Saunders Family Professor of Neurology, and director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine, Mount Sinai

Fred D. Lublin, MD

Let’s look to the future. I’m going to kick this off, as to what we would like, and I think Gavin’s comment gave me the lead-in to this. That is to find markers of individual response because all of the agents we talked about worked. Each one got approved because there was a population of patients who did well on it and continue to do well on it. What we need is individual biomarkers, individual measures of response, and it may be something like neurofilament light, or it may be something else. We shouldn’t do more frequent MRIs because I don’t think that’s practical, but something liquid certainly would help that. Also, this idea of looking at when to do individual dosing decisions. 

We’ve had 2 different conversations about anti-CD20 [monoclonal antibodies]. Gavin said maybe we can wait until B cells start to come back, or more importantly, when memory B cells start to come back, because having naive B cells come back may be a good thing rather than a bad thing. But on the other hand, you also mentioned that maybe we’re not dosing enough. We’re taking the patient down to 0 in terms of the periphery, but maybe there’s more important dosing going on, maybe within the central nervous system, which you alluded to Gavin. Although, trying to treat directly within the central nervous system with anti-CD20 agent rituximab wasn’t a very effective strategy. I think the future, to me, is looking at what we can do individually with our patients to better rationalize our therapies. Now I’ll throw it around to each of you. Let me turn it to you, Lauren. What do you see for the future?

: I agree. I think we’ll continue with individualized therapy plans for patients, and hopefully get better clinical- and research-based data points to guide us toward sequencing drugs better. I think one of the big questions that Gavin has brought up several times is, what do we do about all of the people who we started on ocrelizumab? We’re reaching the 5-year mark of it being FDA approved. At the 5-year point, do we de-escalate? How do we consider the long-term infection, and eventually, malignancy concerns? That’s something I’m looking forward to and am starting to precounsel patients about.

: I agree with Dr Gluck. I don’t have anything further to add.

: Yes, I think we need to do an induction maintenance trial. Fred, I would love to discuss trial design there because it’s quite complicated. It’s not easy to work out how to assess maintenance therapy after saying anti-CD20 therapy is effective or not. I think we’re going to have to go into that smoldering MS [multiple sclerosis] component, so this would be add-on treatments. What can we add to an existing platform, bottom of the pyramid, anti-inflammatory medication to protect damaged axons from dying, to remyelinate them, to promote repair? That’s the sandwich we have to build up, and it’s going to be a nightmare in terms of trial design. That’s where our big challenge is. Then you alluded to it, those other things. One of the components of progressive MS is premature aging. How do we push back aging mechanisms to optimize the brain health of our patients when they get older? Is there anything we can do? One of the things I’ve begun to realize, which we haven’t discussed, is the elephant in the room: poor sleep. Our patients with MS have a whole lot of reasons why they don’t sleep properly…. We don’t address the sleep disorders in our patients with MS. It’s looking after all the small, little things, they all add up. This is what I call a minimal gains hypothesis. If we can focus on those little things that make MS worse, overall they’ll add up, and we can hopefully make a big difference for our patients. There’s a lot of work to still be done.

Yes, especially in progressive disease. Ravi, this is important. Advice for community physicians?

: I think if I had to give 1 piece of advice to community physicians, it would be that we now have upward of 20 different DMTs [disease-modifying therapies] on the market, and rather than getting overwhelmed, the key is to be aware of the key classes and familiarize yourself with, perhaps, only 1 or 2 of each. Know those, let’s say 4 or 5 drugs, well and don’t get bogged down by choosing from 20. Also, don’t forget about resources. I often will get second opinions in particularly difficult cases.

Well, this has been a great discussion, and I thank you Dr Gluck, Dr Dukkipati, and Dr Giovannoni for your contributions. I’ve enjoyed listening to your views.

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Videos

Key opinion leaders in multiple sclerosis (MS) discuss the future of relapsing MS management and unmet needs.  

Future of Relapsing MS Management 

Let’s look ahead a bit. Gavin, I want you to take the lead on this. We mentioned biomarkers a little, at least neurofilament light, but where do you think we’re going with biomarkers?

 I don’t think there’s any 1 biomarker that’s going to take the storm and that’s going to be it. They all add to the picture. We’ve been using CSF [cerebrospinal fluid] neurofilament as an activity marker for about…5 years in our practice. We find it very helpful in terms of not being sure if somebody has ongoing activity, and if the patient has raised neurofilament levels, that gives us some confidence. About 1 in every 10 patients will have raised neurofilament levels and the MRI will be inactive, and they wouldn’t have had obvious relapses or pseudo relapses. It helps sort out pseudo relapses from true relapses. So yes, I think it’s going to be incorporated into clinical practice, but it’s unlikely that it will be used in isolation. It’s going to have to be combined with all the other things we measure. And what’s going to be more valuable is not just 1 measurement, but a trajectory of measurements, to see what happens over time with the neurofilament levels. It’s going to come. The data are overwhelming. It’s a good prognostic marker, and it’s a response marker, but I think overall, it’s looking more like an inflammatory activity marker than a neurodegenerative marker.

 That’s the disappointing aspect, I think, of neurofilament because if you think about its measure of axonal damage, we would have hoped it would be a better marker of neurodegeneration. It’s the opposite, just what you said, it’s a very good predictor of inflammatory activity, on the order of close to MRI. In fact, combining the 2 is a very good way of looking for activity. But in and of itself, I find that a little disappointing in neurofilament.

I think the problem is, we don’t know enough about the peripheral metabolism of neurofilament, but I suspect it’s cleared quite rapidly. I think in the more advanced, progressive, smoldering phases of the disease, the dropout rate is so slow that you’re not going to be picking up raised levels.

 Any other fluid biomarkers that have grabbed your attention?

Yes, this is not in clinical practice, but I think we’re going to have to at some stage target those intrathecal B and plasma cells. I think the intrathecal B cell and plasma cell response is driving some of the progressive component of the disease. We’re going to have to start in the future to clear the CSF of oligoclonal bands and drop the free light chain levels. That’s a biomarker for a specific therapeutic target. There’s nothing in the periphery; you may say GFAP [glial fibrillary acidic protein], but I’m not sure how much that’s going to add to neurofilament in terms of monitoring. So nothing stands out as a prognostic or a treatment response marker. I think in terms of when to retreat, that’s a different story. You alluded to the concept that maybe we’re overtreating with anti-CD20 [monoclonal antibody] therapies and we should only redose when B-cell reconstitution occurs, but that’s a different question. That’s about optimizing the dosing frequency of anti-CD20 therapies, and that’s going to require a lot of work. I don’t think B cells are enough. We may have to look at memory B cells or subpopulations of memory B cells, for example.

 And maybe T regs [regulatory T cells]. Ravi or Lauren, any thoughts about biomarkers?

I don’t have any additional thoughts. I think it’s a matter of establishing more data sets for neurofilaments, for example, and making them more adaptable to day-to-day practice, as an added way to monitor how patients are doing. The goal is to have reliable markers that we can institute early to ensure that our patients are responding to therapy.

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Expert neurologists discuss current and future biomarkers relevant to relapsing multiple sclerosis including cerebrospinal fluid neurofilament.  

Biomarkers for Monitoring Treatment Response in Relapsing MS 

“There are many different topics that we’re going to cover on the future of neurology, and it’s important to remember that neurology has entered, and is expanding into, a golden era of treatment options.”

International Congress on the Future of Neurology

 coming up on September 17-18, in New York City, one of the chairs of the meeting, Fred Lublin, MD, Saunders Family professor of neurology, and director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, spoke with 

 on the topics to be discussed within all areas of neurology, including his specialty, multiple sclerosis (MS).

Lublin will be moderating the MS portion of the conference on Saturday, September 18, where experts will discuss newer MS therapeutics, gaps in care of relapsing-remitting and progressive MS, and symptomatic therapies. He noted particular excitement for the Medical Crossfire debate, where he and panelists Patricia Coyle, MD, director, MS Comprehensive Care Center, Stony Brook Neurosciences Institute; and Stephen Krieger, MD, professor of neurology, , Corinne Goldsmith Dickinson Center for MS, Mount Sinai Medical Center, will discuss starting MS therapy with only highly active agents versus starting with the full array of agents.

IFN 2021 will discuss the most recent advancements in neurology across different lines of care, and Lublin noted that the program would be beneficial for clinicians, practitioners, residents, and fellows, especially those anticipating taking their neurology boards. Attendees can opt to see discussions live at the InterContinental New York Barclay, or tune in virtually, thanks to the event’s hybrid, interactive design.

. For more information and to register for the meeting, 

The director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center spoke on what he is looking forward to at the 2021 International Congress on the Future of Neurology.  

Exciting Multiple Sclerosis Debates at IFN 2021: Fred Lublin, MD

 I want to get into a very important area that Ravi’s going to take the lead on, and that’s shared decision-making.

We touched on this earlier, but shared decision-making is imperative in terms of ensuring patient compliance and adherence. I think our role, as neurologists, isn’t only to provide the most objective information for patients to have, but to direct them to safe treatment options, let’s say, rather than Dr Google or internet chat rooms. But there’s no question that if patients have a clear understanding of their disease, their potential prognosis, the risks and benefits of each choice, they’re more likely to stay on therapy or to be compliant with monitoring requirements. There’s a spillover effect. If they’re engaged with their disease and treatment plan, they are more likely to embrace other treatment options: diet, exercise, and such. There’s no question that we have to incorporate shared decision-making into our practice, and not be too archaic in our approach, throwing a drug at a patient and saying, “This is what I’ve chosen for you.” That’s an extreme. But the other thing that we should shy away from is handing patients 8 booklets and saying, “Read these over call me back in a week,” or, “Call my nurse in a week.” That isn’t of service to a patient. That’s overwhelming and breaks the fundamentals of treating and individualizing treating a patient.

 We can’t minimize this, especially now, with so many agents to inform patients of and to have them engaged. Lauren, tell us a bit about your experience with this.

I agree with everything Dr Dukkipati said. I often say that I can prescribe anything to a patient that I want to, but at the end of the day, they have to take it. So, if they don’t trust what I’m saying, if they don’t believe the reason for me prescribing or recommending certain medications, they’re not going to take my recommendation and they’re not going to do well. I try to understand where they’re coming from, their level of medical understanding, and their willingness to accept different risks. Whether it’s the patient who, if there’s any chance their MS [multiple sclerosis] could get worse at all, they won’t be able to tolerate it, and they want the strongest, most effective medicine, or the patient who can’t accept any risk of a small adverse effect to a drug. We discuss different options for safer DMTs [disease-modifying therapies], but yes, it’s definitely about talking to the patient, understanding their values, and understanding what their life plan is.

Yes. I’ve moved away from this term “patient decision-making” to “guided decision-making” because we’re the experts, and we have so much more understanding. I try to steer the patient down to 1 or 2 choices. I also give them, Ravi, the option of them throwing it back and saying, “You make the decision for me,” because that’s a choice. Paternalistic medicine is a choice. Some people don’t want to be involved. It causes great anxiety, they get panic attacks trying to decide. They just can’t decide between drug X and drug Y. I remember with one of my highly active patients, I caused her almost to have a psychiatric breakdown because I told her she had to choose between alemtuzumab and natalizumab. This was about 4 or 5 years ago, and she was a nurse. I thought she had a lot of insight, and when I phoned her up, she was so relieved that I took the decision away from her. I think we have to identify that some patients don’t have the right makeup to make decisions, and we have to make those decisions for them.

Yes, you bring up a good point, Gavin. I would call it guided decision-making. I typically will educate a patient about 1 or 2 options, and ultimately, allow them to decide whether they would like to move forward.

 Part of the art of medicine is being able to read your patient and meet their needs. There are some people who are very engaged, who say, “Listen, I want to be heavily involved in what I put in my body.” And others are quite the opposite, saying, “This is why I came to you. Tell me what’s the best possibility.” But you still need to consider that there are a number of different choices. This gets into something I wanted to discuss briefly, and that is lifestyle issues because it’s part of the counseling we do with people, things like smoking and weight control. I’d also say diet, but given that we don’t have any good data yet on diet, it’s more a matter of debunking myths. Also comorbidities, which are becoming more important. We’ve alluded to the issues of the older patient with MS and some of the consequences of the medications, but part of those consequences relate to the comorbidities that come with older age that appear to have adverse effects on the underlying MS. Thoughts?

Yes, those are some of the most important things, especially once you have the DMT talk with patients that there are very few modifiable risk factors in multiple sclerosis. The biggest one, arguably, is smoking. If you have a patient who smokes, tell them the data behind the relationship between smoking and MS, and why the risk of increased relapse burden in smokers is so important. Encourage them to get to a place where they’re ready to quit smoking. Get their family involved in it as well. With nutrition, there is a lot of debunking. I tell patients, “You could go on the internet and find a lot of radical ideas. If you think it will benefit your life, go for it. But ultimately, by being at a healthier body weight, and potentially being on a heart-healthy type of diet, the rest of your body will be healthier. Your brain will likely be healthier, and try to control for obesity, which is a baseline inflammatory state.” I think all of those are very important. We talk a lot about vitamin D. There are some data that suggest it improves inflammation in the brain, but at the very least, vitamin D improves mood, energy, and bone health. Especially where I’m located, in New York, no one gets enough sunlight to utilize vitamin D properly, so we should all be supplementing.

A panel of experts emphasize the importance of shared decision making in relapsing multiple sclerosis and discuss lifestyle choices that impact the disease.   

Shared Decision Making and Lifestyle Issues in Relapsing MS 

Gavin, take us through sequencing. We have all these agents, and we talked about the various agents. What do we do next?

 I don’t think there’s any reason why you can’t sequence in any order, so I don’t think starting DMT [disease-modifying therapy] X precludes any other DMT, and vice versa. All you have to do is apply the baseline screening for those DMTs, so sequencing can be driven by tolerance issues or adverse events, be it liver function tests, but that’s a different story to efficacy sequencing. There are different types of efficacy sequencing. There’s upward or downward efficiency sequencing. The reason I say that is, obviously, if you have breakthrough activity and the drug has failed you, you need to move up.

I tend to not move sideways, but to move up in efficacy class, so we go from say the platforms to the intermediate to the high- efficacy treatments. What I find difficult is when you’re at the top end and you’ve gotten breakthrough activity, where do you go? My threshold for shifting there is a little higher, simply because of the question, where do you go? Obviously, for the derisking strategy, let’s give the typical example of PML [progressive multifocal leukoencephalopathy] risk on natalizumab. We would do sequencing there to derisk the patient, in other words, we would try to lower the risk of PML. That is a whole story of its own; how do you derisk a patient? How do you switch from natalizumab to prevent rebound? Which agents do you go to? We have quite a big protocol. We’ve almost completely shifted to anti-CD20 monoclonal antibodies post-natalizumab. We used to go to fingolimod, but now we’re going to ocrelizumab in almost all of our patients. I’ve had a few patients where we’ve moved on to cladribine, and even a few on to alemtuzumab.

You have to be extremely careful when you move to a depleter agent because if you get carry-over PML, then you have a problem because the patients are immunosuppressed by the depletion cycle, and they need their immune systems to recover from PML. We have a very strict protocol to make sure there isn’t any PML, or asymptomatic PML, before switching medications. But Fred, you wanted me to summarize. I think the other message people need to appreciate is that you have to have a lot of detailed information and knowledge about each DMT when you do sequencing because some of the issues around specific sequencing, let’s give you an example. Moving from fingolimod to cladribine, for example, you have to wash a drug out, and not everybody reconstitutes their lymphocyte counts quickly enough. 

We, in our center ,Blizard Institute, Barts and The London School of Medicine and Dentistry, measure the lymphocyte counts weekly, and when they get above 800 per μL, we dose the patient with cladribine. The reason we don’t want to wait until they get above 1 1000/μL, which is on the label, is because you go into that period where you get rebound. You don’t want to have them uncovered, so this is why the issues around sequencing are quite complex and not easy to get across in a 2-minute or 3-minute discussion. I don’t know if Ravi or Lauren have any comments about specific sequencing.

I don’t have anything to add. I think mechanism of action is very important and needs to be taken into account with the considerations of sequencing.

 We’ve had a concern about anti-CD20s and S1Ps [sphingosine-1-phosphate receptors] as well, at least the longer-acting ones, as to whether we might miss the B cells that are sequestered. In practice, we haven’t seen it, checking B-cell counts moving forward, but it is something that needs to be explored more carefully when you switch from one to the other. But one of the other issues that I personally have is that we don’t have good data to define inadequate response. Our goal, our aspiration for any therapy, is neither—no activity whatsoever, no relapses—nothing new in the MRI. It’s a nice aspiration to have, but it’s not the reality of any of our agents, at least early on. How much activity is acceptable and how much says, “No, you need to switch?” At what time point? For example, we do a baseline MRI on all of our patients when we start them on therapy at 3 months. Some people prefer 6 months, but we give the drug at least 3 months to kick in because, I think, that holds for almost all of the agents. We use that moving forward, but even when you move forward, is 1 new MRI lesion per year a reason to switch, or 2? If it were 10, you probably would, but where do you slice it? Thoughts?

 Yes, that’s a very good point, Dr Lublin, and I think clinical trials have rigidly defined parameters, but real-world practices are just that. How many lesions are too many, and how many new symptoms are too many? I think we have to find the balance between switching too prematurely vs waiting too long. To follow up on what Dr Gluck mentioned earlier, in addition to required laboratory monitoring, we see our patients 2 to 3 times per year for follow-up, and more often if they’re having active symptoms. Imaging is a fluid thing in real practice. We image, on average, every year, but sometimes we’ll go longer if a patient is doing well. But we emphasize the importance of periodic surveillance imaging to screen for breakthrough radiographic activity.

Fred, one of the things we’re seeing now, and you must have the same issue, is that you have people who have been stable, without relapses or MRI activity, for several years on fingolimod or any DMT, and then they start coming to you with worsening disability. I would call this a delayed, smoldering component of the disease. But I’m not sure if the drug is failing those people because it’s keeping the relapses and the focal MRI activity away. What’s driving that worsening is probably the processes that our therapies aren’t targeting, and I feel very uncomfortable switching those patients to other anti-inflammatory DMTs because I don’t think it makes a difference in those patients. I don’t know what your opinion is about those. My clinic is now full of these patients who I call, “NEIDA”—no evidence of inflammatory disease activity—but they are getting worse.

Yes, this is a new issue. It’s brought up by this concept of progression independent of relapse activity, which is secondary progressive MS [multiple sclerosis], and how best to deal with that.

Experts in multiple sclerosis (MS) discuss key factors involved in the sequencing of therapies for relapsing MS.   

Sequencing Therapies in Relapsing MS 

 Let’s move onto a new section: sequencing therapies. What we want to discuss is monitoring the patient response to the initial therapy. When do you think it’s time to switch? This is going to be opinion-based discussion because there aren’t a lot of data to support this. Let’s talk about this, monitoring once you’ve started someone on treatment. Lauren, why don’t you kick this off, and then we’ll let Gavin talk about sequencing. But just in your practice.

 Sorry. In terms of monitoring, or in terms of…?

Yes, monitoring once you start treatment.

All of the different drugs come with many different monitoring guidelines. That’s something that you have to be very up front with the patients about. For example, there’s the screening ahead of time, you should be able to say, “I’m drawing blood from you today.” And with things like S1Ps [sphingosine-1-phosphates], “you have to do this as a kind of cost-sharing.” That’s what monitoring requires as well. From from the most benign end, something like glatiramer doesn’t have any actual guidelines to monitor anything, but there are rare cases of hepatotoxicity, so it’s not unreasonable to check liver tests, and CBC [complete blood count] once in a while, in a year or 2 years. With interferons, obviously, you have to check other blood tests, but this carries over to different drugs. 

As I’m speaking, I think a lot of our discussion is guiding me toward what sort of things I monitor to see the drug’s effectiveness, and that is a clinical examination, listening to the patient’s history. When we talk about EDSS [Expanded Disability Status Scale], we look at the patient in the office, and particularly, their walking. MRIs are very useful. Clinically and commercially, we have lower-grade MRIs so we can count the number of T2 chronic lesions, if any have developed in interval periods. We look at new contrast-enhancing lesions, particularly for patients who are newly starting medications within 6 months, and a year later. There are different software programs we can use to estimate whole brain volume that can be useful too. All of those things can be taken into account, in addition to some not immediately neurology-focused things—like sending patients to our ophthalmology colleagues for OCTs [optical coherence tomography images], which measure retinal fiber layer thickness to see if there’s any subclinical change in the optic nerves. We can send them to our neuropsychology colleagues. There are even neuropsychology batteries available commercially through tablets, through computer technology, that can estimate the cognitive side of things, which can sometimes be overlooked.

Lauren Gluck, MD discusses considerations for monitoring response to treatment in relapsing multiple sclerosis.  

Monitoring Outcomes in Relapsing MS 

Let’s move along. The next agent I want to briefly discuss is teriflunomide, which a little like cladribine, is relatively selective for lymphocytes. Lauren?

Yes, on the topic of low-moderate efficacy agents that are safe, teriflunomide is there. It’s a pyrimidine synthesis inhibitor. It’s selective against lymphocytes, so the initial few months on treatment require monthly laboratory monitoring to look for lymphopenia and transaminitis. But beyond that, things flow very smoothly. Lab monitoring is once every 6 months. For patients, it’s very easy to be on teriflunomide. It’s 1 pill a day and has very few [adverse] effects. Statistically, people may have headaches or sore throat, but the one thing that gets a lot of my patients is hair thinning. If people experience hair thinning, it’s usually 1 to 3 months down the line from starting the medicine. It should last only 1 hair follicle cycle, but I have a lot of patients who either experience a lot of hair loss beyond that, or subjectively, get very upset about the concept of hair thinning and want to get off of the medicine, or may not want to start the medicine. This medicine can stay in your system for up to 8 or 9 months if you metabolize it in a specific way. 

One unique thing about this medicine is that there is a rapid elimination protocol, where people can take activated charcoal or cholestyramine for 11 to 14 days. There’s a lab test to check if the metabolite is still in the system, and oftentimes, it’s not. However, even though there is this washout period, this isn’t a medicine I prescribe for women of childbearing age. It has substantial teratogenicity potential. It previously held a black box warning, in the category X rating for teratogenicity. I think that has been modified slightly, but it is still a big concern, especially with how long this medicine can stay in some people’s bodies. So for women, even those who say, “I’m using a barrier contraception, or I’m using oral contraception,” if there’s a risk that contraception may not work, this is probably not a drug you want to give because you don’t want anyone to stay up at night worrying, or for you to worry as well. It’s also one of the only DMTs [disease-modifying therapies] that’s hasn’t had a case of PML [progressive multifocal leukoencephalopathy]. That is a big point toward its safety. Teriflunomide has high safety and low-moderate effectiveness, but it’s good for the patient who may need something stronger than the “platform therapies.” This is the drug for people unwilling to take on risk and who don’t want to inject themselves.

 That was very well summarized. I think teriflunomide has a limited role these days, at least in my practice, WellSpan Medical Group in York, Pennsylvania. It offers modest efficacy and is reasonably well tolerated, but there are better options. I would argue that there are better options in, for example, the chronic, stable patient in whom we may be considering neurosenescence. Cladribine, for example, might be one option where there would be an exit strategy of sorts, and the patient doesn’t need to continue on it indefinitely. The other point is that there’s a reason why teriflunomide is increasingly being used as the active comparator in clinical trials. I think it’s by virtue of its relatively lower efficacy compared to some of the newer higher efficacy agents. Lauren, to your point regarding PML, I believe cladribine hasn’t been associated with PML in the treatment of MS [multiple sclerosis] worldwide. But you’re right, teriflunomide carries that distinction as well.

I must say, in our hands, we have found [teriflunomide] to be safe and reasonably effective. We’ve been pretty happy with it. Gavin, any PML with cladribine?

Cladribine was licensed for CLL [chronic lymphocytic leukemia].

No, I’m not aware of any but there will be carry-over cases. There’s no doubt that when you move high-risk patients from natalizumab and it happens to be cladribine, I suspect that we will, but I don’t think it’ll be due to cladribine. The reason I’m saying that is because you have immune reconstitution, and you’ll have normal immune surveillance within the central nervous system and the periphery. I think what Lauren was pointing out, there’s big literature about leflunomide, which is the pro-drug, and teriflunomide being antiviral and suppressing the BK virus, which is the first cousin of the JC [John Cunningham] virus. They use leflunomide in BK virus nephropathy. So I think you’re probably not going to get a PML risk with teriflunomide because it’s preventing the replication of the virus. That’s my hypothesis.

 Interesting, the whole idea of the antiviral activity in those types of agents needs to be explored further. That’s an interesting point. I’m glad you brought it up.

I think teriflunomide may be the drug of choice to derisk anti-CD20 [monoclonal antibodies]. I’ve said this for a while: induce the patient, get the disease under control with an anti-CD20, and then give the patient teriflunomide for maintenance because teriflunomide is safe in terms of its profile.

Lauren Gluck, MD, and Ravi Dukkipati, MD, provide an overview of teriflunomide for relapsing multiple sclerosis including its safety and tolerability profile. 

Overview of Teriflunomide for Relapsing MS 

Let’s move onto another class that has multiple agents, and that’s the fumarates, so dimethyl and monomethyl. Ravi, do you want to take us briefly through those?

: Sure, thank you. The fumarates, as a class, were introduced after the S1Ps [sphingosine-1-phosphates], and I believe here in the United States at least, they came around 2011, 2012. Initially there was dimethyl fumarate, and then there was a newer iteration of dimethyl fumarate, diroximel fumarate. These have established themselves quite well, in the United States and internationally, as a viable oral option for patients with relapsing remitting multiple sclerosis [MS]. I would characterize their efficacy as modest in comparison to the S1Ps and the B-cell depleters that we just discussed. They are relatively safe. The main evolution, in terms of dimethyl fumarate to the newer diroximel fumarate, isn’t so much about efficacy, but diroximel fumarate demonstrates better tolerability. The one concern with the fumarates has been tolerability, namely GI [gastrointestinal] and flushing. But on the spectrum of agents, the fumarates represent a viable option for patients with mild to moderate relapsing forms of MS. I welcome thoughts from Gavin and Lauren on this.

: This seems like, in my experience at least, the community neurologist’s DMT [disease-modifying therapy]. It is very easy to start. There aren’t a lot of monitoring requirements, before or during treatment. People don’t get strange infections from it, but they do get a lot of adverse effects. I think up to 40% of patients on dimethyl fumarate develop GI adverse effects like heartburn and stomachaches. Sometimes it’s helpful if they eat beforehand, sometimes it’s not. I think on average patients stay on it for about 2 years, but that is definitely a limiting factor. For all of the other new drugs and drug classes we have available, both in this low moderate efficacy range, to the S1Ps that are higher moderate efficiency, fumarates aren’t always my first choice for those reasons. But it is definitely an easy medicine to start and stop.

: The other point to make is, as I pointed out, diroximel fumarate is a newer version of dimethyl fumarate. To Lauren’s point, these are very easy for a neurologist to initiate. There’s relatively little monitoring. Adherence can sometimes be a concern, at least from my perspective. These are BID [twice a day] formulations, and in the case of diroximel fumarate, the dosage is 4 tablets a day. So, while they are easy to initiate and require little monitoring, I think the real concern, back to what we talked about initially, is individualizing patient choices and choosing the right drug for the right patient, and optimizing efficacy. We must understand that we may be compromising efficacy in some cases with the use of this class of medication. I will also add that they are appropriate choices for patients with milder forms of MS.

Experts in the field of multiple sclerosis provide insight into the fumarates as a viable oral option for relapsing MS.  

Considerations for the Use of Fumarates in Relapsing MS 

Let’s move onto another class of agents, the anti-CD20s. Lauren, why don’t you take us through that?

: For ocrelizumab, the trials first studied relapsing remitting MS [multiple sclerosis], and then primary progressive MS when the data was published in 2017, which was exciting because besides mitoxantrone [chemotherapy], this is the only positive study done in a progressive population. Ocrelizumab was based on its older sister drug rituximab, which we knew targeted CD20 B cells and had disease-modifying properties for multiple sclerosis in an empiric and retrospective manner. Ocrelizumab was the updated, fully humanized monoclonal antibody version of rituximab and showed significant improvement against platform therapies, specifically interferon beta, in reducing annualized relapse rate, decreasing sustained disability, and new enhancing lesions abundantly. The second part of this was the ORATORIO study on primary progressive MS, where they showed a statistically significant decrease in disability compared to the placebo—which was no medication at all—because none had been FDA approved for progressive MS at the time. The numbers weren’t as clinically overwhelming in the analysis. Disability progression decreased by about 25%, which is better than the alternative for sure, but when you have patients in your office, it’s good to set expectations about what that means. It’s hard to visualize: if you start this medicine today for your primary progressive MS, and next year you feel worse or you have more disability, does that mean the drug was unsuccessful? Likely, the answer is no, but the medication doesn’t have a 100% effectiveness at decreasing disability, unfortunately.

One of the big questions from this study was regarding its risk of malignancy. We were talking about cladribine earlier, and in this particular study, several women were diagnosed with breast cancer in the ocrelizumab experimental arm, and no one in the placebo, or comparator arm, had breast cancer. So there is a warning about ocrelizumab and breast cancer, which doesn’t seem to have trended in that direction with post marketing studies. But with any immunosuppressants, we should be encouraging our patients to get age-appropriate cancer screenings. If they are female, they should stay up-to-date with their mammograms whenever their primary care doctor or gynecologist recommends it. It is something to mention up front, for patients to understand everything going on, but also to limit their worry, that they’re not guaranteed to get breast cancer with this drug. I think we have all seen very low to no rates of breast cancer with this drug compared with the average population.

: Ofatumumab is an even newer version of a CD20 antibody. It was approved by the FDA several months ago. Its big hallmark update is that instead of having to go to an infusion center twice a year, you can give yourself injections at home with an autoinjector. Patients don’t even need to see the needle. It is very convenient. It’s very good for patients who may not have access to a MS center nearby, or if they live several hours away from their physician. That can be a big improvement in their quality of life. The research behind it was very strong. Its comparator drug was a different medication, teriflunomide [immunomodulatory agent], which also showed about a 50% reduction in annualized relapse rate, in new T1 contrast enhancing lesions, in T2 lesion accrual, as well as neurofilament light chain, a biomarker we’re using more often now. The duration of the studies lasted about 1 and a half years per patient. We expect more to come out on the drug’s effect on disability progression and longer term annualized relapse rate reduction, which is very exciting.

This has been a very useful class of agents. In the United States, it has spun up to a lot of usage and good success. Ravi, any experience with these?

: Nice summary of both. I believe the B-cell depleters, ocrelizumab and ofatumumab, represent the highest efficacy options we have for patients with MS. For certain patients, that is the ideal option: patients with a higher degree of disease activity or breakthrough disease activity on existing agents. The one potential area of concern in some patients is the long term, especially the older patient. I would tie that into long-term potential for certain infections and to the point of malignancy. It’ll be interesting to see the long-term data evolve in terms of prolonged B-cell suppression and its manifestations. The other thing to keep in mind these days is the vaccine component, that is, in this era of COVID-19. But there’s no question that these are the highest efficacy drugs we have currently.

: I want to say that for how effective it is, it has one of the lower risk profiles compared to other strong immunosuppressants, maybe barring cladribine. But looking at something like alemtuzumab, this has a lot less risk associated with it and a lot less monitoring. But again, this raises the question of how long do we keep patients on these medicines safely?

: Yes. I think one of the downsides of the anti-CD20 is the impact on the end organ. The brain volume data, to me, is very poor compared to some of the other higher efficacy treatments like alemtuzumab and even natalizumab. I think there’s a ceiling or floor effect when it comes to suppressing inflammatory activity, relapses, and new enhancing lesions. There’s something not quite right about it, and it’s coming out. We saw that when we looked at the exposure to ocrelizumab based on body size and B-cell depletion, that those who got the highest exposure, the best B-cell depletion, did better on disability progression. I think there’s still more to be done around optimizing the dose of anti-CD20 therapy, and we haven’t learned everything about it yet. Yes, it is very effective and relatively safe in the short term, but I worry about the long-term safety. When you look at the Swedish safety database, where they’ve been using anti-CD20 antibodies for probably about 7 to 8 years in a large proportion of their patients—about two-thirds of the patients in Sweden are on an anti-CD20—you’re beginning to see severe bacterial infections starting to develop around year 5, 6, and 7. I worry that we’re going to have a problem with the anti-CD20 therapies when we start having people on them for 10, 15, 20 years. That’s my worry. We need an exit strategy. How do we de-risk them, put them onto something that’s safer, without the infection risk?

This is a very good point, and of course, following B-cell counts is useful but also following immunoglobulin, because that’s where it seems to correlate with bacterial infection, when the IgG [immunoglobulin G] gets low. But as a class of agents, I agree with Ravi. This has been a remarkably successful agent among our people, and our first agent to show any effect in progressive MS, which belies the brain atrophy data, independent of activity, as best one can tell from the studies. So that opens the door. It’s a very modest effect, and we need to do better on progressive MS. At least it opens the door for treating, not prolonging, the disease.

A panel of experts discuss the use of anti-CD20 monoclonal antibodies in relapsing multiple sclerosis including summaries of the phase III ORATORIO and ASCLEPIOS trials, for ocrelizumab and ofatumumab, respectively.  

Anti-CD20 Agents for Relapsing MS 

 Let’s move onto our most dynamic class of agents. We now have 4 of them and those are the sphingosine-1 phosphate modulators [S1P]. We started with fingolimod [Gilenya] in 2010 and now we have the next generation of S1P selective modulators. Ravi, why don’t you take us through these?

Sure. Thank you. The S1P modulators are well established in the MS [multiple sclerosis] treatment space. They were the first oral mainstream therapies approved, with fingolimod being approved in 2010, followed by siponimod [Mayzent], ozanimod [Zeposia], and ponesimod [Ponvory]. I think they’ve established themselves well as high efficacy oral therapies. The newer iterations—siponimod, ozanimod, and ponesimod—offer increased selectivity in terms of the S1P receptor subtypes. Fingolimod’s mechanism of action is predominantly on all 5 subtypes of the S1P receptor, whereas the newer iterations, siponimod and ozanimod, are more selective. Ponesimod is the most recent entrant and primarily exerts its effect on S1P1 receptors. The newer S1P modulators, in a nutshell, emulate the efficacy— which already well demonstrated both short-term and long-term—while improving safety and tolerability. By increasing selectivity, the newer S1P agents don’t need first dose monitoring as, for example, fingolimod does. The pivotal studies for ozanimod and ponesimod demonstrated some novel outcome measures: trying to tease out brain atrophy and cognition data, and other markers including patient reported fatigue. I think the bottom line is that this class is here to stay. In a sense, that’s why it’s increasingly crowded. In place of the legacy or the term that you don’t prefer to use, platform agents, these are the new platform agents. We go from there. But to summarize, they offer optimum efficacy and are reasonably safe. The newer ones offer more selectivity, which may impart better safety and tolerability profiles. One more recent development that has casted concern is vaccine readiness. I would like to hear what your thoughts are on that.

Yes, the vaccine issue is an interesting one. There’s a report from Israel that showed people on S1P had almost no response, or very low response. We just sent something into ECTRIMS [European Committee for Treatment and Research in Multiple Sclerosis] with a different result, so I can’t go through the data now. We don’t see that concern in the S1Ps. Anti-CD20 [monoclonal antibodies] is a different story. Lauren, thoughts about the safety of this group and the pediatric indication?

Sure. Taking the second part first, fingolimod is the only MS DMT [disease-modifying therapy] with a FDA [Food and Drug Administration] approval for pediatrics, which doesn’t limit us from using other DMTs but is a great reassurance, especially in terms of safety. Because these are overwhelmingly safe, especially in regard to day-to-day adverse effects. Most people don’t have adverse effects. It’s wonderful. Most commonly, in the trials, people complained of headache or sore throat, and, obviously, the lab abnormalities we see. Adverse effects require monitoring with transaminitis and with lymphopenia. But there are signals for strange, opportunistic infections. Things like CMV [cytomegalovirus], meningitis, and disseminated zoster are very rare but diseases to acknowledge if a patient starts complaining of severe headaches or strange rashes. The 1 thing I’ll tack on is that as I’ve shifted toward the newer version of the S1Ps. I’ve noticed a lot of their trial outcome measures focus on cognition, and patients often ignore the reality that MS can not only cause physical disability, but cognitive disability as well. Bringing that to the forefront of discussion is very important and sometimes helps convince patients the gravity of why they need to start early treatment and how physical isn’t the only disability that can be a problem in the future.

 Fred, could I just add a few caveats? One of the problems about the S1Ps is pregnancy. You can’t be pregnant while taking them because of the teratogenicity risk and, at least with fingolimod—as I would imagine it’s going to be similar with other agents— because of the rebound phenomenon. When you wash the drug out, there’s potential for severe recurrence of activity. I personally feel negatively for the class. Particularly because most people with MS tend to be young women. When they present, I don’t want to use S1Ps in young women, who are planning families because of the issues around pregnancy, having to stop treatment, and the rebound. The other 1 is also the older population. You know S1P is a chronic immunosuppressant, and I know it’s not as potent of an immunosuppressant but we’ve seen, for example, a large number of cases of warts, some strange fungal dermatitis, and a cryptococcal meningitis in our center in the Blizard Institute, Barts and The London School of Medicine and Dentistry in London, United Kingdom. Although it isn’t a big signal, there is worry that in the older population, where immune senescence is a concern, you may see more opportunistic infections and potential malignancy signals. The signals of the basal cells, squamous carcinoma, the lymphoma are quite clear now. Yes, it is a good drug class but there are certain populations that I would steer away from using them in.

 Yes. Of course, we don’t know about the rebound effect on the ones with the shorter half-life, like siponimod and ponesimod, yet. You discussed a bit about natalizumab [Tysabri], which we’re not spending a lot of time on, but you have the same sort of issues where you have to consider rebound. When you start someone on that, you want to plan on continuing that treatment. Of course, the best way of avoiding rebound is rapidly switching to another agent if you must stop. Pregnancy is a different issue. 

Did you see that case report, which was just published about 3 weeks ago, of a patient that was switched from fingolimod to siponimod because they had secondary progressive MS? There wasn’t any wash out, but he or she went from fingolimod to siponimod and developed profound rebound, which makes you think that fingolimod may have a different profile compared to siponimod because we know it works on more receptors. There’s S1P1, 3, 4, and 5. Siponimod is 1 and 5. There’s more to this class of agents than just lumping these agents together. I suspect there are going to be some subtleties regarding the mode of action.

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Expert neurologists discuss the role of sphingosine-1-phosphate (S1P) receptor modulators in relapsing multiple sclerosis including vaccine considerations and pediatric use.  