Latest Treatment Advances in MS: Need-to-Know Science and Implications for Practice

Course Director

Daniel Ontaneda, MD, MS

Daniel Ontaneda, MD, MS
Cleveland Clinic Lerner College of Medicine
Case Western Reserve University
Cleveland, Ohio

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Part 1 of a 2-part series

Dr. Ontaneda provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


The treatment landscape for multiple sclerosis (MS) is undergoing a rapid evolution. While the current and emerging therapies are certainly helping to improve outcomes in patients with MS, they have made clinical decision-making for these patients more complicated. Many questions about how to optimally use these therapies remain, and neurologists often look to new information from major scientific conferences, such as the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the American Academy of Neurology (AAN) Annual Meeting, for answers and further guidance regarding patient-care challenges. In this activity, Dr. Daniel Ontaneda highlights findings from some of the key trials reported at recent meetings and elaborates on the potential implications for clinical practice.


This activity is supported by educational grants from Biogen Idec and Novartis Pharmaceuticals Corporation.

Course Director
Daniel Ontaneda, MD, MS, has a financial interest/relationship or affiliation in the form of:
Consultant for Acorda Therapeutics; Biogen Idec; and Novartis Corporation.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD currently has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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What can be concluded based on the latest evidence about the potential of early initiation of treatment to slow down disease progression and improve long-term outcomes in patients who present with early stage MS?

Dr. Ontaneda: That is a great question. At the recent European Committee for Treatment and Research in Multiple Sclerosis meeting [ECTRIMS 2013] in Denmark, several presentations actually addressed that very question.

I'll start off by discussing the TOPIC study.1 So, TOPIC was a double-blind, placebo-controlled study that examined patients with clinically isolated syndrome [CIS] and found that teriflunomide, at doses of 7 mg and 14 mg, [significantly] reduced the conversion from clinically isolated syndrome to clinically definite MS. Both doses were also effective in the reduction of relapses and new MRI lesions. These results are important as they confirm that oral agents can be used early and they can delay the onset of MS. And certainly this will help prevent the accrual of disability when the agents are used in the earliest stages of multiple sclerosis.

This is in line with results of the oral cladribine in CIS study, which is also known as ORACLE [Oral Cladribine in Early MS].2 This study was actually presented at the American Academy of Neurology Annual Meeting this past March [2013]. ORACLE examined patients with a first demyelinating event—the definition of CIS was slightly different in ORACLE—and they basically randomized treatment of patients to placebo or oral cladribine. And the doses of oral cladribine were 5.25 or 3.5 mg[/kg]. Patients were followed for 96 weeks, and cladribine was found to reduce the risk of clinically definite MS by 61.9% and 67.3%, respectively.

These are important data. Although the development of cladribine has been halted—and that was due to a concern of malignancy found in phase 3 trials in relapsing-remitting multiple sclerosis—the study did demonstrate efficacy of an oral agent early in the course of multiple sclerosis.

We are also interested in collecting further data regarding the effect of early treatment in our injectable agents and our infusion agents.

Narrator: Several trials reported at ECTRIMS 2013 showed that earlier initiation of natalizumab treatment results in reductions in MS disease activity.3-5 An analysis of the AFFIRM trial data looked at baseline characteristics associated with no evidence of clinical or MRI disease activity at two years. In patients treated with natalizumab versus placebo, the beneficial effects were significantly greater in those with a baseline EDSS score of <3.0 versus ≥3.0.3,4

Dr. Ontaneda: A poster was also presented at the ECTRIMS meeting that demonstrated benefits of early treatment with natalizumab in the six-year follow-up data of the STRATA study.5 The study basically gathered long-term follow-up from open-label extensions from several different natalizumab clinical trials. The most interesting observation of this study was the comparison between patients who started natalizumab earlier versus those who started the medication later in the individual clinical trials. And what the long-term data showed was that patients starting natalizumab earlier had fewer relapses overall and also had lower EDSS scores at the completion of the study, compared with those who had started it later.

It also demonstrated that patients who had accrued disability while off the medication in that first phase, when they were typically on a placebo medication, did not improve with subsequent treatment. Although this point does seem quite obvious, given the mechanism of action of disease-modifying medications in multiple sclerosis, it does highlight why early treatment and control of disease activity are important: That is, that when patients are off treatment and they accrue disability, it's difficult for them to take back that accrued disability.

In line with the above results, also at ECTRIMS, data were presented from a large multinational cohort called MSBase.6 Basically, the MSBase registry is a worldwide network of MS centers that collects data from clinical practice.7 The study that was presented examined predictors of confirmed three- and 12-month disability among patients with clinically isolated syndrome. No CSF [cerebral spinal fluid] or MRI findings were found to be independent predictors.

This was somewhat surprising because MRI is such an important prognostic factor in several other studies. But, nonetheless, what they did find was that treatment with a disease-modifying agent—and in this cohort of patients this was mostly glatiramer acetate or interferon medications—did significantly delay disease progression. So this is a very large, multinational cohort, which is important because the data were obtained outside the setting of a clinical trial, and it's likely that this data are much more similar to clinical practice.

In conclusion, I would say that there does appear to be a strong rationale for early treatment in multiple sclerosis, and it seems that this holds true also for our new oral therapies.

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New data from clinical trials evaluating currently available and novel therapies for MS continue to emerge, but what are their relevance to and applicability in real-world practice?

Dr. Ontaneda: Yes, we always must ask ourselves about the generalizability and applicability of clinical trials to our individual patients. Patients and physicians, in general, will be more interested in effectiveness, but clinical trials and registry data will typically focus more on efficacy data. So the results of combined and extension studies, in addition to clinical trials, are very important, as many times serious side effects are identified only in extension or open-label studies. This is especially important right now, as we are currently using several relatively new medications to treat multiple sclerosis, so gathering this data prospectively is certainly going to be of importance and will guide clinical practice going forward.

Several studies of fingolimod in clinical practice were presented in ECTRIMS. These studies confirmed the overall safety of this disease-modifying agent in clinical practice.

Notable among the studies was a large Danish study that examined 496 patients treated with fingolimod.8 The incidence of cardiac and pulmonary side effects was similar to that seen in clinical trials.

Another large study of 536 fingolimod-treated patients from the MSBase registry examined patients switching to fingolimod from natalizumab.9 In this large study of 536 patients, the authors found that a large gap in treatment—greater than two months—was actually a predictor of time to the first relapse on fingolimod. The authors therefore concluded that clinicians should limit the washout period between natalizumab and fingolimod to less than two months.

And this confirms data that were presented by a French group previously that showed that there was a substantial risk of disease reactivation during the washout when switching from natalizumab to fingolimod.10 And the duration of the washout period in this French study was the main prognostic factor in reactivation of the disease. So the results of these two studies, taken together, show quite convincingly that washouts should be minimized in patients switching from natalizumab to fingolimod.

So turning now to another one of our oral agents, dimethyl fumarate: Interesting four-year follow-up of patients treated with dimethyl fumarate from the DEFINE, CONFIRM, and ENDORSE studies were presented.11  

Narrator: The ENDORSE study was an extension phase of the DEFINE and CONFIRM trials. The interim results indicated that patients who continued on dimethyl fumarate for two more years experienced sustained clinical efficacy, measured by relapse and disability progression endpoints, similar to that previously seen in the DEFINE and CONFIRM studies.

Dr. Ontaneda: The [ENDORSE] study confirms the long-term efficacy of dimethyl fumarate. Given that dimethyl fumarate was approved recently—in March of this current year [2013]—having that four-year data is certainly helpful.

Some integrated safety data were also reported, and I would like to highlight safety data on lymphocyte counts.12 Basically, they showed that there was an 11% drop in white blood cell counts and a 30% drop in lymphocyte counts in patients treated with dimethyl fumarate. It turns out that lymphocyte counts are not correlated with infections, and in most patients, the counts remained within normal limits. One surprising finding was that lymphocyte counts did increase after treatment discontinuation, but did not reach previous baseline levels. So although lymphocyte reduction does not appear to predict infectious complications, in my practice, certainly patients with low lymphocyte counts are monitored closely for possible infections, along with serial blood counts.

Turning to one of our other oral medications, the efficacy of teriflunomide in an eight-year, open-label extension of the TEMSO study was also presented.13 It showed that teriflunomide had sustained effects on annualized relapse rate and six-month confirmed disability progression. This is interesting in that it is a significant amount of follow-up, which is eight years. It is worth mentioning that only about half the patients remained in the extension study; and, therefore, there is some dropout of patients, so that has to be computed when one takes into account these results.

In summary, I would say that treatment efficacy and side effects seem to be sustained in most instances of long-term extension, and several lessons can be learned from observational, real-world studies, which help mold clinical practice.

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Are there any new data to help guide risk stratification and mitigation strategies in MS care?

Dr. Ontaneda: With an increasing number of agents and with varying risk-benefit ratios among them, risk stratification now is one of the most important subjects in MS clinical care and certainly also in research efforts.

This topic was highlighted at the recent ECTRIMS meeting, and I want to share some findings which I found interesting. Some of these are somewhat removed still from clinical practice, but carry promise of possible mitigation strategies in the future.

As you probably know, the use of JC virus serology to stratify risk among patients using natalizumab is well established and is being used extensively by neurologists across the country.14,15 Although JC virus serology is excellent at determining which patients are less likely to develop progressive multifocal leukoencephalopathy [PML], currently there is no way to predict why only a small proportion of JC-virus–positive patients go on to develop PML when exposed to natalizumab.

Recent evidence shows that the JC-virus–antibody index may be helpful to further stratify patients with positive JCV status into high- and low-risk groups.16 It appears that one can run an antibody index, and if the antibody index is a certain level or higher, it confers a greater risk of PML. So the idea would be that you have a test which will help you prognosticate which JC-virus–positive patients were at a higher risk or lower risk of going on to develop PML. Although there currently is not a standardized cutoff, I think there are efforts in trying to create a standardized cutoff so clinicians will know how to interpret and how to use this data effectively.

Along the same lines of progressive multifocal leukoencephalopathy, a novel anti-lipid IgM oligoclonal band from the CSF was investigated by a group from Spain.17 The anti-lipid IgM oligoclonal bands have been seen as markers of increased disease activity, but in this case were being studied in the context of the risk of PML. It turns out that a combination of JCV positivity and an absence of anti-lipid IgM bands confirmed a greater risk of PML. So the authors suggest that anti-lipid IgM may be a further marker of stratification for PML and may be used in conjunction with the JC-virus testing to better define risk of progressive multifocal leukoencephalopathy in patients treated with natalizumab.

A study also, along the lines of PML, examined CSF from 27 cases of natalizumab-associated PML. The authors found that patients who developed PML had higher JC-virus–antibody specificity index in CSF at times of PML when compared to natalizumab[-treated] patients who did not develop PML.18 This JC-virus–antibody specificity index in CSF is being proposed as an early diagnostic marker of PML. The idea would be in a patient where there is a suspicion of PML, one could potentially run this test and elevated titers would predict an increasing risk of the occurrence of PML.

In summary, we have new prognostic factors that are emerging, and these may provide a more exact estimate of PML risk.

Turning now to alemtuzumab, a medication that is currently under FDA review and may be reaching clinical practice, we know that the main side effect of alemtuzumab is novel autoimmunity.19-22 That can present itself most frequently in the form of thyroid autoimmunity, but also immune thrombocytopenia and immune renal disease. Data presented at ECTRIMS showed that the presence of binding and inhibitory autoantibodies against alemtuzumab did not appear to have an effect on adverse events or efficacy measurement.23 So the idea would be that maybe patients with autoantibodies would have a higher risk of adverse effects, but it seems like that is not true.

Certainly also serum levels of IL-21 have been proposed as a marker that may help predict the development of autoimmune complications from alemtuzumab:24-26 The idea being that one would start alemtuzumab and monitor IL-21 levels as predictors potentially of patients who would go on to develop novel autoimmunity. So it is important going forward, as alemtuzumab makes its way into clinical practice, [and] given the very high proportion of novel autoimmunity, that clinicians have tools to help detect or at least help to prognosticate the presence of autoimmune events in a timely and cost efficient manner.

In summary, risk stratification is important, and tools to further stratify risk for specific therapies will be of growing importance in clinical practice. Ongoing research will help us identify and elect treatments that put patients at the lowest risk of adverse effects with a high potential for control of disease activity.

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  1. Miller A et al. 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis [ECTRIMS 2013]. Abstract 99.
  2. Leist TP et al. 65th American Academy of Neurology Annual Meeting [AAN 2013] Abstract P07.114.
  3. Havrdova E et al. ECTRIMS 2013. Poster P519.
  4. Lublin F et al. ECTRIMS 2013. Poster P524.
  5. Rudick R et al. ECTRIMS 2013. P593.
  6. Jokubaitis VG et al. ECTRIMS 2013. Abstract 59.
  7. MSBase Registry. Available at: Accessed November 13, 2013.
  8. Voldsgaard A et al. ECTRIMS 2013. Abstract 178.
  9. Spelman T et al. ECTRIMS 2013. Abstract 179.
  10. Cohen M et al. ECTRIMS 2013. Poster 623.
  11. Gold R et al. ECTRIMS 2013. Poster 538.
  12. Phillips JT et al. ECTRIMS 2013. Poster 996.
  13. Freedman MS et al. ECTRIMS 2013. Poster 544.
  14. Gorelik L et al. Ann Neurol. 2010:68:295-303.
  15. Sorenson P et al. Mult Scler. 2012;18:143-152.
  16. Plavina T et al. 27th Annual Meeting of the Consortium of Multiple Sclerosis Centers [CMSC 2013]. Poster DX51.
  17. Villar L et al. ECTRIMS 2013. Abstract 180.
  18. Warnke C et al. ECTRIMS 2013. Abstract 181.
  19. CAMMS223 Trial Investigators, Coles AJ et al. N Engl J Med. 2008;359:1786.
  20. Cohen JA et al. Lancet. 2012;380:1819.
  21. Coles AJ et al. Lancet. 2012;380:1829.
  22. Coles AJ et al. Neurology. 2012;78:1069.
  23. Ziemssen T et al. ECTRIMS 2013. Poster 523.
  24. Cossburn M et al. J Neurol Neurosurg Psychiatry. 2012;83:e1. doi:10.1136/jnnp-2011-301993.171.
  25. Costelloe L, Jones J, Coles A. Expert Rev Neurother. 2012;12:335-341. doi:10.1586/ern.12.5.

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Biogen Idec Novartis Pharmaceuticals Corporation

This activity is supported by educational grants from Biogen Idec and Novartis Pharmaceuticals Corporation.

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