Switching Disease Modifying Therapies in MS Due to Breakthrough Disease Activity, Inadequate Response to Therapy

Continued relapse represents a critical unmet need in the MS treatment landscape. Jonathan E. Howard, MD, provides insight on predicting treatment failure and rationale for switching disease modifying therapies in patients with MS. Dr Howard is an associate professor of neurology and psychiatry at New York University Grossman School of Medicine and director of neurology service at Bellevue Hospital Center in New York, New York.

There have been recent observations made about treatment patterns and their effectiveness in reducing relapses in patients with MS.^1,2 Are there certain types of patients who are more likely to have a poor response to treatment or is the need to switch medication driven by the drugs themselves?

It is a combination of the 2 factors, because MS is a very heterogeneous disease. If a patient with aggressive disease is placed on a low-efficacy medication, then there is a high potential for breakthrough disease. A patient with mild disease who is placed on a high-efficacy medication may not have needed treatment or had relapses regardless of drug choices.

How do you determine if a breakthrough is sufficient to warrant switching therapies?

This is a determination that should be made based on the patient consultation and physician’s decision making. Also, identifying exactly what constitutes treatment breakthrough can be a bit of a gray area. NEDA has become the gold standard for treatment decisions. There is no exact rule for how many relapses or new MRI lesions over a certain period of time should be cause for switching therapies. If a patient has been on a stable medication for a decade and they have a relapse or a new magnetic resonance imaging (MRI) lesion, is that enough of a breakthrough to switch their current therapy? It depends. On the other hand, if a patient has 3 relapses in a year, switching therapies becomes a more obvious decision. Of course, the patient’s current medication also must be considered when determining whether switching would benefit the patient’s treatment.

Which therapies do you see currently being used in clinical practice for the treatment of MS?

All the available medications are still being used in the treatment of early MS, although the platform agents are probably not started as often in patients newly diagnosed with MS. The oral and infusion agents are used as second-line agents. I do not think anyone is going to start their patient on cladribine or alemtuzumab. Most of the other agents are used as first-line therapies. What you really need to consider when you make therapy decisions with the patient is whether you are more concerned about the medication or the disease. Obviously, the treatment decision is based on a multitude of factors, including patient consultation, their risk tolerance, and their preference for route of administration.

What are the some of the reasons that would necessitate switching from an anti-CD20 therapy to another agent?

There are very few issues that would require this change, which is why I think very few patients have switched from these medications. When I talk about most medications with patients, I say, “Here is the positive…, and here is the negative…,” but I do not have a ton of negative things to say about anti-CD20 therapies. Thus far, I have not had to switch a patient from an anti-CD20 therapy due to breakthrough disease.
 
With the anti-CD20 therapies, there is an increased risk of immunosuppression and certain infections. In addition, there are some observational studies suggesting that patients with COVID-19 tend to have worse outcomes while on these agents so these are certainly concerns to consider.³ It is important for patients with MS to be vaccinated against COVID-19 and other diseases such as shingles.

If a patient is receiving another class of medication, which factors might influence a switch to an anti-CD20 therapy? Would a patient newly diagnosed with MS automatically be put on an anti-CD20 therapy?

Patients newly diagnosed with MS would not necessarily be put on an anti-CD20 therapy. If a patient presents with mild disease — perhaps with optic neuritis and 1 or 2 lesions on a brain MRI that do not meet the formal diagnostic criteria for MS — then it would be reasonable to prioritize safety and tolerability over efficacy for the patient. If the patient wants to start on an oral or even an injectable agent based on the idea that the agent has been used for 20 years for hundreds of thousands of patients, then that would be a very reasonable place to start. Then, if they have breakthrough disease, there is room to further escalate therapy.
 
With the anti-B-cell medications, there have not been many head-to-head studies, certainly not comparing them to some of the more effective oral therapies or other monoclonal antibodies. So while we have a sense of which therapies may be more effective, this understanding is not driven by science. Without being able to point to head-to-head studies, you really can’t state with absolute certainty that one medication is more effective over another.

What other factors should be considered before switching?

There are several factors to consider, including the patient’s current medication. If a patient with MS is on a low-efficacy medication and they experience a relapse, I would have a low threshold for switching. In this case, I don’t see what the disadvantage would be, given that I think the anti-B-cell medications have pretty good safety and tolerability profiles. 
 
Another area to consider would be MRI lesions. If a patient is feeling fine but their MRI shows a new lesion, many physicians might consider switching at this point. However, a new lesion can mean a lot of things. It can be just a tiny dot on an MRI or it can be a big, active, enhancing lesion that happens to be in what we call an “ineloquent cortex,” so the patient does not feel it.
 
Even the phrase “new lesion” has some variability to it, making the decision to switch more difficult. If the concern is that the patient is eventually going to have a lesion in a spot that they feel or that the lesions could cause problems down the line in terms of cognitive problems or fatigue, then why not make the switch if you have a safe and effective higher efficacy medication?

The modified Rio score defines treatment failure as “the presence of a 1 point increase in EDSS [Expanded Disability Status Scale], 2 clinical attacks, 1 clinical attack and progression, 1 clinical attack and new lesion on MRI except associated with an attack, or new lesion in 2 different MRIs taken at least 3 months apart.“⁴ Do you find this to be a useful measure?

Yes and some physicians use the modified Rio score to evaluate treatment failure but when you are sitting in front of a patient, it really becomes an individual decision. While I think that most physicians would suggest a change in treatment if there were an increase in the modified Rio score, it depends on which medication the patient is currently taking and how comfortable the patient is with changing therapies.

There is a 2020 paper by Kantor et al² that looked at treatment patterns and suggested that among those taking oral medications, patients who were previously treatment-naive experienced less relapses. What is the significance of this outcome?

It shows that oral therapies can be more effective than injectable medications at reducing relapses and that patients are more likely to adhere to oral therapies. Therefore, if a patient has signs of aggressive disease, avoiding the platform injectable medications should be considered.
 
Another reason to switch from injectable medications is tolerability. Patients may have flu-like symptoms following injection or experience needle fatigue or needle phobia, and these are all very good reasons to switch.  The same is true of stomach upset with the fumarate medications. A rule of medication is that the medication should not cause more problems than it solves. I have had patients who take interferons on a Friday and spend all day Saturday in bed feeling like they have the flu. That does not make any sense to me. Some of the fumarate medications can cause flushing, stomach upset, and, while it does not happen a lot, infusion reactions.
 
Also, a patient may be switched from injectable medications due to safety concerns. For example, in patients taking natalizumab, there is the risk of developing progressive multifocal leukoencephalopathy. If a patient converts from John Cunningham virus-negative to John Cunningham virus-positive, this is a development for which a physician would consider switching medication.

Is there an emerging strategy for switching medications or is it something that is based on patient comfort?

It is probably based more on patient comfort, although I do think a lot of physicians aim for NEDA and may be intolerant of new lesions and relapses. Given the availability of higher efficacy drugs, it is hard to argue against switching in some cases. However, when you envision a scenario in which a patient has been on one of the platform agents for a decade and they develop a new lesion for the first time, you have to question whether that is reason enough to switch — probably not. I think that with most patients, you should try to achieve NEDA. It is a high bar, but one we should aim for.

Are there any problems with transitioning from one therapy to another?

For the most part, there is not. Some of these drugs can have rebound effects, especially the S1P1 inhibitors or natalizumab. If a patient stops the medication abruptly, they are at risk for rebound shortly thereafter. I think this shows that patients who are switching from S1P1 inhibitors or natalizumab to another medication should start the new medication as soon as possible without a wash-out period.

Is there an emerging strategy for choosing the next therapy? Is an oral or injectable medication preferred when selecting the a new therapeutic option?

If you are switching for efficacy, then you would want to pick a higher efficacy agent. It does not make a lot of sense to go from one S1P1 inhibitor to another S1P1 inhibitor or from dimethyl fumarate to diroximel fumarate because you are making a lateral switch. Even making a switch from dimethyl fumarate to fingolimod or from fingolimod to dimethyl fumarate does not make sense to me. You would want to pick a higher, more powerful agent. If you are switching the medication for tolerability reasons, then all other agents would be on the table. Oral agents might also be considered.

Do you see any impact on the patient from switching therapies one or more times? Does it affect their confidence in the treatments?

Whenever you must switch MS medications, it is because treatment has not gone as planned so while it is not ideal, it is also not something to catastrophize. I tell patients who were newly diagnosed with MS that it is easy to switch most medications, especially at the start of treatment. Of course, if someone has cycled through 3 or 4 medications and has experienced relapse on them all, then the relentless progression despite treatment can be upsetting to patients. In these situations, the physician might advise the patient that successful treatment is likely achievable with the high-efficacy drugs available.