Cases in Point: Incorporating Novel Therapies for MS into Practice

Course Director

Aaron Boster, MD

Aaron Boster, MD
The Ohio State University Multiple Sclerosis Center
The Ohio State University Medical Center
Columbus, Ohio


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Part 2 of a 2-part series

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

Overview

Successful management of multiple sclerosis (MS) has changed dramatically and rapidly in the past several years. The availability of oral therapies has greatly increased the range of effective treatment options, but may raise questions regarding how and when to incorporate these agents into practice. In addition to questions about the safety and efficacy of oral therapies, clinicians may have questions about how to sequence therapy, and how to create individualized regimens that address specific patient situations. In this activity, Dr. Aaron Boster answers some of these key questions and offers practical insights into individualizing therapy with new agents in patients with MS.


Disclosures

This activity is supported by educational grants from Teva CNS and Genzyme, a Sanofi Company.

Course Director
Aaron Boster, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Biogen Idec; EMD Serono, Inc.; Genentech, Inc.; Medtronic, Inc.; Novartis Corporation; and Teva Neuroscience, Inc.
Grant/Research Support from Actelion Pharmaceuticals US, Inc.; Biogen Idec; CNS Therapeutics, Inc.; DioGenix Inc.; EMD Serono, Inc.; Hoffmann-La Roche Inc.; Jazz Pharmaceuticals; Novartis Corporation; and Sun Pharmaceutical Industries Limited.
Medical Director
Annette Wiggins
Answers in CME, Inc.
Annette Wiggins 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 are the recommendations for managing the patient who is symptomatically stable but has a worsening MRI?

Dr. Boster: The way that I would consider a surveillance MRI scan is to look for asymptomatic disease activity. Imagine a patient who is clinically doing well; they're not having any MS attacks. When you examine them, their exam is stable in that it hasn't changed from the last time you saw them. Then you get an MRI scan and you find that they have four new T2 hyperintense lesions that they didn't have just a year ago. So you have this clinical/radiographic paradox where the patient's clinical presentation and their MRI don't match.

Dr. Rick Rudick demonstrated that, on interferon therapy, if you develop three or more new spots in the first two years, you prognostically are not going to do well on an interferon.1 That is terribly useful information for managing patients on interferon.  Unfortunately, we don't have that same kind of data for all the different drugs. 

The way that I have come to think of it is as follows: If you're on a given therapy, I will give you two strikes before I'm going to want to switch your therapy. Those two strikes can come one of three ways: Either you have clear, clinical disease activity, like an MS relapse—and you have to ask yourself, what is the annualized relapse rate of that drug? If we take an interferon or glatiramer for example, statistically we can expect to see an attack once every three years. If you have one attack, I can't tell you ”you've failed a therapy,” because maybe you won't have another attack for three years. If, however, a year later or two years later you have a second attack, your attack frequency is now inappropriate and I would consider switching their therapy.

An alternate way of hitting a strike is to have sustained disability on your examination. If you developed a limp and three months later when I see you in followup your limp is still there, you've accrued disability and that's a strike against you. A third way is to show progression on the MRI. The easiest thing to look for, in my opinion, is the development of new T2 hyperintense lesions or bright spots.

If you have MRI activity, with let's say four new T2 hyperintense lesions, I'm putting your disease-modifying therapy on warning. I will likely consider another MRI in six months to a year. But if I get another MRI at six months or 12 months and I see, again, new T2 hyperintense lesions developing, I’m now concerned and I will change your therapy. Alternatively, if you have an MRI that shows new spots and you have another attack or you accrue disability, you've had two strikes and I change you. Now this is a style of disease management which has been put forth in an algorithm by Dr. Rίo and this has been published.2

I will add a few things which have less data to support their use. T1 hypointensities, or black holes, correlate with disability as well.3 I like to look at the T1 to T2 ratio. I would like the ratio of bright spots to dark spots to be 10:1 or no more than 10:2. If I'm seeing that almost half or more of your bright spots are accompanied by an associated dark spot, I'm concerned that things aren't going well. Now I don't have data to tell me to switch this drug. Yet I'm personally going to use this as a strike against the drug.

Similarly, we know that atrophy is accelerated in the MS patient and we know that the drugs that have been FDA approved largely show slowing down of atrophy. Ideally, I would like to be able to easily measure atrophy in my clinic and I would like to change a drug when I see it, although I don't have those tools at my disposal at present.

One other thing: Maybe the single-most easy marker in MS is a contrast-enhancing lesion. Unfortunately, a lot of clinicians, when they see an enhancing lesion, they are driven to switch [therapy]. When I look at the meta-analysis by Dr. Kappos, I'm struck that a single enhancing lesion does not necessarily suggest a treatment failure or disability progression equivocally.4 So, I would not make a switch on a patient's drug based on the presence of enhancement on one single scan.

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What are treatment options for a young woman with high frequency of relapses? She has progressed on interferon, experienced relapses on glatiramer acetate, and had an allergic reaction to natalizumab. She is of childbearing age with child wish but not immediately.

Dr. Boster: So when we think about options, we may think about oral agents such as fingolimod, dimethyl fumarate, and teriflunomide. Fingolimod has been demonstrated in a post hoc analysis of the FREEDOMS trial to show efficacy in patients with frequent relapses and patients that have failed other therapies.5 The efficacy may not be as robust as in treatment-naïve patients, but it has been shown to work. And so fingolimod is an option that I would consider. The fact that the woman wants to become pregnant at some point in time is a factor and we would have to reiterate the importance of appropriate birth control measures, and at least in our clinic, we want the patient to be off fingolimod for a period of no less than three months prior to attempts at conception.

Another oral possibility might be dimethyl fumarate. Dimethyl fumarate has evidence for its use in relapsing MS based on the CONFIRM and the DEFINE trials,6,7 although at least to my knowledge, I'm unaware of a sensitivity analysis that suggests robust response in patients that have failed multiple drugs. It might be a consideration, and as with any drug you're going to have to survey her very carefully. The pregnancy issues are really the same that you have to have that conversation about the importance of adequate contraception.

A third option might be teriflunomide. Teriflunomide has been shown to be non-inferior to interferons, and one could argue if they didn't respond to an interferon then maybe you could consider teriflunomide. The effect size on teriflunomide may be a bit modest. I don't feel like I have excellent sensitivity analyses to suggest that patients who have broken through other medicines and patients that have ongoing relapses would do better on teriflunomide as compared to some other drug. In my personal practice, I would probably consider the therapies in the order that I described them.

The stakes are very high in this patient. Almost any MS clinical trial that you look at makes a point that patients that were not on therapy or patients that didn't respond to therapy and later were switched to something that works for them have accrued disability that they never regained. So this is a patient that deserves a tremendous effort and, at our clinic, someone that we might be very aggressive with, in terms of trying to get their disease to calm down. And so I still would like to set the bar at no disease activity. Now I may fail in my attempts, but that's what I'm shooting for.

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What is the best way to manage patients with JC [John Cunningham] virus (JCV)? Are oral therapies considered a safe option for these patients?

Dr. Boster: In my clinical practice, [in] every relapsing MS patient, we check the JCV antibody status.  And the reason is—when considering the ordering of medicines— we have to consider if the medicine I'm about to put you on doesn't work, what is my next plan?

We know that a patient who has prior immunosuppression has an increased risk factor for the development of PML, if they go on to natalizumab.8 JCV positivity is another risk factor. So knowing this upfront may factor into our decision-making for what we place the person on before natalizumab, or even if we use natalizumab first line.

There is an argument to be made that natalizumab can be used first line. Supportive evidence includes the fact that it was tested first line: 90% of all the patients in the AFFIRM trial were treatment-naïve.9 It is FDA-approved to be used first line, although it's not recommended.

In the JCV antibody-negative patient, the safety profile is rather favorable. The antibody-positive patient, that's a different patient.8 There is now an opportunity with the second-generation JCV antibody assay to obtain an optical density which will tell you whether they have a high positive or low positive. If the patient has never seen prior immunosuppression, you can use this information to help further stratify their risk for PML. A JCV antibody-high-positive patient, in my opinion, is someone that I'm less likely to put on natalizumab, and if I do, it would be for a very truncated period of time.10

A JCV low-positive patient is someone that I would still consider putting on natalizumab, although I would survey them with frequent MRIs, to look for asymptomatic PML.

Now a patient who is JCV antibody-negative that's put on natalizumab has a risk of conversion from antibody-negative to -positive. The party line is that that risk is about 2.5% a year.11-13 Because of the potential risk for PML, our negative patients are screened rather frequently: two- if not four-times annually. The reason is I'm disinclined to infuse a patient who has recently converted from antibody-negative to -positive without first sitting down and talking to them about the risk factors.

Are oral therapies considered a safe option in JCV antibody-positive patients? In my opinion, yes, they are. There has been one case of a patient who was on natalizumab and then later switched to fingolimod and subsequently was diagnosed with PML. I think there is ample evidence that they had PML at the time they were on natalizumab.

Similarly, the parent compound from which dimethyl fumarate was essentially fashioned after, has been used in disease states that are associated with PML. There have been four reported cases of patients that were receiving the parent compound, and who developed PML. Although in all of those cases, they were either on concomitant immunosuppressives or had been exposed to drugs which are known to cause PML before this, or had disease states that can cause PML.

The third oral, teriflunomide—as far as whether or not it's a safe option, we have to borrow data from the parent compound. I am unaware of any cases of PML associated with teriflunomide. I wouldn't consider [it] a hard “No” in placing a patient who was JCV antibody-positive on teriflunomide.

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References

  1. Rudick RA et al. N Engl J Med. 2006;354:911-923. 
  2. Rίo J et al. Curr Opin Neurol. 2011;24:230-237.
  3. Sinnecker T et al. Arch Neurol. 2012;69:739-745.
  4. Kappos L et al. Lancet. 1999;353:964-969.
  5. Devonshire V et al. Lancet Neurol. 2012;11:420-428.
  6. Gold R et al. N Engl J Med. 2012;367:1098-1107.
  7. Fox RJ et al. N Engl J Med. 2012;367:1087-1097
  8. Bloomgren G et al. N Engl J Med. 2012;366:1870-1880.
  9. Polman CH et al. N Engl J Med. 2006;354:899-910.
  10. Plavina T et al. 5th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis (CMSC-ACTRIMS 2013). Abstract DX51.
  11. Lee P et al. 22nd Meeting of the European Neurological Society (ENS 2012). Poster P467.
  12. Gorelik L et al. Ann Neurol. 2010;68:295-303.
  13. Bozic C et al. Ann Neurol. 2011;70:742-750.

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Teva CNS Genzyme, a Sanofi Company

This activity is supported by educational grants from Teva CNS and Genzyme, a Sanofi Company.

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