Professor of Medicine in Neurology, University of Ottawa; Director, Multiple Sclerosis Research Unit, Ottawa Hospital; Senior Scientist, Ottawa Hospital Research Institute

Mark Freedman, MD, MSc, HBSc, CSPQ, FANA, FAAN, FRCPC

For the longest time, the only somewhat predictable marker for monitoring multiple sclerosis (MS) and offering something in the way of prognosis has been MRI. However, MRI typically looks only at the head and perhaps the cervical spine (missing the optic nerves and the rest of the spinal cord), has its greatest predictability in the early stages of MS and loses its predictability with length of disease, and cannot be used with any degree of accuracy to monitor response to therapy with disease-modifying treatments (DMTs).

 MRI is also fraught with differences in image acquisition from one machine to another, slice thickness, and even orientation in the scanner, making it problematic to compare one set of images to another in time, causing the “noise” or heterogeneity contributing to inaccuracy. The utility of MRI was validated in clinical trials where strict adherence to all the previously mentioned factors led to a significant reduction in this noise—a far cry from real life. Could a simple blood test be found that is measured in a standardized fashion to inform on prognosis and response to therapy similar to the erythrocyte sedimentation rate used for years by rheumatologists? 

The call has been answered with the measurement of neurofilament light chain (NfL), which is found within neurons and axons and, when measured in the blood or spinal fluid, results from neuro-axonal injury. In that sense, it is nonspecific and any cause for neuro-axonal injury could lead to an increase in this measured marker. However, in a situation such as MS, uncomplicated with other nervous system comorbidity, it can reflect the amount of damage that is arising from that disease. It is first released into cerebrospinal fluid (CSF) but eventually leaches out into the periphery, where it can be measured in blood or serum, albeit at ~1/500 the CSF concentration. Although, in the serum, NfL can remain increased for several months.

 This is important, since a spot measurement does not necessarily reflect real-time damage but accumulated damage that may have occurred within a few months of the measurement, drawing a similarity with the hemoglobin A1c measurement used by endocrinologists to look at glycemic control in diabetics. 

Many laboratories are now offering the specialized technology to measure NfL in the serum/blood using the SiMoA (single molecule assay) analytical method. These machines are now commercialized and standardized and able to measure NfL accurately in the serum well within the picogram range. Since the amount of NfL reflects neurological injury, it is not surprising that it has been studied in virtually all neurological conditions. such as the neurodegenerative diseases (eg, motor neuron disease, dementia, Parkinson disease), where levels can be confounded by the effects of age, which itself leads to serum increases, but typically not until age 60.

 That is why most of the research has been in MS, where patients are typically young and devoid of other conditions that might confound measurements. 

We have shown that baseline measurement of serum NfL, when a patient presents with their disease for the first time, is a predictor of disease progression some decades later,

 and finding such levels might lead a neurologist to choose a higher-efficacy DMT to start. Studies now reveal that following NfL levels over time might predict patients who will relapse or show early progression, prompting, perhaps, a change in therapy.

 Serum NfL has even been more predictive of longer-term MRI changes, such as brain atrophy, than MRI itself.

 Serum NfL is now included as an outcome measure in all ongoing clinical trials for DMT in MS and, similar to MRI, all successful and approved therapies to date have demonstrated an ability to lower serum NfL levels. Some therapies’ efficacies are now being judged on the magnitude to which they lower NfL levels,

 the greatest being autologous hematopoietic stem cell transplantation.

It may also be reflective of ongoing progression once patients are in the progressive phase of their illness.

MRI is costly and time-consuming and, with all its inaccuracies, it has become difficult to use it as a guide to treatment response. Most accurate measurements are performed in the brain, but most progression tends to come from spinal cord lesions that are not accurately measured. Additionally, it is not clear what sort of change over time on the MRI would dictate a change in therapy. We have cautiously advised that if more than 3 new lesions develop over the course of a year on DMT, that alone might be cause for a change in therapy because such data come from group analyses that are difficult to apply to an individual.

 Serum NfL is also fraught with a similar problem in that we know that elevations indicate new levels of damage, but what sort of level change is important for an individual patient, since once again, all of the data have come from group analyses. 

All agree that having a simple, standardized serum biomarker to measure disease activity would offer the greatest utility in treating a medical condition such as MS, which now has a variety of graded therapies available. I would argue that serum NfL is the closest we have to such a marker, and the sooner we all adopt it as our own “sed rate,” the more we will realize its utility. 

REFERENCES 
1. Wattjes MP, Rovira À, Miller D, et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—establishing disease prognosis and monitoring patients. 

. 2015;11(10):597-606.  oi:10.1038/nrneurol.2015.157 
2. Thebault S, Booth RA, Freedman MS. Blood neurofilament light chain: the neurologist’s troponin? 

. 2020;8(11):523. doi:10.3390/biomedicines8110523 
3. Khalil M, Pirpamer L, Hofer E, et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. 

n. 2020;11(1):812. doi:10.1038/s41467-020-14612-6 
4. Thebault S, Abdoli M, Fereshtehnejad SM, Tessier D, Tabard-Cossa V, Freedman MS. Serum neurofilament light chain predicts long term clinical outcomes in multiple sclerosis. 

. 2020;10(1):10381. doi:10.1038/s41598-020-67504-6 
5. Kuhle J, Kropshofer H, Haering DA, et al. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. 

. 2019;92(10):e1007-e1015. doi:10.1212/WNL.0000000000007032 
6. Khalil M, Teunissen CE, Otto M, et al. Neurofilaments as biomarkers in neurological disorders. 

. 2018;14(10):577-589. doi:10.1038/s41582-018-0058-z 
7. Delcoigne B, Manouchehrinia A, Barro C, et al. Blood neurofilament light levels segregate treatment effects in multiple sclerosis. 

. 2020;94(11):e1201-e1212. doi:10.1212/WNL.0000000000009097 
8. Thebault S, Tessier DR, Lee H, et al. High serum neurofilament light chain normalizes after hematopoietic stem cell transplantation for MS. 

. 2019;6(5):e598. doi:10.1212/NXI.0000000000000598 
9. Kapoor R, Smith KE, Allegretta M, et al. Serum neurofilament light as a biomarker in progressive multiple sclerosis. 

. 2020;95(10):436-444. doi:10.1212/WNL.0000000000010346 
10. Freedman MS, Devonshire V, Duquette P, et al. Treatment optimization in multiple sclerosis: Canadian MS Working Group recommendations. 

. 2020;47(4):437-455. doi:10.1017/cjn.2020.66

Articles

All agree that having a simple, standardized serum biomarker to measure disease activity would offer the greatest utility in treating a medical condition such as MS, which now has a variety of graded therapies available.

Do We Finally Have a Useful “Sed Rate” for Multiple Sclerosis?

The panel sums up the future of managing multiple sclerosis, including the need for individual prognostication, neuroprotective agents, combination therapy, and the possible use of bone marrow transplantation.

: This has been a great discussion. Let’s close out with some thoughts for the future. What does the future hold for managing multiple sclerosis [MS]? Pat, why don’t you start?

: In the United States, we have 25 distinct agents for relapsing forms of MS covering 10 mechanisms of action. What we don’t have are a lot of treatments for the neurodegenerative phase of MS and progressive MS. That is an ongoing key focus, and it’s very likely that neurodegeneration has to be hit from the earliest time point, ideally even before there is clinically apparent progression. We’re going to see a real emphasis on that.

In addition, we do not have any meaningful CNS [central nervous system] repair strategies, including re-myelinization and cell-based strategies to induce axonal sprouting. We just had a very disappointing failure of opicinumab. That’s off the table, with regard to CNS repair. This is a focus. It’s very promising that we have multiple studies in MS looking at CNS repair, but that’s a big deficit. We need CNS repair. We need neuroprotection agents. We need progressive MS agents. We need neurodegenerative strategies. They need to employed early. We need to make sure we are promoting wellness programs and the recognition of how bad comorbid conditions can be in MS, so that they’re identified and optimally managed. With that, the MS individual will age better.

: As always, Pat, you’re so eloquent. You cover everything, and there’s very little to add, but I will add a couple of facts. One is that although we’ve talked about high-efficacy therapies, we haven’t talked about the highest-efficacy treatment. That is full-on bone marrow transplantation, which is becoming a bit more common across the world. People are recognizing its benefit in a select group of patients who have early, aggressive disease. They have a study going on in the United States, which will no doubt prove it is better than any of the other higher-efficacy therapies when appropriately applied to the right patient group. That’s an option that is still on the table for certain types of people.

The second is the evolving use of a biomarker to inform our outcomes. Neurofilament light [NFL] has gone beyond an experimental type. Maybe we should do it, and maybe not. It should be commonplace. These assays are readily available. They’re giving you some information about what kind of axonal damage is occurring under the water. In the appropriate patient who is young and has no confounders that might lead to the destruction of axons, neurofilament light is cheap and easy to do. It’s a blood test. You can do it on a regular basis and get at the entire brain.

The MRIs of the brain are done routinely. You get a bit of the spinal cord and the cervical spine, but if there’s damage anywhere, it will give rise to the axonal loss that you can measure with the NFL. That’s a biomarker moving forward, which you’ll see adopted quite readily. That’s another piece that can help inform, not only on prognosis, because we’ve seen those data, but also on monitoring treatment response.

That’s what I see moving forward. There’s 1 other thing that I want throw in there for good measure. Unfortunately, Scott Newsome had to leave. He talked about this 90% suppression of gadolinium [Gad]-enhancing lesions. That’s good. You and I both know, Fred, that there was another study that led to almost 90% suppression of Gad-enhancing lesions. That’s when interferon beta and teriflunomide were combined. They produced that same 90% suppression using 2 drugs that are relatively safe. Maybe the future for combination therapy should at least be explored.

: I don’t think I have much to add to what you both said. But I’ll throw in this idea of wanting to have individual prognostication. We’re good at prognosticating for groups, and we’re terrible at prognosticating for individuals. Biomarkers may be a part of that, but we need to build some individual metrics for a given individual, which will then inform our choice of therapies.

Thank you for this rich and important discussion. Thanks to our viewers for watching this NeurologyLive® Peer Exchange. If you enjoyed the content, please subscribe to their e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

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The Future of Managing Multiple Sclerosis

Fumarates for Treatment of RMS

The rationale for use of the sphingosine-1-phosphate (S1P) receptor modulators for relapsing multiple sclerosis is outlined by Dr. Patricia K. Coyle.

Fred Lublin, MD: Let’s discuss the sphingosine-1-phosphate [S1P] receptor modulators. We have 3 on the market. One has a successful phase 3 trial, as we just discussed. Tell us about those, Pat.

Patricia K. Coyle, MD: Fingolimod was the first-in-class S1P receptor modulator, and it hits S1P receptors 1, 3, 4, and 5. I will mention a very positive pediatric MS [multiple sclerosis] trial, against IM [intramuscular] interferon beta-1a, in which it did very well.

We now have 2 approved, second-generation S1P receptor modulators. Both of them are aimed at S1P receptors 1 and 5. They deliberately got rid of receptor 3 targeting, which is enriched in the cardiac tissue, in the hopes of getting away from the first-dose, 6-hour observation. Both of them, for the most part, offer you that. 

You dose-escalate over the first week or so, and the majority of individuals do not need a formal dose escalation. The first approved was siponimod. What’s a bit special about siponimod is that its phase 3 trial, EXPAND, was in secondary progressive multiple sclerosis [SPMS] individuals. They had to be progressing and gradually worsening. In this trial, which was very large, with over 1600 SPMS patients, individuals were randomized 2 to 1 to siponimod 2 mg daily. They escalated up over the first week vs placebo. The primary outcome was confirmed disability progression at 3 months. This is a progressive population, and they met that primary outcome. They weren’t knock-your-socks-off data. There was an editorial associated that said this may be statistically significant, but is it clinically meaningful? They had about 21% reduction in confirmed disability progression. I think it was 26% vs 32%. You saw benefits on the occasional superimposed relapses and on MRI-detected disease activity in favor of siponimod. 

I was impressed with this study. We know that siponimod enters the CNS [central nervous system]. Fingolimod failed, as Fred knows very well, in a phase 3 primary progressive trial. They were able to meet an outcome on progression in SPMS. They were likely hoping to get an approval for secondary progressive MS, and they did not.

What came down for siponimod was an approval for relapsing forms of MS. The FDA made this assessment. That means clinically isolated relapsing-remitting and active secondary progressive MS. They were using analyses that indicated that if the secondary progressive individual had a focal inflammatory component with clinical attacks in the 2 years prior and enhancement on the entry, you could show stronger data. I get that, but they entered secondary progressive MS.

I would like to know if this is an agent that enters the CNS and has a direct impact in decreasing neurodegeneration, unlike and anti-CD20 monoclonal antibodies. Those do not get in. There is less than 0.1% penetrance. But that was enough for ocrelizumab to get approved. I would like to see data that help me understand that better. Siponimod is on the market now. It is certainly being used on secondary progressive patients. You do need to do genotyping.

The other second-generation S1P receptor modulator is ozanimod. That was studied in 2 phase 3 trials in relapsing MS. Radiance was a 2-year study, and SUNBEAM was a 1-year study. Ozanimod is interesting because it breaks down to 2 active metabolites, as well as ozanimod. The metabolites have a longer half-life, so the drug does take longer to wash out. The label has a bit of a concern about other drugs like MAO inhibitors and anything that might cause a serotonin surge. I would think about avoiding those. We need better data there. It went up against IM interferon beta-1a weekly. It didn’t meet disability with pooled data from Radiance and SUNBEAM, but it certainly had good relapse data and MRI data, which favored it. It does give us an alternative choice to fingolimod. We’re dealing with fingolimod, siponimod, and ozanimod. We’re likely to have ponesimod. It’s going to be a very crowded field among the S1P receptor modulators.

S1P Receptor Modulators for Treatment of RMS

The panel reviews the use of cladribine for treatment of relapsing multiple sclerosis, including patient selection.

: Let’s take a look at cladribine. Mark?

: Our discussion brings me to the mechanism of a drug like cladribine.

I know that the terminology of so-called immune reconstitution isn’t something that is commonplace in the United States, but the whole point is that a drug and treatment like cladribine has been around for quite some time. We moved to this well after it was obvious that mitoxantrone was causing a problem, but we like mitoxantrone. It was probably 1 of the prototypic immune reconstitution drugs because it had its built-in limitation. You could give only so much. But if you followed these people, as the French did for years, they saw that 5 to 7 years down the road, these patients didn’t need anything else. That gave us the idea that maybe there are other therapies one could use. Cladribine treatment is similar.

It’s based on the notion that there’s a certain dosage that will control the disease. This is given like a cancer drug in select treatment groups. It is administered 1 week of the month, times 2 in the first year. Administration is the same in the second year, but the cumulative dose is 3.5 mg/kg. That’s the dose that was studied in the CLARITY trial, both in the original study and in the extension going out 4 or 5 years. It’s a unique study. It’s also a gutsy study, because they answered the question that the B-cell people have not. They took the people who were randomized to the alternative therapy and gave them the drug. But at the same time, after a few years of taking cladribine, they stopped the drug randomly. They didn’t tell them. They kept them blinded and moved them to placebo to see what happened. That’s what happened in the extension.

The overall results from the clinical end point were that the people who had 4 successive years of cladribine were no better clinically than those that had only 2 years and then 2 years of placebo. This tells you that the up-front treatment has some durability, and we’ve seen the same thing with alemtuzumab. That is the other prototypic induction agent with which you knock down the immune system, allow it to recover over time, and then watch for the durability of the response. That’s the uniqueness of cladribine.

Knowing how the drug works and that it’s highly efficacious, an additional study went after the CIS [clinically isolated syndrome] population. At that time, the group probably included about half the patients who today would have met the McDonald 2017 criteria for MS diagnosis. Regardless, they went after this early treatment group. One could have anticipated that the results from the ORACLE study weren’t much better than in any of the other CIS trials. Those were done with only the injectables. The only oral tested was teriflunomide.

With cladribine, you have this dose induction. Let’s wait and see, and follow the patients for a few years. The option is there to re-treat if you needed to, but you can get a durable response from the focused-set therapy based on surface area or weight.

Scott D. Newsome, DO: For cladribine, I would say in full transparency that I haven’t used it a lot. I do have some patients on it. As you said, Mark, it does have this durable treatment effect. It’s a short course. Its oral. The people I have put on this medication have had great tolerance to it. They love the fact that for 2 months, they do the treatment, and they don’t have to do anything for the next 8 months. There is also the possibility of not having to continue a therapy after 2 years of treatment, or to at least have an extended period of time when you don’t have to do another treatment. It does remind me of the mitoxantrone induction. It may be possible to put someone on a lower-efficacy therapy like Copaxone [glatiramer acetate], which was done in the past. I don’t know if this will be brought back to life with cladribine. Alemtuzumab was also mentioned.

The 1 caution that I have is that cladribine, alemtuzumab, and other high-efficacy drugs aren’t cures. Even if you’re reboosting the immune system, I don’t think we have a lot of data yet to support that notion, at least with cladribine and alemtuzumab. I feel uncomfortable, as many of our other patients feel uncomfortable, not just doing the watchful waiting approach and having that reactive approach to treatment after you use a therapy like cladribine.

It is effective. I would lump it into a higher-efficacy bucket. In fact, for our PCORI [Patient-Centered Outcomes Research Institute]–funded trial looking at modestly-effective vs high-efficacy medications, cladribine was put into the high-efficacy bin because of the clinical trial data that Mark just went over.

: Cladribine is a very interesting agent. I consider it the most efficacious of the oral therapies. It’s not as efficacious as the monoclonal antibodies. The greatest difficulty is that in the United States, the label says you give your 2 courses and then they’re silent. That’s a big issue. That needs to be resolved.

: Can I make 1 other comment about how cladribine, potentially the B-cell–depleting therapies, and even alemtuzumab have a leg up on some of the other therapies we have in pregnancy? A lot of us are using these medications that have a durable treatment response in patients who have an interest in getting pregnant but who you’re worried about, from a disease activity perspective. We’ve been using these therapies in that fashion, as opposed to maybe natalizumab or fingolimod. You think, “OK, if I stop the drug today, we have a potential issue with rebound attacks because you have to wash the drug out, or at least it’s recommended to wash the drug out for a little while.” That’s where I like using the therapies that are B-cell depleters vs just blocking cells.

Cladribine for Treatment of RMS

The rationale for using anti-CD20 monoclonal antibodies ofatumumab and ocrelizumab for treatment of relapsing multiple sclerosis is discussed.

: Let’s look at some of our therapies. We have our oldest therapies, which are interferon and glatiramer acetate. I’ve had not 0, but precious few, interferon starts. We have had starts with glatiramer acetate. It’s been around for a long time, and it works for some patients. The group of patients who are most interested in that are the people who come in and ask, “What’s the safest drug you have, and how long has that drug been around?” Glatiramer acetate fills the bill on that and satisfies those for whom safety is the biggest concern.

Moving into some of the others, we can look at the other end of the spectrum. The highest-efficacy agents we have are things like the anti-CD20 therapies. Scott wanted to discuss ocrelizumab and ofatumumab.

: Let’s talk about the 50,000-foot view with regard to B cells. For a number of years, it was thought that MS [multiple sclerosis] was just a T-cell-driven disease. But over the past decade or longer, it’s been recognized that B cells are integral to the pathogenesis of MS.

If you look at the fundamentals of immunology, we know B cells are the main antigen-presenting cell to T cells. In a disease where T cells are heavily involved, how do they get activated and how do they misbehave? In part, it’s because B cells have that antigen presentation and 2 T cells to activate them. That has been recognized for a long time.

We know that antibodies are produced by plasma cells. What are the precursors of plasma cells? They’re the B cells. We know that antibodies are a part of the pathogenesis of MS. They can do direct damage to axonal myelin. If we think about what other things B cells do, they cause proinflammatory cytokines. There was mention of cytokines earlier. Those cytokines can activate additional immune cells, including the innate immune system.

You have B cells, which have an integral part in the pathogenesis of MS. What if we directly target B cells? That’s where ocrelizumab and ofatumumab have come down the pipeline, and we also have rituximab. That’s been around for decades. We’ve used that in neuroinflammatory conditions.

If we look at the OPERA I and OPERA II clinical trials, which were the pivotal trials for ocrelizumab vs interferon beta-1a given 3 times a week, we saw clear evidence on all markers of disease activity that ocrelizumab was superior to interferon. For example, the annualized relapse rate was close to 50% in favor of ocrelizumab.

Then, if we look at the Gad-enhancing lesions, there was very strong suppression of new Gad-enhanced lesions. That measure favored ocrelizumab by more than 90%, which surprised me. I’d like to hear if others felt similarly. If you look at the pivotal trials with interferon, it does a pretty good job of suppressing inflammation, as it relates to new Gad-enhancing lesions, into the 80th percentile. Now, you have a B-cell–depleting therapy with which you’re suppressing into the 90th percentile. It’s really impressive by those metrics. Other secondary end points were met as well.

If we shift our attention to ofatumumab—this study was vs teriflunomide, not interferon—there were similar results, in terms of suppression of annualized relapse rate into the 50th percentile. It was similar in terms of suppressing Gad-enhancing lesions into the greater-than-90th percentile if you’re going to compare the 2 pivotal trials between the B-cell–depleting therapies.

If we look at the disability data, how good were the B-cell–depleting therapies vs their active comparator in suppressing that disability measured by EDSS [Expanded Disability Status Scale]? If we look at the ocrelizumab data—they’re pooled—there was 40% reduction if I recall correctly vs interferon. For ofatumumab, it was around 30% reduction in disability progression.

As I mentioned earlier, will we start to see those curves coming closer together as someone is on their respective therapies long term, from a disability perspective? But at least short term, and probably intermediate term, we know that the B-cell–depleting therapies do a much better job in suppressing the inflammatory disease activity. That includes relapses, Gad-enhancing lesions, and T2 lesions, which may speak to those observational studies that I referenced. I don’t know how others feel about the data. They’re compelling enough for me to think about using the B-cell–depleting therapies as a first line.

: I had some comments about the B cells as well. I’ll just throw in a caveat that, at some point in your life, you might need a B cell. The untold story and the data that we need are concerning how long you need to suppress the B cells to obtain a long-term response. You may not need to maintain the barrage against the B cells year after year. There may be a point where you can stop and still glean the benefit from those early treatments.

: The Swedish folks have published a number of good studies with rituximab. You can argue back and forth about ocrelizumab and ofatumumab. Maybe they’re different drugs, but you’re still targeting B cells. They have shown that you can treat up front with a protocol that’s similar for a couple of years and then back off on either the frequency or the dosing. You still have a good therapeutic response, and maybe that will help prevent some of the long-term complications. I totally agree with that approach.

Also, Annette Langer-Gould has also been involved, at least in the United States, in looking at similar data from Kaiser Permanente showing that you don’t have to continue to flog the B cells the same way for a very long period of time. We’ll have to see. The long term will help prevent further disease activity. We don’t have those data yet.

: I’ll just mention with regard to the anti-CD20s that we now have 2 competitive, high-efficacy, relatively safe agents. One can be given at home. For the other, you go to an infusion center. We’re likely to have a third. We certainly use anti-CD20 agents in treatment-naïve individuals. It’s very well tolerated and a great choice. We are monitoring immunoglobulins on an annual basis. There is a concern, and it may very well be that we don’t need to continue to give it at the same pace. That needs to be determined.

Anti-CD20 Monoclonal Antibodies for Treatment of RMS

Scott D. Newsome, DO, details strategies for choosing initial therapy for treatment of multiple sclerosis, including emerging data suggesting more aggressive up-front treatment when starting therapy.

: Let’s move into our next section looking at currently approved therapies.

Scott or Mark alluded to these strategies for choosing an initial therapy, which boils down to this idea of escalation vs starting with the high-efficacy therapies. We’re hopeful about getting data to guide these decisions. Right now, they’re based on the clinician’s assessment of prognosis, understanding the difficulties of individual prognostication, the extent of their disease, how serious it is, and where it is involved. 

The patient preferences are critical issues. How concerned are they about safety? How risk averse are they? What are their pregnancy plans? What are the insurance issues? There are many factors beyond the idea of starting with a drug that’s been around for a long time that we know works in some people. We can say, “Let’s try it. If that doesn’t work, we’ll go to a drug for which the safety may not be as good, but the efficacy may be better vs starting people hard up front.” Let’s get your thoughts on all that. Scott, why don’t you start?

: As Mark or Pat alluded to earlier, we don’t have that ultimate biomarker, not only for diagnosis but also for the person sitting in front of you. Which biomarker or which clinical factor gives you a certain level of confidence that you need to go in a different direction, in terms of treatment, whether it’s a low-efficacy, modest-efficacy, or high-efficacy drug?

If this is the question you’re asking, I try to use clinical and paraclinical factors of what I call “badness” in determining the direction of treatment. There are emerging data from observational studies that are pointing toward being more aggressive up front in treating MS [multiple sclerosis]. In my practice, I’ve not prescribed a self-administered injectable therapy in a very long time for that reason. Usually, when I see a patient up front, regardless of what their clinical type is for relapsing disease, I will often go with an oral therapy or an infusible therapy. If I start someone on an oral therapy, I have a low threshold to escalate to an infusible therapy. That could occur within the first year of treatment, as long as someone is compliant with their medication and they’ve been on their treatment for at least 6 months. If they have a Gad-enhancing lesion on a lower-efficacy therapy, it’s worth considering switching to higher-efficacy therapy.

Do I have a high level of confidence that the escalation going to put someone in a better place, from a disability perspective, 20 years down the road? I don’t think we have data to support that. However, the observational studies hint toward that from the MS-based cohort.

Strategies for Choosing Initial Therapy in MS

Mark Freedman, MD, MSc, discusses the secondary end point of fatigue-related symptoms assessed by the Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIS-RMS), a new MS-specific, 20-item patient-reported outcome measure. Scores suggested statistically significant effects on fatigue symptoms with ponesimod in comparison to teriflunomide.

: While we have you, Mark, let’s talk about the OPTIMUM study. That’s unique as it relates to fatigue.

: When that study was put together—I’m on the steering committee, so I take the Fifth here—we knew we were going to be in an era of competing S1P receptor agonists. How do we come above all the other drugs? What element could we use to show that there’s some added benefit to this particular S1P receptor agonist? Is there anything we can show that no one else has done? More and more, we’re hearing that patient-related outcomes are important. The differences that we’re seeing, even in relapse rates, are so small that they’re amounting to 1 or 2 attack differences over the years for patients. What is the true meaning of that, especially in a comparative study in which you’re not able to show an effect on disability? You’re dealing with 2 active agents and time periods that are too short to demonstrate that. We know that the outcomes are going to be measured by MRI and relapse rate. Is there anything else that can feed into that? 

The thought was, let’s go after an important patient-related outcome that is undertreated and for which there is a huge unmet need. Since we’ve been talking about fatigue, that was the outcome that was chosen. It’s probably the No. 1 reason, or close to the No. 1 reason, patients are dropping out of gainful employment. They’re not able to meet the needs of their lives, not only at work but at home. It’s a huge dent in quality of life.

Kudos to the group. They took a big chance, as you know, in the OPTIMUM study. That study compared ponesimod and teriflunomide. They looked at the usual primary outcome measure of relapse rate. But when they came to the secondary outcome measures, which are often MRI and EDSS [Expanded Disability Status Scale], they instead looked at fatigue in a hierarchical analysis. That was the first secondary end point. Had they not hit a superiority threshold in that measure, they wouldn’t have been able to look at any of the other secondary outcomes. It was very risky in that sense.

They developed and used a fatigue impact questionnaire under the guidelines of the FDA to establish what is a good PRO [patient-reported outcome]. Using that, they were able to show superiority over the teriflunomide comparator, which is of interest because both drugs did control relapse rates. The S1P agonist was better than teriflunomide in that particular study, but we started to see an effect on fatigue that got better and better. It wasn’t a transient effect from starting the drug. It improved as the trial went on. Maybe this particular drug is impacting the primary fatigue that Pat was talking about.

We’ve seen exploratory outcomes of all the other drugs that have been out there. Those suggested an effect on fatigue post hoc, but here’s 1 of the trials that looked at prospective and chose it as the first secondary outcome measure.

That’s a wrap on the study, but if you want to get into particulars, I’m happy to discuss those too, Fred.

: Scott, do you have thoughts about this?

: Yes. Fred, you mentioned the value of PROs. Moving forward, at least in the United States, the FDA is requiring PROs to be in clinical trials. We’re learning the value of PROs. It’s interesting. They took a big risk using that as a main secondary end point. Am I necessarily surprised by the results? I suspect that some of our other current therapies, if that approach were taken, would probably have hit as well. If you shut down a lot of inflammation within the CNS [central nervous system], that may translate into improving some of those invisible symptoms, as Pat had mentioned. That’s true of fatigue and, potentially, cognitive fogging. Whether that’s a secondary by-product or is getting at the primary fatigue, we still need more data to describe that.

I agree with Mark. It was a big risk to do that. They hit, which is great. Thinking about the mechanism of action of the medications, the S1P modulators obviously work on the CNS side. Maybe the drugs that work on the CNS side have a greater potential to affect primary fatigue in MS [multiple sclerosis].

It’s interesting. We’ll have to see with more studies whether that will be the case with other medications. We need to continue to look at PROs in clinical trials, because at least in my practice, there was that disconnect between what the patient was experiencing and what I was seeing. They have a lot of value.

: That’s the issue with all patient-reported outcomes. There can be a disconnect there, and it could confound what you’re trying to measure. Some of it is just the way you measure them, and some of it is not understanding what the role of the specific medication is.

: It was surprising to see the benefit of teriflunomide benefit on fatigue, to be candid. The data are the data, but we’ve had S1P receptor modulators, and no one has told me the fatigue got so much better in my patients. I haven’t seen it. They also used an FSIQ [Fatigue Symptoms and Impact Questionnaire], which people were not familiar with. I know it’s a validated PRO for fatigue, but it’s not a typical one. It’s quite interesting. I can’t argue with the data. It will be interesting to see if they get it in the label. I know they’re in front of the FDA right now.

I’d like to see some additional backup, because maybe it’s giving some insight. Remember that ponesimod is theoretically just S19 receptor 1, so it’s interesting.

: Any thoughts on the pathophysiologic mechanism?

: Absolutely not. I am a doubting Thomas. Give me some more data.

: There is a bit of S1P receptor 5 in there, but that idea doesn’t have the good data that some of the other S1P agonists have on CNS penetrance. If you’re thinking of a CNS-penetrance type of phenomenon, then that may be harder to prove. There are a considerable amount of data that cytokine release can drive fatigue. Many of these drugs, and others, cut down on cytokine release. Overall, they lower it with time. I don’t know which 1, or compilation of several, is driving the fatigue.

Some of the data that will be looked in this and other studies concern the reduction in the overall cytokine levels and matching that to fatigue levels. That has been hard to do, as you know, because measuring cytokine levels over time is difficult. They’re all over the place most of the time, even in a normal person. It’s a real challenge to do that, but the theory behind it is that we know certain cytokines are driving fatigue. I know IL-1 is 1 of the first cytokines. That’s the endogenous pyrogen in the brain. It drives fever, so it’s not surprising that some of these other inflammatory cytokines have the ability to drift into the brain and impact that primary fatigue mechanism.

It’s not unique to MS. A lot of the autoimmune diseases, which also enhance cytokines, are associated with very severe fatigue.

: Yes, that’s true, especially for things like lupus. 

OPTIMUM Phase 3 Trial: Secondary End Point Effect on Fatigue

Panelists debate the results of the TRIUMPHANT-MS clinical trial of 3 commonly used medications for treatment of MS-related fatigue (amantadine, modafinil, methylphenidate) vs placebo in fatigued subjects with MS.

: I want to ask Scott to tell us a bit about the TRIUMPHANT-MS trial. Prior studies of medications to treat MS fatigue have been less than entirely satisfactory. They produce conflicting results, and it’s been difficult to study. Scott, take us through this particular trial.

: This is an interesting study. A colleague of mine at Johns Hopkins Medicine spearheaded this. It was PCORI [Patient-Centered Outcomes Research Institute] funded. What are the more common oral therapies that we use in clinical practice for fatigue in our patients? We sometimes try amantadine, Adderall [amphetamine-dextroamphetamine], Ritalin [methylphenidate], or Provigil [modafinil]. Bardia Nourbakhsh was interested in looking at 3 of the more common antifatigue medications, including amantadine, Provigil, and methylphenidate vs placebo. Patients were randomized. At different timepoints, they were all on 1 of these medications and then would switch to another. The bullet point here is that none of the treatments that we typically use for fatigue in MS were superior to placebo.

It was interesting because I use these medicines all the time in patients. It’s like a flip of a coin which of these medicines will help, even if it’s subjective. It was interesting to see the final results. It was a small study. It was a pilot trial. It was short in duration. Given the small sample size, maybe there are subgroups of patients who would benefit from 1 of these therapies.

If you look at some of the secondary end points, there was some suggestion of statistically significant improvements in fatigue or psychosocial fatigue with these medications vs placebo. That says to me that in certain circumstances, maybe these medicines will be helpful. There was a sleep index that showed significance. You wonder, is that just an effect because someone is tired? You give them Provigil, for example, which we know was approved for narcolepsy. Maybe the added benefit is for those who don’t sleep very well.

The question is, has that changed my practice for my patients currently? Not really. I will still try these medications, just because we have nothing else to offer outside sleep study, exercising in moderation, or quitting smoking. It’s about healthier lifestyle choices. If you’re on interferon and we can connect that the fatigue worsened in that context, maybe we can switch the therapy because of that.

Right now, we need further data. We need a larger study to prove that there’s not a subgroup of people who would respond to the therapies that were studied. That’s my 50,000-foot view on it.

: Right now, I have a lot of it. It could be a lot of things. It could be that you’re not happy in your life, whether it’s your home life or you lost your job. It’s a pretty broad umbrella.

: Pat, what are your thoughts on current strategies for treating fatigue?

: If we could figure out the cause of primary MS fatigue, that would give us meaningful treatments. We can see that there are maybe 3 popular antifatigue medications. We disabuse patients. We say there’s maybe a fifty-fifty chance they will fail—granted, it’s a preliminary study, but they all failed. They fell on their faces. We don’t have great treatments. I’m not very encouraging. I’m happy to try them, and I still do. It argues for figuring out what causes primary MS fatigue, because then we could target development of treatments much better.

: I would like to have seen a fifth arm in a study like this. I work closely with an exercise physiologist, and she is adamant about regular exercise. We all know this, because the data are coming in regularly. It doesn’t matter how you do it, at what stage you’re doing it, or a patient’s EDSS [Expanded Disability Status Scale] rating. There is an established benefit of exercise at every level. One of the factors that’s been affected by exercise is fatigue.

If a patient can increase their exercise tolerance, by definition, they’re doing away with the fatigue. If nothing else, adding that to whatever pharmacological measure you’re using will probably give you much more benefit. My bet is that if you did the randomized study with that fifth arm, that would probably come out on top.

The problem with the Hopkins study was that, as both of you have alluded to, fatigue is this huge, heterogeneous category. There are probably patients in there that are in need of a booster for their wakefulness. That’s where these drugs with amphetamine bases are probably going to have some benefit. But the downside is they cause insomnia, and that may worsen the sleep problem.

In select patients, some of these medications are useful. The study does show us that if you throw everyone in there using the fatigue index as a measure, you’ve got so much heterogeneous response that the overall outcome is negative.

TRIUMPHANT-MS Trial: Fatigue in MS

Patricia K. Coyle, MD, explains the different types of fatigue associated with multiple sclerosis and the importance of questioning patients about their fatigue in order to help identify the cause.

: Pat, why don’t you take us through the MS [multiple sclerosis] fatigue and what people need to know about it?

: Fatigue is 1 of the invisible symptoms of MS. Many people feel it’s the most significant MS symptom and can be the most debilitating. It is reported in up to 80% to 90% of individuals. It’s a very important symptom to talk about. You have to ask the patient, and then you can see by probing the impact it may have on daily activities. What have they given up because of their fatigue? You can also confirm it with family members. There are a number of patient-reported outcomes that are used to report on fatigue.

When approaching fatigue, I remind myself that there are different forms of fatigue. There’s normal fatigue. Very rarely, there may be fatigue related to a medical problem like thyroid disease, which is increased in MS, anemia, or respiratory difficulties. There’s a fatigue associated with depression, and depression is a symptom of MS. It’s a comorbid condition that can manifest with increased fatigue. You can have sleep disorders that are producing fatigue during the day. You may have physical disabilities that prevent the patient from being able to be as physically active as they can be and contribute to fatigue. Then you have the mysterious primary MS fatigue. I’ll mention that you can also have fatigue secondary to medication that the individual is taking. You need to think about that. There may be more than 1 type of fatigue in the MS individual. You have to probe for that specifically, and it should be in an organized fashion.

The primary MS fatigue is the thing that’s left that seems to be associated with MS. We don’t have great treatments for that. It has to be a multimodal approach. One of the peculiar features is often that it’s heat sensitive. Thus, temperature manipulation can be used as a treatment. It seems to be central, not peripheral, and people are searching for the pathogenesis.

Why does primary MS fatigue occur? What causes it? That might lead us to the most effective treatments. It’s been associated with certain atrophy in the brain, particularly of certain gray matter. It’s been related to immune inflammatory factors. There are even some recent data suggesting the gut microbiome may be linked to primary MS fatigue. There’s evidence of disruption in circuits within the brain, which is a burgeoning area. Functional MRI scans can look at that. There may be dietary issues, and the serotonin pathway is involved.

The bottom line is, we don’t know what causes primary MS fatigue, but it’s very important to identify and try to optimally treat. Interestingly enough, a good aerobic exercise program can help to decrease fatigue.

: Pat, tell us a bit how you approach the patient to sort out sleep patterns, mood issues, and such.

: I’m going to tick off those things when we determine that a patient has significant fatigue, and I may want verification. I may ask them for examples. How is this preventing you from doing things? I might speak to family members as well. Then I’m going to assess them for depression. I’m going to talk about their sleep and interrogate whether sleep hygiene is good or if there may be an issue there. I’m going to review their medications and see if they’re on anything that temporally may be related to the worsening fatigue. We’re going to look at their activities and whether they program in some rest periods. Are they doing very strenuous things? Do they have long commutes to work, for example? Do they need to go upstairs to use the bathroom at work? That could be modified. These are all things you can think about.

If they’re not following a wellness program, I’m going to institute that. I’m going to talk about exercise as being helpful in combatting fatigue. I’m going to treat any of the associated issues, and then we’re left with primary MS fatigue. If I can manipulate the temperature system, great. If they need assistive devices, we’ll talk about that. We may try some of the medications, although quite frankly, they’re not great.

: Yes, we’re going to get into that. Are there any disease-modifying therapies that you would avoid in a patient who is complaining of a lot of fatigue?

: I might be a bit concerned about the interferon betas in that regard, but not strongly concerned.

: Mark, do you have any thoughts on that question?

: In terms of avoiding therapies, I agree with Pat. Anything that’s going to produce that feverish adverse effect is going to make the fatigue worse, or at least perceived as worse. I don’t think any of the others have been worrisome in terms of fatigue, but we’re now starting to see emerging evidence that some of our disease-modifying medications might affect fatigue positively.