftentimes patients are not aware of the very earliest symptoms, so that [PML can] potentially be diagnosed earlier and improve outcomes.

With fingolimod, there’ll be a number of challenges. This drug can affect most organs in the body in one way or another. Clinicians, again, will need to educate patients and families as to the risks, particularly related to the retinal disease of macular edema, and [clinicians should] also be able to help monitor and manage the cardiac side effects that may occur with drug use. Of course, liver function tests will need to be monitored on a regular basis because this drug can lead to hepatitis. As I mentioned, infections are probably slightly more common and potentially more severe. In addition, there may be more subtle issues, such as in vaccination. Perhaps patients should not receive attenuated live vaccines [when taking this drug] because of the potential for getting an overwhelming infection. Finally, [clinicians should monitor for any treatment-related] pulmonary effects. This drug can result in bronchoconstriction and, for smokers and patients with preexisting lung disease, fingolimod may make their symptoms worse.

The newer drugs that are not yet out but might be out within the next year or so, including alemtuzumab and cladribine, will similarly be challenging to use. Alemtuzumab is associated with the induction of autoimmunity, and autoimmune thyroid disease, kidney disease, and other problems [can develop], the most serious of which is probably idiopathic thrombocytopenic purpura. Again, the safety issues will need to be explained to patients and their families in great detail. There also is risk for infection with alemtuzumab. Cladribine similarly suppresses the immune system; [there is] substantial risk for infection. With both of these drugs, herpes zoster may be much more common, and patients will have to be educated that it is one of the likely consequences of using these medications.

Then, of course, with long-term use of all these agents, we’re concerned about neoplasms, lymphomas, leukemias, and possibly solid organ cancers that may emerge over time with treatment. Those areas are still unknown. It will take careful management and observation of patients to optimize their risk profile.

Dr. Zwibel: Right. Over a period of time.

Dr. Vollmer: Yes.

Dr. Zwibel: Thank you Tim. Thank you for your time and thank you for your insight coming from ECTRIMS. I appreciate the discussion of the risks and benefits of the new MS therapies, including their proposed effects on the immune system. Please proceed to the next video interview and thank you for joining us today.

This article is part of a CME/CE certified activity. The complete activity is available at:http://medscape.com/advances-in/ectrims2010

References 1. Morrow SA, Hoogs M, Weinstock-Guttman B, et al. Deep grey matter atrophy is associated with cognitive impairment in patients with multiple sclerosis. Multiple Sclerosis. 2010;16:S269. Abstract P776.

2. Leavitt V, Wylie G, Chiaravalloti N, DeLuca J. Does memory retraining in multiple sclerosis increase white matter integrity in the brain? Multiple Sclerosis. 2010;16:S104. Abstract P328.

3. Cree B. Clinical consequences of planned dosage interruption in natalizumab-treated patients. Multiple Sclerosis. 2010;16:S305. Abstract P868.

4. Svenningsson A, Lassmann H, Airas L. Paradoxical activation of multiple sclerosis after induction of neutralising antibodies against natalizumab. Multiple Sclerosis. 2010;16:S129-S130. Abstract P397.

5. Baumgartner A, Stich O, Rauer S. Clinical and radiological disease reactivation after cessation of long-term therapy with natalizumab. Multiple Sclerosis. 2010;16:S145. Abstract P439.

6. Kerbrat Lecuyer A, Le Page E, Leray E, et al. Assessment of disease activity within 6 months after natalizumab discontinuation: an observational study of 28 consecutive relapsing-remitting multiple sclerosis patients. Multiple Sclerosis. 2010;16:S128. Abstract P394.

7. Havrdova E, Galetta S, Hutchinson M, et al. Demographic and baseline disease characteristics associated with freedom from disease activity in natalizumab-treated patients. Multiple Sclerosis. 2010;16:S320. Abstract P905.

8. Iaffaldano P, Viterbo RG, Paolicelli D, et al. Impact of natalizumab treatment on cognitive performance, fatigue and health- related quality of life in relapsing multiple sclerosis. Multiple Sclerosis. 2010;16:S293. Abstract P837.

9. Calabrese M, Rinaldi F, Grossi P, et al. Effect of natalizumab on cortical lesions in multiple sclerosis. A two-year longitudinal study. Multiple Sclerosis. 2010;16:S290-S291. Abstract P831.


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10. Ghezzi A, Pozzilli C, Grimaldi L, et al. Safety and efficacy of natalizumab in a cohort of 34 paediatric MS patients. Multiple Sclerosis. 2010;16:S144. Abstract P437.

11. De Vera A, Kappos L, Zhang-Auberson L, Tang D, Cohen JA. Pooled efficacy data demonstrate that fingolimod reduces multiple sclerosis relapse rate with no evidence of rebound after discontinuing treatment. Multiple Sclerosis. 2010;16:S295- S296. Abstract P844.

12. Oppermann K, Pilz G, Wipfler P, et al. Short- and long-term decrease of soluble adhesion molecules (sICAM-1, -2, -3 and sVCAM-1) during natalizumab treatment. Multiple Sclerosis. 2010;16:S131. Abstract P401.

13. Kowarik MC, Pellkofer H, Cepok S, et al. Differential effects of fingolimod (FTY720) therapy on immune cells in the cerebro spinal fluid and blood of multiple sclerosis patients. Multiple Sclerosis. 2010;16:S133. Abstract P406.

14. Thöne J, Lee D, Seubert S, Hayardeny L, Linker R, Gold R. Laquinimod ameliorates experimental autoimmune encephalomyelitis via BDNF-dependent mechanisms. Multiple Sclerosis. 2010;16:S310. Abstract P881.

15. Nussbaum S, Snir A, Ram ES, et al. Immunomodulation by laquinimod of human B-cells from healthy individuals and patients with MS: targeting B-cell regulatory networks. Multiple Sclerosis. 2010;16:S298. Abstract P850.

16. Edan G. Cytotoxic therapeutic agents in MS. Multiple Sclerosis. 2010;16:S32. Oral presentation 110.

17. Polman CH. Sphingosine 1 phosphate receptor agonists as immunomodulators in MS. Multiple Sclerosis. 2010;16:S32. Oral presentation 111.

18. Vermersch P, Foley J, Gold R, et al. Overview of clinical outcomes in cases of natalizumab-associated progressive multifocal leukoencephalopathy. Multiple Sclerosis. 2010;16:S32-S33. Oral presentation 112.

19. Kappos L, Calabresi P, O’Connor P, et al. Efficacy and safety of ocrelizumab in patients with relapsing-remitting multiple sclerosis: results of a phase II randomised placebo-controlled multicentre trial. Multiple Sclerosis. 2010;16:S33-S34. Oral presentation 114.

DisclaimerThe material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on www.medscapecme.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.MedscapeCME Neurology & Neurosurgery © 2010 MedscapeCME

AnExpertInterviewonClinicalRelevanceofImmunologic,Genetic,andBiomarkerDatainMSCME/CE

Howard L. Zwibel, MD; Suhayl Dhib-Jalbut, MDPosted: 10/20/2010

Howard L. Zwibel, MD: Hello. I’m Dr. Howard Zwibel. I am currently the Director Emeritus of the Neuroscience Consultants Comprehensive Care Multiple Sclerosis (MS) Center located in Coral Gables, Florida. It is my pleasure to welcome you to this series of video interviews titled Clinical Perspectives on Key Research at ECTRIMS 2010. I’m conducting these directly from Gothenburg, Sweden, during the 26th Congress of the European Committee on Treatment and Research on MS, better known as ECTRIMS.

I am privileged today to be speaking with my colleague, Professor Suhayl Dhib-Jalbut, Professor and Chairman of the Department of Neurology, UMDNJ-Robert Wood Johnson Medical School in New Brunswick, New Jersey. Thank you for taking this time to participate in this interview.

The goal for this activity is to identify and evaluate therapeutic implications of novel conference data related to MS therapies. This interview will focus on trends in immunology and genetics presented at the meeting.

Before we begin, I want to note at this point that during this activity we may discuss data on a number of different agents, some of which have not yet been approved by the FDA [US Food and Drug Administration].

For the first question, Suhayl, is there any new genetic immune information related to the risk for MS, its diagnosis, or its clinical course?

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Suhayl Dhib-Jalbut, MD: Thank you, Howard. Yes, there is new information related to the genetic risk for MS as well as the interaction between the genes and the environment. Classically, MS has been associated with human leukocyte antigen (HLA)-DR2. We now have new information implicating another locus of the HLA gene, and that’s HLA class 1; specifically, HLA-A2 seems to carry a high risk for MS, although it’s not as strong as the association with HLA-DR. Also, there is new information on at least 8 to 10 non-HLA-related genes that might be associated with MS.

What’s even more interesting is that we now have information on the interaction between genetic risk factors and environmental factors. The 3 most talked about environmental factors are the Epstein-Barr virus, smoking, and vitamin D. A number of studies were presented by Dr. Olsson during this meeting.[1] If you carry the HLA risk genes and you have elevated titers [of Epstein-Barr virus], then your risk for coming down with MS is even higher than having either one of those risk factors alone. The same seems to be true for smoking. If you have the HLA risk genes and you’re also a smoker, then your risk goes up significantly. With vitamin D, there does not seem to be an association. Although vitamin D deficiency is a risk factor, there does not seem to be a connection with the HLA genes. In this regard, the interaction between HLA genes and the environment seems to be significant.

There are also additional genes that I would like to mention. Non-HLA genes seem to be associated with the risk for MS. For example, one of them is called the NAV1 gene, which is a risk for coming down with the animal model for MS, experimental autoimmune encephalomyelitis (EAE). This is a gene that has to do with T-cell receptor signaling. It seems to correlate with tumor necrosis factor (TNF)-alpha production and interferon gamma production, which are both pro-inflammatory cytokines. So it would be interesting to see if this gene would also be a significant risk factor in MS.

The second non-HLA-related risk gene is the interleukin (IL)-22 receptor alpha. This is, again, a risk gene in EAE that has to do with macrophage function, and in a small study in Nordic MS patients, there was an association found.

There was also new information [presented] regarding immunology of MS. Of particular interest is the role of commensal gut bacteria, either in using MS or being associated with relapses. There was a study done in EAE showing that a particular component of the Bacteroides fragilis, which is called Bacteroides fragilis polysaccharide-A or PSA, seems to be protective if expressed in the gut.[2] Mice in which this particular protein was knocked out did much worse. It looks like this bacterial protein induces regulatory T cells, as well as anti-inflammatory cytokines, which downregulate the disease process. This indicates that bacterial flora may have something to do with MS relapses, or even the onset of MS. I think this could be connected to some of the clinical trials that are being done with antibiotic treatments. For example, minoxidil, which we think might [not cross] the blood brain barrier, might actually alter the bacterial flora in such a way that could be beneficial or harmful. I think this is an important area of immunologic research that we’ll be hearing more about.

Another immunologic finding that I thought was interesting is related to vitamin D. A study addressed the question [does] vitamin D have effects on demyelination independent of inflammation.[3] In a cuprizone model of demyelination -- and cuprizone is a demyelinating agent that does not really induce much or any inflammation -- animals pretreated with vitamin D followed by the toxin cuprizone for about 6 weeks came down with demyelination, but the additional vitamin D helped significantly reduce the degree of demyelination. This was observed at high doses of vitamin D, not low doses. The question of whether these doses are relevant to humans remains to be seen, but the study does suggest that vitamin D might have beneficial effects independent of its anti-inflammatory effects.

Dr. Zwibel: Thank you, Suhayl, and thank you for giving both the highly scientific and the very practical answer. The next question I’d like to ask you is what is new in the field of disease biomarkers, particularly those that help early prediction of conversion from a clinically isolated syndrome (CIS) to clinically definite MS?

Dr. Dhib-Jalbut: This is an important question that patients often ask. There are some immunologic advances in this area that might help answer that question or come up with that prediction. One of them has to do with the discovery of autoantibodies against antigens that are not well recognized or that we do not know much about. As you know, there is increased B-cell activity and elevated immunoglobulins in patients with MS, indicating that there must be some antigens recognized by these antibodies.

If you use protein microarrays as a method of fishing out those proteins against which the antibodies are directed, it can give you a clue about the relevance of these antibodies in terms of the pathogenesis of MS. So when those studies were done, the investigators identified new targets for those antibodies that have to do with cell cycle proteins, targets that are involved in proliferation, and antigens that have to do with gene expression.[4] It seems that these antibodies might help predict whether a patient is going to convert from CIS to clinically definite MS, and maybe how fast that process is going to happen.

The second related study is a proteomic study done on the spinal fluid of MS patients with CIS.[5] Luckily, some of those patients had serum collected before they came down with [clinically definite MS], which provided an opportunity to look at protein changes before patients had their first event. When those proteins were analyzed, some of them turned out to be altered in quantity between patients who remained with CIS vs those who converted to clinically definite MS. So I think the field of pro-teomics and determining the specificity of antibodies in MS can help predict who is going to convert into clinically definite MS and who might remain stable.

Dr. Zwibel: Very novel thinking. And our science is advancing in the area of MS, so this becomes very exciting, particularly for those who are watching these interviews. I would like to ask you next, are there promising laboratory or MR predictors of disease progression?


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Dr. Dhib-Jalbut: Again, this is another question that patients ask about, and there are advances in this area, particularly in the field of micro RNAs. Micro RNAs are small RNA that plays a role in cancer biology as well as in neurodegenerative disorders, and they might control abnormal protein accumulation in the brain, for example, in a disease like Parkinson’s disease.

In the setting of MS, it was found that some of these micro RNAs are overexpressed, and some are underexpressed, and profiles of those RNAs that are overexpressed or underexpressed seem to correlate with whether the patient is in remission or in relapse.[6] Furthermore, if you compare patients who have CIS vs definite MS, there seems to be a difference also in the profile of these micro RNAs. Those studies, of course, if verified and reproduced, would have important implications for the diagnosis of MS, as well as for following up patients either without treatment or on treatment.

The other interesting thing has to do with the MS variant Devic’s disease or neuromyelitis optica [NMO]. One study showed that not only do the presence of these antibodies help you in differentiating NMO from MS, but the degree of elevation in those antibodies has a prognostic value in terms of how active the disease is going to be.[7] So the higher these NMO antibodies are, the more likely that the patient will have more active disease, more relapsing disease, and maybe more progressing disease.

Dr. Zwibel: Thank you again. Lastly, I would like to ask you a question related to many sessions that I’ve attended that seem to be part of a recurrent theme of many discussants at this meeting. There are now several therapeutic options for MS. Are we any closer to customized medicine, and are there predictive biomarkers of treatment response that one can test for before deciding which treatment is best for an individual patient?

Dr. Dhib-Jalbut: This is a question on every physician’s mind. Yes, there are a number of new studies that are beginning to address the predictive value of biomarkers that we know are associated with MS or MS treatment.

For example, one study reported at this meeting looked at baseline cytokine levels in patients who are about to receive treatment with glatiramer acetate.[8] Surprisingly, the study reported that patients who did well on glatiramer acetate had elevated levels of a pro-inflammatory cytokine called IL-17. You would have expected the opposite, but it’s interesting that the patients who had IL-17 at baseline did better on glatiramer acetate. The interpretation for this is that in patients with active disease, T-cell and B-cell immunity is higher, which is why IL-17 is high at baseline and why, if you treat them with a drug like glatiramer acetate, IL-17 would come down.

What’s also interesting is that the opposite thing was observed in patients treated with interferon beta in a study already published by Axell and his colleagues.[9] They showed that elevation of IL-17 at baseline was a predictor, at least in half of the patients they looked at, of lack of response to interferon beta, which is the opposite observation with glatiramer acetate. If these studies pan out, you would then, for example, measure IL-17 at baseline. If it is elevated, you would not treat the patient with interferon beta, but rather with glatiramer acetate. Alternatively, if the opposite is the case, you would do it the other way around. So we’re beginning to see prognostic indicators at baseline that might help decide what is the best treatment for a patient at a point in the disease.

We have also conducted similar studies that we reported on at this meeting, and one of the important predictors at baseline that we have found in the context of glatiramer acetate treatment is the association with HLA-DQ6.[10] If you are HLA-DQ6 positive, you have almost a 90% chance of being a responder to glatiramer acetate at 2 years of follow-up. If you are HLA-DQ6 negative, you have only a 50% chance of being a responder. So testing for HLA-DQ6 before you put the patient on treatment might guide you or give you additional information that you can share with the patient in terms of what is an expected response from glatiramer acetate.

There is another question once the patient goes on treatment: can we do any tests early on during the first few months of treatment that would help us predict the outcome at 2 years or further down the line? We addressed this question also in the context of treatment with glatiramer acetate. We found a number of cytokines altered early during treatment that might predict the response to glatiramer acetate at 2 years.[10] The most prominent among these was a combination of the pro-inflammatory cytokine IL-18 and enzymes that control IL-18, which is caspase-1, so the 2 are related.

What we found is that if you treat with glatiramer acetate and the patient’s IL-18 and caspase-1 levels go down at 3 to 6 months of treatment compared with baseline, this is highly associated with a beneficial effect at 2 years. In fact, the positive predictive value in the sensitivity of this assay is about 95% and its specificity is about 75%, which is pretty good. And IL-18 and caspase-1 are easy to measure; they are measured in serum.

When you are looking at predictors, you want to have a test that is practical, with easily accessible samples, and this is the case here. You can measure IL-18 and caspase-1 in serum by a simple enzyme-linked immunosorbent assay (ELISA), and if there is a reduction during treatment, then the patient is expected to do well at 3 years.

Another study of interest is in the context of prediction of response to interferon beta. Investigators looked at gene polymorphism for a molecule involved in interferon signaling called interferon response factor 5, or IRF5.[11] What they found is that 2 out of 5 polymorphisms seem to be associated with lack of response to interferon beta. And these 2 polymorphisms correlated quite well with T2 lesion load on MRI, as well as with duration of time to first event.

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So, in summary, we are beginning to see predictors at baseline, as well as during therapy in the context of glatiramer acetate and interferon beta that can help us predict how the patient is going to do in the long run, and I think we’re going to see more of these studies coming out.

Dr. Zwibel: Thank you, Suhayl, for your time and for making this very scientific knowledge very practical for our viewers. We have learned about new developments in genetics, immunology, and biomarkers in MS. Please proceed to the next video interview, and thank you for joining us today.


References 1. Olsson T. Genes and life style/environmental factors in MS. Multiple Sclerosis. 2010;16:S11. Oral presentation 29.

2. Ochoa-Reparaz J, Wang Y, Mielcarz DW, et al. A human commensal antigen protects against CNS demyelinating disease in mice and modulates regulatory T-cell phenotypes in humans. Multiple Sclerosis. 2010;16:S9-S10. Oral presentation 14.

3. Wergeland S, Torkildsen O, Myhr KM, Aksnes L, Mork S, Bo L. Dietary vitamin D3 supplements reduces demyelination in the cuprizone model. Multiple Sclerosis. 2010;16:S10. Oral presentation 16.

4. Decard BF, Goehler H, Lueking A, Gold R, Chan A. Early traces -- autoantibody profile in preclinical multiple sclerosis identified with a novel protein microarray approach. Multiple Sclerosis. 2010;16:S190. Abstract P560.

5. Tumani H, Rau D, Lehmensiek V, Lauda F, Süssmuth S, Brettschneider J. CSF proteome analysis in clinically isolated syndrome: candidate markers for conversion to definite multiple sclerosis. Multiple Sclerosis. 2010;16:S193-S194. Abstract P570.

6. Muñoz-Culla M, Irizar H, Calvo B, et al. miRNA: biomarkers in MS? Multiple Sclerosis. 2010;16:S189. Abstract P558.

7. Radaelli M, Dalla Libera D, Moiola L, et al. Relapsing neuromyelitis optica: clinical characteristics and identification of prognostic factors. Multiple Sclerosis. 2010;16:S47-S48. Abstract P163.

8. Kasper L, Bergeron A, DeLong J, Ryan K, Smith K, Channon J. Cytokine levels at baseline may predict clinical response to glatiramer acetate. Multiple Sclerosis. 2010;16:S187-S188. Abstract P553.

9. Axtell RC, de Jong BA, Boniface K, et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010;16:406-412. Abstract

10. Dhib-Jalbut S, Ito K, Buyske S, Valenzuela R. Novel immunogenetic biomarkers predict clinical response to glatiramer acetate in multiple sclerosis. Multiple Sclerosis. 2010;16:S188. Abstract P554.

11. Vosslamber S, van der Voort LF, van der Elskamp IJ, et al. IRF5 gene variant as biomarker to predict the interferon beta re sponse in multiple sclerosis. Multiple Sclerosis. 2010;16:S7-S8. Oral presentation 6.

Disclaimer The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on www.medscapecme.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.MedscapeCME Neurology & Neurosurgery © 2010 MedscapeCME

AnExpertInterviewonClinicalApplicationsofMRImaginginMSCME/CE

Howard L. Zwibel, MD; Massimo Filippi, MDPosted: 10/20/2010

Howard L. Zwibel, MD: Welcome. I’m Dr. Howard Zwibel, founding Director Emeritus of the Neuroscience Consultants Compre-hensive Care Multiple Sclerosis (MS) Center in Coral Gables, Florida. It is my pleasure to welcome you to this series of video inter-views titled Clinical Perspectives on Key Research at ECTRIMS 2010. I am conducting these directly from Gothenburg, Sweden, during the 26th Congress of the European Committee on Treatment and Research in MS, better known as ECTRIMS.It is my pleasure today to be speaking with my colleague Dr. Massimo Filippi, Professor in the Department of Neuroscience and Director of the Neuroimaging Research Unit at the Scientific Institute and University Hospital San Raffaele in Milan, Italy. Welcome, Dr. Filippi.


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The goal of this activity is to identify and evaluate therapeutic implications of novel conference data related to MS therapies. This interview will focus on advances in magnetic resonance imaging (MRI) presented at the meeting.

Before we begin, I want to note at this point that during this activity we may discuss data on a number of different agents some of which have not yet been approved by the FDA [US Food and Drug Administration].

Massimo, the first question I would like to ask you is this: what did you find most interesting at ECTRIMS this year with regard to the application of MRI in MS?

Massimo Filippi, MD: What impressed me most at this conference was that there were a number of studies which highlighted the role of MRI to provide prognostic markers for the long-term accumulation of irreversible disability and cognitive impairment in MS. Indeed, the ability of MRI to predict the course of the disease is still suboptimal. These data suggest that, at least partially, this might be related to the fact that MRI takes time to translate into clinical disability.

Many presentations also indicated that topographical assessment of the distribution of damage might be a rewarding strategy to improve the correlation between MRI and clinical findings, including fatigue. In addition, it was exciting to see several papers devoted to improving our understanding of the characteristic features of MS damage, which may help to differentiate MS from other conditions that mimic it clinically, such as neuromyelitis optica.

Dr. Zwibel: Thank you, Massimo. So our MR abilities are also moving forward as our therapeutic powers are moving forward. It is very good for our viewers to understand that our surrogate marker in MR is also advancing. Next, I would like to ask you about a session on MR applications to study MS pathology that was presented at ECTRIMS. Can you comment on practical takeaways from this session?

Dr. Filippi: There were several take-home messages to my mind from these presentations that are useful.[1] The first one is that neurodegeneration is a process that occurs early in the course of MS. Nevertheless, this translates to the accrual of clinical disability very slowly in the disease. As a consequence, as we said before, long-term studies are required to fully assess the predictive value of magnetic resonance imaging changes believed to be markers of neurodegeneration.

The second take-home message is that MS is not just a white matter disease causing focal large microscopic lesions. It is a more global disease of the central nervous system, which also affects the gray matter and results in subtle and diffuse changes through the so-called normal-appearing white matter.

The third one is that the relationship between neurodegeneration and inflammatory demyelination, which is the old mark of the disease, is still unclear, especially in terms of the timing of the 2 processes, which take time to develop.

In this regard, there was a positron emission tomography (PET) study that showed that in the gray matter of MS patients, binding activity of benzodiazepine receptors, which reflect neuronal and dendritic viability, are reduced early in the course of the disease and are not correlated with the standard white matter lesions.[2]

And finally in this area, it is important that the use and increased availability of ultra-high field scanners, such as 7-Tesla scanners, will allow distinguishing different features of T2 hyperintense lesions, which are likely to reflect the different pathologic sub-strates.

Dr. Zwibel: I thank you for your expertise. I wish we all had 7-Tesla units available to us, as you do in Milan. Let me move on and ask you another question. Cortical involvement is now an established finding in patients with MS. What is the contribution of MR techniques to image cortical pathology in these patients?

Dr. Filippi: Yes. So as you know in the past few years, MR has improved dramatically our ability to image MS-related cortical involvement. For instance, using double inversion recovery (DIR) sequences, which suppress the signal both from the white mat-ter and the cerebrospinal fluid, we can detect many cortical lesions. Of course, we are aware from pathologic studies that we are still missing many of these lesions, but the introduction of these sequences has dramatically improved the detection.

Also nonconventional structural MR techniques allow us to estimate the overall cortical involvement, which is not only caused by focal lesions but also by secondary degeneration of lesions passing through abnormalities in the white matter. And finally, through functional MRI, we are able to see the ability of the cortex to rearrange in order to compensate for accrual tissue damage. So this is a sort of summary of what we know now [about] cortical damage and the function in MS.

At this meeting, there were [reports of ] some major advancements in the field. One of which was the confirmation that using 3-dimensional DIR imaging is very sensitive for detecting gray matter lesions, enabling a relative gain of more than 200% for purely intracortical lesions compared with 3-dimensional fluid-attenuated inversion-recovery (FLAIR), which is the standard approach now.[3] And these lesions are likely to be associated with cortical atrophy and clinical status of the patient, especially cognitive impairment.

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There are also new sequences that have been tested, such as phase sensitive inversion recovery (PSIR), which are increasingly being used in the clinical arena. At this meeting, a 3-Tesla study using PSIR showed that this sequence detects almost 3 times more cortical lesions than DIR in half the time.[4]

Another aspect which is very important that we’ve seen is that cortical lesions contribute to identifying patients with clinically isolated syndrome at risk of evolving to clinically definite MS, [which suggests] that cortical lesions should be incorporated in new MR-based criteria for showing dissemination of the disease in space. There was a proposal suggesting rules for multicenter consensus criteria that might be useful for scoring cortical lesions using DIR sequences in MS.[5] And there was initial work with 7-Tesla showing that the harvest of cortical lesions can be significantly increased using such high-field scanners.[6]

Finally, there was also work on functional MRI, which first confirmed cortical reorganization of curves in all MS phenotypes, including CIS and primary progressive MS, and that it might have an adaptive role in limiting the clinical consequences of tissue damage. Previous studies mainly focused on motor function. The novelty at this congress was to show that this is the case also for cognition, emotional changes, and fatigue.

Again, in the field of functional MRI, there were a few studies assessing the so-called resting state networks.[7-9] Assessment of resting state networks is a valuable tool, especially in disabled patients because these patients may not be able to perform active tasks as controls do, and this would bias the functional MRI results. At this meeting, resting state function of MRI studies showed abnormalities of the visual, sensory motor, and cognitive brain matters, which are associated to the patient clinical status. Another study showed that active and resting state function in MRI is able to provide useful markers to assess the efficacy of cognitive rehabilitation in patients with relapse-remitting MS.[9]

Dr. Zwibel: Thank you, Massimo. This is very important information for our viewers as we’re now using MRI not only to see the status of our MS patients, but we also to use it to help us try and address the symptomatic therapies that we need to approach with our MS patients. Clearly, this is a positive step in the right direction using the MR scanner.

I’m going to change direction now. I would like you to discuss, if you would, the MR evidence both in favor and against a role for chronic cerebrospinal venous insufficiency or CCSVI in MS.

Dr. Filippi: Let me first review what we know from the past. We know that in MS patients, Zamboni and coworkers[10] described anomalies of the venous outflow [found on] color-doppler high-resolution examination and multiple severe extracranial stenosis at venography, affecting the internal jugular, the vertebral, and the azygous veins. The authors focused their evaluation on 5 anomalous parameters of cerebral venous drainage and defined as abnormal the presence in a single subject of at least 2 of these parameters. This picture was termed CCSVI and was found in all MS patients studied and none of the controls.

A recent survey, however, performed at the University of Buffalo reported a narrowing of the extracranial veins in only 55% of the first 500 MS patients enrolled, but also in roughly 26% of 161 healthy controls.[11]

An extracranial and transcranial color-coded sonography study of 56 MS patients and 20 controls performed by a German group not only was unable to replicate Zamboni’s original findings, but found no significant difference in the cerebral and cervical venous drainage between patients and controls.[12] In addition to that, a phase contrast MR study in again roughly 20 relapsing-remitting patients and 20 healthy controls found no difference between patients and controls regarding the internal jugular venous outflow, acqueductal CSF flow, or the presence of internal jugular blood reflux.[13]

So, at this meeting, there were a few studies presented that argued against this theory, similar to the last few studies I just quickly went through.

One study was based on 3T MRI venography, which showed that venous stenoses appeared to be slightly more common in [those with] MS than in healthy controls, but an abnormal cranial venous system with abnormal drainage occurs equally frequently in both individual groups. This study also found a normal venous flow in all subjects, suggesting that venous abnormalities may reflect anatomic variance of venous drainage rather than clinically relevant venous outflow obstructions.[14]

Another study performed in London, Ontario, showed that patients with internal jugular venous stenosis or occlusion [measured by] MR venography were an older minority, and these abnormalities were equally observed in patients with or without MS.[15]

There was also a study using susceptibility weighted imaging at 3-Tesla, which showed lower brain parenchymal venous vasculature visibility in MS patients.[16] But occlusion of the venous vasculature should lead to an intracranial venous engorgement with increased and not decreased venous vascular visibility.

In conclusion, the findings that led to the formulation of the CCSVI theory are open to interpretation within the presently accepted pathophysiologic framework of MS, at least in my understanding. Indeed, given the tight coupling between arterial flow, tissue metabolism, and venous flow, the reduced intracranial venous volume and the structural changes in the extracranial veins draining the CNS in MS patients may simply represent an adaptive physiological response to low intracranial vascular-arterial input and low brain metabolism. Given the elasticity and collapsibility of veins, it is probably not surprising that in some MS patients, narrowing stenosis may occur as a result of the disease process.


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At this meeting, additional data against this theory have been presented. This suggests that well-designed research studies are needed to confirm or disprove this theory and that endovascular treatment, which is not without major risks to patients, should not be performed until firm conclusions are reached.

Dr. Zwibel: Thank you. This, of course, is a subject that has caused great interest and discussion around the world, and I thank you very much for putting this in the latest perspective from ECTRIMS this year. I’m going to turn again to another thought.As an author on 2 conference abstracts on clinical markers in MS, can you comment on the MR results of the 5-year extension data of the PreCISe [Study to Evaluate Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite MS in Subjects Presenting With Clinically Isolated Syndrome] study that further evaluate the value of early vs delayed treatment with glatiramer acetate in patients who have experienced a first clinical episode and have MR features consistent with MS?

Dr. Filippi: Okay. In the initial placebo-controlled phase of this study, patients with a first single unifocal clinical event suggestive of MS and a minimum of 2 T2 lesions were randomized to receive either glatiramer acetate at 20 mg daily (243 patients) or placebo (238 patients) subcutaneously for 36 months unless a second attack occurred that led to a diagnosis of clinically definite MS.[17]

Patients were then eligible to enter the open-label phase. In the current prospectively planned analysis of 5 years after randomization, the effects of early treatment with glatiramer acetate were compared with those of delayed treatment initiated after diagnosis of definite MS, or after 3 years on the study. We had 85% of patients enter the open-label phase. Sixty percent completed an average of 4 years of postrandomization follow-up.

The analysis of the clinical outcomes showed that early treatment reduced the risk of clinically definite MS by 41% vs delayed treatment. Confirmed progression [of disability measured by the Expanded Disability Status Scale] occurred in only 21% of patients over 5 years, with no difference between the early treatment vs the delayed treatment groups. Glatiramer acetate was well tolerated, with only a 43% overall withdrawal over 5 years.

Then, we have the analysis of the MR outcomes, which demonstrated that the cumulative number of new T2 lesions and T2 lesion volume were lower in the early treatment group vs the delayed treatment group. The changes in brain atrophy over the entire period were also significantly lower in early treated patients.

Dr. Zwibel: Thank you, Massimo. Last question: can you comment on MRI measures of efficacy in other treatment trials presented at this conference?

Dr. Filippi: There were many treatment trials presented at the Congress, some of which were based on, let me say, old drugs, and some of which were based on the new drugs. We’ve tried to review some of them here. One of the most important findings shown refers back to what I said earlier about gray matter; the treatment effect of interferon beta-1a given intramuscularly on whole brain atrophy is almost entirely due to slowing gray matter atrophy.[18] Associations between treatment groups, grey matter atrophy, and worsening disability suggests that gray matter atrophy may be a surrogate marker of disability progression as well as a marker of therapeutic response in MS.

There were a few studies on natalizumab, one which showed that natalizumab, which is known to exert a strong effect on MR markers of information, was also able to stabilize MR measures associated with demyelination and axonal loss both in lesions and in normal-appearing white matter of MS patients, as well as reduce the accumulation of cortical inflammatory lesions.[19] There were several studies that showed that MR disease activity increases dramatically after discontinuing natalizumab.[20-23] Such data do not support a drug holiday in these patients.

There were also studies on fingolimod and cladribine. The study on fingolimod showed that relapse rate and MRI activity remained low in patients treated with fingolimod for 2 years, and both were lower than patients who switched from interferon beta to fingolimod.[24,25] With cladribine, it was shown that two thirds of patients treated with cladribine were free of disease activity -- meaning no clinical and no MRI signs of activity -- 24 weeks after initiating treatment. This was sustained by the end of the study 96 weeks later.[26]

Another study assessed teriflunomide: patients treated with 2 different doses of teriflunomide (7 mg, 14 mg) for 2 years were compared [with patients who received] placebo.[27] The change from baseline in total lesion volume was lower in teriflunomide-treated patients than patients in the placebo group. Teriflunomide also had a dose-dependent effect on the number of gadolinium enhancing lesions per scan, the proportion of patients free from gadolinium activity, and the number of unique active lesions per scan, so teriflunomide has a dramatic effect on MR measures of inflammation.

There was also a new drug compound, ofatumumab, with MR data presented from a phase 2 study. Ofatumumab is a fully humanized monoclonal antibody binding to CD20 antigen on B lymphocytes, which results in cell death. The results of the phase 2 multicenter double-blind randomized placebo-controlled trial in active relapsing-remitting MS patients were presented [at ECTRIMS 2010].[28] There were 3 cohorts of subjects who were safely randomized to increasing doses of the drug or placebo (2:1 ratio). MRI was performed at 4 weeks before baseline, at baseline, and at weeks 4, 8, 12, 16, 20, and 24.

Following treatment, the mean cumulative number of new gadolinium enhancing lesions on monthly MRI scans from weeks

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8 to 24 was 0.04 in the combined ofatumumab group compared with almost 10 in the combined placebo group. Using a generalized linear model based on a negative binomial distribution, the estimated relative reduction was found to be 99.8%, which is dramatic.

Dr. Zwibel: Thank you, Massimo. Thank you very much for our viewers who [need to] understand the latest updates with MR ap-plications in MS and the results of trials with our newer therapies. I thank you again for your time.

We have learned about the current situation on the use and promise of MR imaging in MS. Please proceed to the next video inter-view. And thank you for joining us today.


References 1. Fisniku LK. MRI as a predictive tool in MS. Multiple Sclerosis. 2010;16:S34. Oral presentation 115.

2. Freeman L, Leroy C, Galanaud D, et al. Early neuronal damage in patients with MS detected by PET using [11C]-flumazenil. Multiple Sclerosis. 2010;16:S34. Oral presentation 117.

3. Seewann A, Kooi EJ, Roosendaal S, et al. How reliable is 3D double inversion recovery in the detection of cortical lesions? Combined postmortem MR-imaging and histopathology. Multiple Sclerosis. 2010;15:S35. Oral presentation 118.

4. Chard D, Yousry T, Muhlert N, et al. Detection of grey matter lesions in multiple sclerosis using magnetic resonance imaging: preliminary results of a comparison of phase-sensitive inversion recovery with dual inversion recovery imaging at 3T. Multiple Sclerosis. 2010;16:S258. Abstract P749.

5. Geurts JJG, Roosendaal SD, Calabrese M, et al. Proposed guidelines for in vivo MS cortical lesion scoring using double inversion recovery MR imaging. Multiple Sclerosis. 2010;16:S265. Abstract P767.

6. de Graaf WL, Wattjes MP, Visser F, et al. 7 Tesla 3D-MP-Flair and 3D-MP-DIR: cortical lesion detection in multiple sclerosis. Multiple Sclerosis. 2010;16:S262. Abstract P759.

7. Moreira F, Tovar-Moll F, Lima D, et al. Pattern of brain activation in multiple sclerosis patients with fatigue: a functional magnetic resonance study. Multiple Sclerosis. 2010;16:S105-S106. Abstract P333.

8. Gallo A, Bonavita S, Cirillo M, et al. Distributed changes in the default-mode resting-state network in multiple sclerosis. Multiple Sclerosis. 2010;16:S259. Abstract P752.

9. Louapre C, Perlbarg V, Urbanski M, et al. Early cognitive impairment in multiple sclerosis: a consequence of a decrease in anatomical and functional connectivity within brain associative pathways. Multiple Sclerosis. 2010;16:S253. Abstract P736.

10. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80:392-399. Abstract

11. First blinded study of venous insufficiency prevalence in MS shows promising results. News release. University of Buffalo: The State University of New York. February 2010. Available at http://www.buffalo.edu/news/10937 Accessed October 27, 2010.

12. Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010;68:173-183. Abstract

13. Sundström P, Wåhlin A, Ambarki K, Birgander R, Eklund A, Malm J. Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study. Ann Neurol. 2010;68:255-259. Abstract

14. Wattjes MP, van Oosten B, de Graaf WL, et al. No association of abnormal cranial venous system drainage with multiple sclerosis: an MR venography and flow-quantification study. Multiple Sclerosis. 2010;16:S102. Abstract P324.

15. Alikhani K, Kremenchutzky MC. Magnetic resonance venography findings of the cervical veins in patients followed at the MS clinic in London, Ontario. Multiple Sclerosis. 2010;16:S270. Abstract P778.

16. Zivadinov R, Poloni G, Schirda C, et al. Presence and severity of chronic cerebrospinal venous insufficiency is related to lower brain parenchyma venous vasculature visibility on susceptibility-weighted imaging in patients with multiple


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sclerosis. Multiple Sclerosis. 2010;16:S24-S25. Oral presentation 82.

17. Filippi M, Rocca MA, Perego E, et al. Benefit of early treatment with glatiramer acetate: MRI results from the 5-year pro spectively planned follow up in patients with clinically isolated syndrome enrolled in the PreCISe study. Multiple Sclerosis. 2010;16:S349-S350. Abstract P986.

18. Fisher E, Nakamura K, Pace A, Lee JC, Foulds P, Rudick RA. Associations between grey matter atrophy and disability in a placebo-controlled trial of interferon beta-1a in relapsing-remitting multiple sclerosis. Multiple Sclerosis. 2010;16:S303. Abstract P864.

19. Mellergård J, Tisell A, Dahlqvist Leinhard O, et al. MR spectroscopy and quantitative MRI in multiple sclerosis patients treated with natalizumab: changes in normal-appearing white matter are associated to intrathecal inflammation and clinical variables. Multiple Sclerosis. 2010;16:S106-S107. Abstract P335.

20. Baumgartner A, Stich O, Rauer S. Clinical and radiological disease reactivation after cessation of long-term therapy with natalizumab. Multiple Sclerosis. 2010;16:S145. Abstract P439.

21. Kerbrat Lecuyer A, Le Page E, Leray E, et al. Assessment of disease activity within 6 months after natalizumab discontinuation: an observational study of 28 consecutive relapsing-remitting multiple sclerosis patients. Multiple Sclerosis. 2010;16:S128. Abstract P394.

22. Cocco E, Lorefice L, Frau J, et al. Natalizumab discontinuation in multiple sclerosis: experience of a single centre. Multiple Sclerosis. 2010;16:S299-S300. Abstract P854.

23. Pesci I, Magnani S, Carini D, Manneschi L, Guareschi A, Montanari E. Stopping natalizumab therapy: experience of follow-up in a MS Centre, Fidenza, Italy. Multiple Sclerosis. 2010;16:S153. Abstract P460.

24. Hartung HP, Comi G, Barkhof F, et al. Sustained benefit of continuous therapy with oral fingolimod 0.5 mg or 1.25 mg as compared to switching to fingolimod after one year of treatment with interferon beta-1a in patients with relapsing-remit ting multiple sclerosis: results of the transforms. Multiple Sclerosis. 2010;16:S282-S283. Abstract P812.

25. Cohen J, Montalban X, Pelletier J, et al. Efficacy and safety of fingolimod in patients switched from intramuscular interferon beta-1a: results from the TRANSFORMS extension study. Multiple Sclerosis. 2010;16:S289. Abstract P827.

26. Comi G, Cook S, Giovannoni G, et al. Consistent MRI benefits with short-course cladribine tablets therapy across the range of patients with relapsing-remitting multiple sclerosis in the double-blind, placebo-controlled, 96-week CLARITY study. Multiple Sclerosis. 2010;16:S131-S132. Abstract P403.

27. Wolinsky J, O’Connor P, Confavreux C, et al. A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: magnetic resonance imaging (MRI) outcomes. Multiple Sclerosis. 2010;16:S347-S348. Abstract P982.

28. Soelberg Sorensen P, Drulovic J, Havrdova E, Lisby S, Graff O, Shackelford S. Magnetic resonance imaging (MRI) efficacy of ofatumumab in relapsing-remitting multiple sclerosis (RRMS) -- 24-week results of a phase II study Multiple Sclerosis. 2010;16:S37-S38. Oral presentation 136.


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AnExpertInterviewonEmergingTherapiesandClinicalTrialHighlightsinMSCME/CE

Howard L. Zwibel, MD; Fred D. Lublin, MDPosted: 10/20/2010

Howard L. Zwibel, MD: Hello. I’m Dr. Howard Zwibel, the founding Director Emeritus of the Neuroscience Consultants Comprehensive Care Multiple Sclerosis (MS) Center in Coral Gables, Florida. It is my pleasure today to welcome you to this series of video interviews titled Clinical Perspectives on Key Research at ECTRIMS 2010. I am conducting these directly from Gothenburg, Sweden, during the 26th Congress of the European Committee on Treatment and Research in MS, better known as ECTRIMS.

It is my pleasure today to be speaking with my colleague, Dr. Fred Lublin, Saunders Family Professor of Neurology and Director of the Corinne Goldsmith Dickinson Center for MS at Mount Sinai Medical Center in New York. Welcome Fred.

The goal for this activity is to identify and evaluate therapeutic implications of novel conference data related to MS therapies. This interview will focus on trial highlights on MS presented at the meeting. Before we begin, I want to note at this point that during this activity we will disuses data on a number of different agents that have not yet been approved by the FDA [US Food and Drug Administration].

Fred, I’d like to begin this morning by asking you what your thoughts are at this year’s ECTRIMS meeting in Sweden.

Fred D. Lublin, MD: Well, Howard, this was a very good ECTRIMS meeting, maybe one of the best I’ve ever attended. Not only did they have excellent scientific presentations, but we also had [data presented from] at least 3 clinical trials, including one phase 3 clinical trial introduced at ECTRIMS, which we’ll discuss later. That’s not been the case in past years, so it made for an interesting and exciting meeting, and there was a lot of good scientific material presented to provide the basis for the clinical trials that we have moving forward.

Dr. Zwibel: Good. I agree. This has been a very exciting time in Sweden, and each year ECTRIMS seems to change and mostly im-prove. Thank you. I’d like to ask you first about the session that you chaired that included teriflunomide data from the TEMSO trial in patients with relapsing-remitting MS. Can you discuss for our audience the outcomes of that trial?

Dr. Lublin: The TEMSO [Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis] trial was a phase 3 trial of teriflunomide, which is an immunomodulatory agent that’s been used in MS. They had a successful phase 2 trial and have a few more as well, but these are their first phase 3 results. TEMSO is a placebo-controlled trial comparing 2 doses of teriflunomide, 7 and 14 mg, taken daily as an oral preparation compared with placebo.

What they showed was that both doses were superior to placebo in reducing annualized relapse rate, and the higher dose, the 14 mg dose, also was significantly better than placebo in reducing disability.[1] This is now our third successful phase 3 trial in the last year and a half or so, following on fingolimod and cladribine. As you know, fingolimod is now approved in the United States and Russia for treatment of relapsing forms of MS. Cladribine is in the queue, at least in the United States; it’s having some difficulty with the European authorities but they’ll probably work that out in some way. Now, teriflunomide is the third of the pills that had a successful phase 3 trial. There are 2 more coming along: laquinimod and oral fumarate.

The interesting thing as well in TEMSO, beyond the fact that it was successful -- and they had the usual MRI metrics that paralleled the successful clinical outcome[2] -- was that the relapse rates seen in this trial were higher than have occurred in other recent trials. As you are aware, there’s been a trend toward decreased annualized relapse rates (ARR) over the entire course of this century compared [with rates in] studies that were done in the 1990s. They had been coming down to where the placebo group in the last 2 trials was approximately 0.4 and 0.3 or so ARR.

In TEMSO, the placebo group ARR was approximately 0.54, and the reduction was about 30% both for ARR and also for the disability in the higher dose. We’re seeing that sort of trend upward again. It’s hard to know what it means because we don’t know why it went down in the first place, but this is the first trial in modern times that we’ve seen where that relapse rate is moving back up again in the placebo group. Of course, that means there’s a difference in all the groups. It may be an interesting biological issue, but the exciting thing for us is it’s a successful trial. They have at least 2 more trials coming along that hopefully will confirm this.

Dr. Zwibel: Thank you. Are we not ready yet to move to the FDA with teriflunomide?

Dr. Lublin: I don’t know what the regulatory plan is. I don’t know if they’re waiting for another study or not.

Dr. Zwibel: From teriflunomide, let’s move on to alemtuzumab. Was there any data that may have been updated at ECTRIMS this year?

Dr. Lublin: The continuing story of alemtuzumab, which is still a phase 2 story, is that it continues to show outstanding long-term results from just a couple of doses.[3-6] It’s dosed yearly, but it looks to be an extremely potent therapy. There is a collection of side


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effects that have occurred with it that are continuing to be followed, but in terms of efficacy, at least at phase 2, it’s been highly impressive. There were also some data presented that showed an improved metric in individuals [treated with alemtuzumab]. I’m not sure what that means biologically yet, but more people improved on therapy than on placebo, at least in the phase 2 trial. We’ve seen that with other trials as well, but this is fairly impressive. We hope to see their phase 3 data probably at some time next year.

Dr. Zwibel: It’s exciting. Let’s turn our attention to laquinimod. Where are we with laquinimod?

Dr. Lublin: Laquinimod phase 2 data have been completed and presented.[7] It was a successful phase 2 trial, especially in their higher [0.6 mg] dose. Their phase 3 trials are underway and they should have data on their first phase 3 trial in the first quarter of 2011. One of the interesting stories that is emerging with laquinimod is the potential for neuroprotection. Neuroprotection is becoming our next holy grail. The holy grail target keeps moving, but this is an important one in terms of salvaging brain tissue. There are some interesting mechanistic studies and animal studies suggesting that laquinimod may have a protective effect, and this was presented in some seminars and there are some papers as well discussing how this may occur.[7-11] We’ll see what their phase 3 data look like to really determine the neuroprotective effect. It will take slightly different types of studies than the early studies done on proof of principle.

Dr. Zwibel: Thank you. I would like now to move on and ask you to comment on the 5-year clinical data on PreCISe [Study to Evaluate Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite MS in Subjects Presenting With Clinically Isolated Syndrome]. This is the trial on patients with clinically isolated syndrome (CIS) treated with glatiramer acetate. The data were presented by Giancarlo Comi. If you would comment please just on the clinical results of that 5-year trial.

Dr. Lublin: PreCISe is the fourth of the CIS trials. They’ve all succeeded in showing us over the short term that the earlier you start treatment -- and CIS means you start before you actually can define MS, but you have an attack of something that looks like MS and an MRI that’s consistent -- if you treat at that point, all of these studies, including PreCISe, have shown that you lessen the risk of having a next attack, which becomes the MS-defining attack. These studies have pushed our practice from starting treatment of relapsing-remitting MS to starting after the first therapy. [Results across CIS trials] have been remarkably consistent, including PreCISe. PreCISe was the latest and looked at [the effects of ] glatiramer acetate starting at the first attack or placebo. When the trial was stopped -- and it was stopped a little early because of its success -- [patients on placebo] were rolled over on to active drug, so you have an early treatment group and a late-starting treatment group. Then they were followed through 5 years.

What Professor Comi presented was that at the end of those 5 years, even though everyone’s now on drug, the early treatment group had fewer exacerbations than the late-treatment group.[12] There wasn’t a difference in disability but that’s not really a surprise in this sort of population. It’s yet another study that’s [in line with the other studies] that showed that the earlier you start treating MS, the better subjects do.

Dr. Zwibel: Thank you. Of course, that’s the direction in which we’re moving clinically to treat our patients early, particularly if they have MR evidence of more disseminated disease.

Dr. Lublin: Exactly.

Dr. Zwibel: Next I want to ask you if there were any additional data that you thought important on ocrelizumab at the ECTRIMS meeting.

Dr. Lublin: Ocrelizumab is a humanized monoclonal antibody directed against CD20. It’s an anti-CD20 B-cell monoclonal anti-body designed to be similar to rituximab, but it’s a more humanized monoclonal antibody and therefore less likely to be antigen-ic. That has some advantages.

Data reported were on the phase 2 proof of principle trial based on looking at the reduction in gadolinium-enhancing lesions over a short period of time, as has been done in multiple other studies.[13] [The investigators] reported a very successful trial, where 2 doses of ocrelizumab reduced the number of gadolinium-enhancing lesions significantly and more impressively than placebo. Ocrelizumab also showed a reduction in the relapse rate that was significant compared with placebo. We would expect this molecule to move forward.

The safety in this trial was good. There were some safety issues with this molecule in trials of rheumatoid arthritis and lupus, but from what they’ve reported, the safety looked pretty good.

Dr. Zwibel: Thank you. Our pipeline is not quite full, but getting there. It’s very exciting for our patients and for those of us who care for MS patients, both in the States and around the world.

Lastly, Fred, I’d like you to update us and comment on your trial, the CombiRx trial, which is familiar to many of our viewers, but an update from you would be most helpful at this point.

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Dr. Lublin: I’d behappy to. CombiRx is our combination trial comparing the combined use of interferon beta-1a intramuscular once weekly and glatiramer acetate subcutaneous once daily.[14] Everyone in the trial is either taking those injections or one or the other with a matched placebo. Everyone takes 8 injections a week. What we’re trying to answer is whether the combination of the 2, interferon and glatiramer acetate, is better than either one alone. The trial’s moving along now. We will finish in January of 2012, so we have 15 months left. At this point, it’s fully enrolled and the mean time on study is 39 months. What’s been a remarkable finding thus far is that 39 months into the study -- and we have some people who [have been in] the study much longer than that obviously because that’s the mean -- 86% of the individuals are still in the trial. It’s an extremely low dropout rate. They’re tolerating these injections quite nicely.

At the moment, what we’re doing is analyzing the baseline data. We’ve presented our baseline demographics and it looks like an early MS population.

At ECTRIMS here, Henry McFarland, Stacey Cofield, and our other colleagues are reporting on biomarker data, because we have 1008 patients enrolled in the study. Of that group, 700 consented to a biomarker study where we’ve collected DNA, HLA [human leukocyte antigen], RNA expression, and serum for proteomics. We’re starting to analyze that and we’re presenting HLA data, which shows that, not surprisingly, DR1B*1501 is an MS susceptibility gene. When we look at our baseline population stratified by MRI lesion load, it’s not a severity gene. It doesn’t segregate out by how much lesion load you have.

We’ve also found that there is another HLA marker that may be a protective marker, so less susceptibility [for developing MS]. We’re now going to look at this with a genome-wide association study, looking at the snips to see if we can find individual genes that are reflective not only of susceptibility -- because those sorts of data have been reported -- but also on severity of disease. Once we finish the study, then we’ll start looking at how patients tracked and use the biomarkers to tell us who’s a responder, who’s a nonresponder, who’s destined to do poorly, and who’s destined to do well.

Dr. Zwibel: That’s the information that we are beginning to need more and more with all of our therapies, which is who may respond and who may not respond as we individualize therapy for our young patients when they come to see us.

Dr. Lublin: Personalized medicine is our future. The pipeline that you refer to, which is really remarkable for a disease like MS, has a wide range of agents that have potentially very good tolerance and potentially significant side effects, but also have a wide range of efficacy. We need to figure out who needs a riskier molecule early because they need the high efficacy vs who could get along with something that’s better tolerated.

Dr. Zwibel: I agree. Thank you, Fred. Thank you very much for your time today. We have learned about trial highlights of new treat-ment strategies in MS. I’d like to thank you, our viewers, for participating in this CME and nurse CE series of interviews. You may now proceed to the online post-test by clicking on the Earn CME Credit link on this page.


References 1. O’Connor P, Wolinsky J, Confavreux C, et al; Teriflunomide Multiple Sclerosis Trial Group. A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: clinical efficacy and safety outcomes. Multiple Sclerosis. 2010;16:S23. Oral presentation 79.

2. Wolinsky J, O’Connor P, Confavreux C, et al, for the Teriflunomide Multiple Sclerosis Trial Group and the MRI Analysis Center in Houston, USA. A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: magnetic resonance imaging (MRI) outcomes. Multiple Sclerosis. 2010;16:S347-S348. Abstract P982.

3. Coles A, on behalf of the CAMMS223 Study Group. Alemtuzumab long-term safety and efficacy: five years of the CAMMS223 trial. Multiple Sclerosis. 2010;16:S134-S135. Abstract P410.

4. Wynn D, on behalf of the CAMMS223 Study Group. Disability progression-free efficacy of alemtuzumab in relapsing-remit ting multiple sclerosis patients in the CAMMS223 Trial. Multiple Sclerosis. 2010;16:S140. Abstract P426.

5. Herbert J, Wynn D, on behalf of the CAMMS223 Study Group. Alemtuzumab’s efficacy in the CAMMS223 trial as assessed with the multiple sclerosis severity score. Multiple Sclerosis. 2010;16:S140-S141. Abstract P428.

6. Wingerchuk D, on behalf of the CAMMS223 Study Group. Efficacy of alemtuzumab in highly active relapsing-remitting multiple sclerosis patients in the CAMMS223 trial. Multiple Sclerosis. 2010;16:S141. Abstract P429.

7. Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing remitting multiple sclerosis: a multicentre, randomized, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371:2085-2092. Abstract


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8. Ruffini F, Bergamaschi A, Marinaro C, et al. Laquinimod prevents the inflammation-induced derangement of neurogenic niches in experimental autoimmune encephalomyelitis mice. Multiple Sclerosis. 2010;16:S311-S312. Abstract P885.

9. Thöne J, Lee D, Seubert S, Hayardeny L, Linker R, Gold R. Laquinimod ameliorates experimental autoimmune encephalomyelitis via BDNF-dependent mechanisms. Multiple Sclerosis. 2010;16:S310. Abstract P881.

10. Silva C, Wang J, Mishra M, Yong VW. Differential activity of laquinimod on production of inflammatory molecules and neurotrophic factors by human microglia and macrophages. Multiple Sclerosis. 2010;16:S310. Abstract P882.

11. Wegner C, Pförtner R, Brück W. Laquinimod rescue therapy in mice with experimental autoimmune encephalomyelitis. Multiple Sclerosis. 2010;16:S77. Abstract P251.

12. Comi G, Martinelli V, Rodegher M, et al. Benefit of early treatment with glatiramer acetate (COPAXONE): results from the 5-year prospectively planned follow up in patients with clinically isolated syndrome from the PreCISe study. Multiple Sclerosis. 2010;16:S37. Oral presentation 135.

13. Kappos L, Calabresi P, O’Connor P, et al. Efficacy and safety of ocrelizumab in patients with relapsing-remitting multiple sclerosis: results of a phase II randomised placebo-controlled multicentre trial. Oral presentation 114.

14. McFarland HF, Jacobson S, Lublin FD, et al, for The CombiRx Biomarker Investigator Trial Group. HLA in the CombiRx bio marker cohort and controls at baseline. Multiple Sclerosis. 2010;16:S349. Abstract P985.


This article is a CME/CE-certified activity. To earn credit for this activity visit: medscape.com/advances-in/ectrims2010

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