Novel Oral Therapies for Multiple Sclerosis: The State of the Science

Course Director

Gary A. Thomas, MD

Gary A. Thomas, MD
Assistant Professor of Neurology
Penn State Milton S. Hershey Medical Center
Penn State College of Medicine
Hershey, Pennsylvania


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Part 2 of a 3-part series

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

Overview

The current trend in multiple sclerosis is to treat earlier and more aggressively. In addition to recently approved agents, a number of emerging therapies are being studied in an effort to add to the armamentarium. Understanding how and when to incorporate these agents into practice is critical to ensuring that patients derive the greatest benefit with minimal risk. In this activity, Dr. Gary Thomas provides clinical insights on recently approved and emerging therapies and explores their potential role in the management of patients with MS.


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Can oral therapies be used first line for patients with MS?

Dr. Thomas: The answer is, of course, yes. All three of the FDA-approved oral therapies—fingolimod, teriflunomide, and dimethyl fumarate [BG-12]—are approved as first-line therapies (Kappos L, et al. N Engl J Med. 2010;362:387‐401; Khatri B et al. Lancet Neurol. 2011;10:520. Cohen JA et al. N Engl J Med. 2010;362:402‐415).
           
Both doctors and patients are excited about oral therapies, because what patient wouldn’t want to take a pill rather than injection if they could? But they're also a little bit cautious because the clinical trials or precursor molecules to these oral therapies have had some side effect issues, or in some cases safety issues. A recent survey indicates 10% or 11% of respondents [neurologists] consider using oral therapies, and the doctors who are cautious—and I would put us in that category—we really spend a lot of time, when we talk to other doctors, trying to find out their experience with the oral therapies, to figure out if there are any safety or monitoring issues that we were not aware of.

Interestingly, patients will often come to us and [say] they're very interested in the oral therapies when they're announced and approved. You try to present the information from the package insert in a very clear, careful, unbiased way, and often you'll hear patients say, "That sounds really interesting. Maybe I'll wait six months and see how it does. Maybe I'll wait a year and see how it does." It gives them sort of a light at the end of the tunnel that one of the orals may be both effective and safe, but they would like somebody else to be the first one to try the medication. 

This may be because of our experience with natalizumab. Natalizumab is a strong medication to suppress MS exacerbations, but also had some serious infection issues that we weren't aware of at the time it was approved. The drug was pulled from the market and then reintroduced with a safety monitoring program. That really heightened the patients’ awareness that whenever a new drug comes out there could be safety issues.

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How should I select among oral therapies for my patients with MS? That is, are certain agents more suited to particular patients?

Dr. Thomas: That's a question that the neurology community has not completely figured out. The three oral agents each showed great efficacy against placebo; and in fact, each one, when compared in trials that included platform drugs, did very well—similar or even maybe slightly better than platform therapy against placebo.

These are excellent drugs, but each one also has some key side effects that are of concern. Fingolimod, the first drug that was approved more than two years ago now, turned out to be a very effective drug. The patients who take fingolimod are doing well and happy with the drug, but we have also learned about some infection issues and cardiac safety issues associated with fingolimod. So maybe it will be used more cautiously as a second-line agent, even though you're allowed to use it as a first-line agent (Gilenya [fingolimod]: Drug Safety Communication ‐ Safety Review of a Reported Death After the First Dose. Available at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm284355.htm; Gilenya risk evaluation and mitigation strategy [2010]. Available at: www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm227965.pdf).

Teriflunomide—it is pregnancy category X, it also has some GI side effects and hair loss side effects which could be concerning (Genzyme, a Sanofi company. Press Release, December 20, 2011. http://online.wsj.com/article/PR-CO-20111220-900070.html. Accessed January 8, 2013). [Also,] the precursor drug for teriflunomide, [leflunomide,] had some safety issues; that does not mean that teriflunomide will have those same safety issues, but it's something that neurologists are looking at to make sure they understand the drug and explain the drug to the patient before they just start the drug.

Finally, dimethyl fumarate has some longer-standing use in another country, for a different condition, and has some GI issues and some minor safety issues that patients and doctors are trying to weed through as well (Fox R et al. N Engl J Med. 2012;367:1087-1097; Gold R et al. N Engl J Med. 2012;367:1098-1107).

Narrator: In fact, there have been recent reports of PML cases in patients with psoriasis treated with dimethyl fumarate (van Oosten B et al. N Engl J Med. 2013;368:1658-1659). Although no cases have been seen to date in patients with MS, longer-term safety data may help elucidate the risk in this population.

Dr. Thomas: The one thing that we do tell patients is that the only drug available to treat MS that has a pregnancy category B is one of the injectables, glatiramer acetate. If pregnancy is an issue, maybe the oral class shouldn't be something that you go to right away.

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Where and how do oral therapies fit into the overall treatment paradigm for MS?

Dr. Thomas: I think this, again, is something that we're still trying to figure out. I think that if we consider injectable therapies as clearly first line and if we consider infusion therapy, such as natalizumab—and if it gets approved, alemtuzumab—as clearly second or third line, the orals will fit somewhere in between.

Two of these medications have come out within [the last] six months, and so we really don't have enough information to build an algorithm that is rational for exactly where they fit into the overall paradigm. A lot of doctors think, "Well, it doesn't hurt to see what happens in three months or six months or 10 months."  There is nothing to lose that way.

When a drug hits about 50,000 patient-years, then we feel like we're starting to see really what's going on. And so fingolimod actually hit over 50,000 [patient-years]; we do see there is some infection and some cardiac issues. It's maybe a small number, but we understand it better. The second drug, teriflunomide, has not hit 50,000 [patient-years] yet; dimethyl fumarate will hit 50,000 [patient-years] in about a year, and then we'll see. If one of the orals turns out to be very safe, it may move in the direction of the first line. If one of the orals tends to have severe or significant safety issues, it will move towards a third-line role.

As time goes on, the safety of these drugs will determine which one is first line, which one is second line, which one is third line. I don't think right now there is any consensus. If you put neurologists in a room together, you're still going to see a lot of people writing for injectable therapies for first line, and when you talk about oral medications, you're going to see the doctors well distributed among their experience—and their comfort—with each of the oral therapies. The thing that is exciting for neurologists and for patients is that there are treatments for MS that are working, and if one treatment isn't working, there are other options.

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New and Emerging Therapies for the Treatment of Multiple Sclerosis: What is Their Potential Role in Patient Management?

  1. Updates in Multiple Sclerosis: What Does the Future Hold for Injectable Therapies?
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