Hello and welcome to this NeurologyLive® Peer Exchange titled, “Management of Progressive Multiple Sclerosis.” I’m Dr Bruce Cree from the University of California San Francisco Multiple Sclerosis Center. 

Joining me today in this virtual discussion are my colleagues, Dr Joseph Berger from the MS [multiple sclerosis] Division at the University of Pennsylvania, in Philadelphia; Dr Robert Fox from the Cleveland Clinic in Ohio; Dr Kristen Krysko from St. Michael’s Hospital-Unity Health Toronto, in Canada; and Dr Fred Lublin from the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center in New York. 

Today, we’re going to discuss a number of topics pertaining to the diagnosis and treatment of secondary progressive and primary progressive multiple sclerosis. Let’s get started on our first topic.

I’d like to begin with an overview of relapsing-remitting MS, secondary progressive MS, primary progressive MS, and the clinical subtypes of MS, including the presentation and prevalence. Joe, would you like to go ahead and start our discussion on that? 

 Sure. I’d be delighted. Traditionally, we’ve divided multiple sclerosis into different clinical subtypes. The one that is most prevalent is the relapsing-remitting form of the disease, where an individual has an event that occurs with resolution of those symptoms—maybe not in their entirety—and then a second event and a third event. It’s called relapsing-remitting for that reason.

It is the type that is seen most commonly. Of all the individuals who present, around 80% present with relapsing-remitting disease. However, at the initial presentation before you can define it as relapsing-remitting disease, they may present with an isolated event without having anything before that could be recognized as a clinical event related to multiple sclerosis. We refer to that as the clinically isolated syndrome. 

As many as 50% of individuals who have had this disease for 10 or 15 years, at least prior to the availability of disease-modifying therapies, would enter a phase of the illness that has been classified as secondary progressive multiple sclerosis, where they have a slow progression of the disease without there necessarily being clinically identified relapses superimposed on it. 

Those individuals generally have increasing difficulty with their gait, balance, and cognition. You may see other manifestations as well. In my opinion, the frequency with which that is seen has decreased very considerably with the availability of disease-modifying therapies. In years past, the data suggested that 50% of people within 10 to 15 years of onset of their disease would evolve to a secondary progressive form. I don’t think that’s necessarily the case any longer. 

About 10% of the people we see present with what is referred to as a primary progressive MS subtype or phenotype. That’s the individual who slowly gets worse over time. It’s generally an individual who comes in with spinal cord manifestations, worsening gait, and worsening balance. It is sometimes an extraordinarily difficult diagnosis to confirm. Sometimes it’s quite easy, but sometimes it can be quite difficult. There are other things that can appear similar. Those individuals tend to be older than the individuals who present with relapsing-remitting disease. Those are the 4 subtypes that we generally classify MS into. 

 Joe, I’m going to follow that up with a question. For clarity, does secondary progressive MS, which is going to be one of the key topics we review today, always begin with a relapsing-remitting onset?

 Not necessarily. There are individuals who will come in with a progressive phenotype when they present to you. When you question them very carefully, they’ll say, “You know, 5 years ago, I had numbness on the right side of my body. It lasted for 3 days. I thought I slept on it funny.” Or they’ll say, “I had some problems with my vision and it went away.” They often get classified as primary progressive disease, but there’s evidence in their history that there are preceding events that were misclassified. 

A number of people we label with primary progressive disease have actually had an active component, a relapsing-remitting component, sometime in the past.

 Everything Joe just said was true, except for his answer to your question, where he said, “Not necessarily.” Necessarily by definition, they have to start with a relapse. Sometimes the relapse wasn’t recognized at the time.

 Yes, I think that’s what Joe was getting at, and that’s exactly right. Sometimes you do get remote histories reported by the patients, and we don’t necessarily have medical records from those events from 10 or 20 years ago. There may not even be a medical record. Sometimes people will relay an episode of monocular vision loss that clears up spontaneously after a few days, and we don’t exactly know what that event was. 

I’d like to comment on that. It’s the rare individual who comes into the office and when you look at their MRIs, you don’t see evidence of their having had past disease. Almost invariably, you’ll see evidence of there having been disease that they were totally unaware of. We have no idea when the disease starts in the vast majority of our patients. This is an ongoing process.

 It’s important to recognize some of these episodes are really hard to know. A patient may say, “I had some numbness in my leg 5 years ago, but I also had some back pain, and I’d just been lifting,” so we’re not sure. Was it sciatica? Was it a partial transverse myelitis? They might say, “I had a couple of days of some difficulties with my vision,” but it’s hard to tell if it was optic neuritis, irritation, or conjunctivitis. Oftentimes, it’s very fuzzy to know if this was an undiagnosed relapse in the past or some other neurologic symptom unrelated to MS. 

The diagnosis of MS is not always entirely straightforward, nor is the classification. When we can make those classifications, it’s great.

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Clinical Subtypes of MS 

 I want to now turn to the topic of how to diagnose when a patient converts from a relapsing disease course to a progressive disease course. Dr Krysko, what are your criteria for making a diagnosis of secondary progressive MS [multiple sclerosis]? How do you make that determination in clinical practice?

As we’ve been talking about, generally it’s steadily worsening neurological dysfunction after someone has begun with a relapsing-remitting course. There should be worsening of disability independent of relapses. It can be pretty difficult sometimes to tell when that transition occurs because someone may continue to have relapses superimposed. There’s no specific test available clinically that we can use to say that someone’s transitioned to secondary progression. It’s really a clinical judgment, which can be difficult to make.

A study out of Mount Sinai in New York led by Aaron] Miller, MD, showed it took about 3 years to determine when that transition occurred. There was a period of uncertainty over a 3-year interval, despite being a very experienced clinician. It can be difficult to diagnose. We know relapses tend to decrease with age and over time. Development of secondary progression could be an age-dependent phenomenon, so I tend to watch more closely when someone’s in their 40s or 50s.

After they’ve had the disease for a long time, the natural history studies show a median of about 20 years from onset that a transition to progressive disease occurs. Although with new therapies, maybe that’s not as common as in the past. In the future, it’d be helpful to have specific biomarkers that might help us identify that transition better. 

 Do you think that transition might occur early on? Some patients have a progressive phenotype embedded within what we would normally consider a relapsing disease. If you look at the patients and carefully follow them, we sometimes see progression in terms of disability worsening that is not clinically recognized. We recognize it in retrospect when we look at things like the EDSS [Expanded Disability Status Scale] score, timed 25-foot walk, or other measures of disability. 

Do you think that these processes really are one leading to the other, or do you think that the 2 processes are superimposed on top of each other?

 I think there is a lot of overlap. Some of the more recent studies, like your EPIC study, did show the term “silent progression.” There were patients who were classified as relapsing-remitting in the clinic, who did have worsening independent of relapses. We’re recognizing that more, where there could be a gradual worsening, even in the younger patients with a relapsing-remitting definition of MS. 

 There are 2 issues to think about that you’re getting at here, Bruce. One is: is progression there in everyone? I would posit no. The second is: is progression born or made? Is it there in the progressive patients from the very start, or does something happen to relapsing-remitting patients along the course of their disease that then leads them into this transition into progressive disease? I’d be interested in comments on that.

 We know that patients who have a lot of spinal cord lesions are more likely to evolve into progressive MS than patients who don’t. That suggests that there is something back at the inception of the lesions, whenever those lesions develop, that may set into process something that leads to progressive MS. I’m not sure we know the answers to that, although they’re important questions.

Another facet is that it depends on what the patient does. I have a couple of patients who are long-distance runners who first noticed their progressive MS when they were in mile 21 or 22 of their marathon runs. Then it gradually moved back to mile 15, mile 12, then mile 8 of their long-distance runs. When they’re not running, they’re totally fine. Is that consistent with progressive MS? Absolutely. But what if they weren’t runners? If they weren’t runners, we wouldn’t know that they have progressive MS. We have patients who only notice the slowing when they do long walks around the block or when they climb stairs. What happens if they didn’t do long walks or climb stairs? We wouldn’t know they have progressive MS.

Some of progressive MS is defined based on what patients are doing, which is a pretty crummy way to make a diagnosis, but that’s what we’re stuck with. It goes back to when the system is being pushed really hard, whether it’s long distance running, climbing stairs, or long walks around the block. When the system is being pushed for a long duration, that’s when it starts breaking down and we start noticing the progressive aspects of progressive MS.

What I would say is that the illness is extremely capricious, and every patient is different. There are individuals who have relapsing-remitting disease that looks very bad at the inception and then have nothing for extensive periods thereafter. Then there are individuals who have no evidence as best as you can tell, even people who continue to exercise vigorously without any evidence of progression. 

On the other hand, there are people who are wheelchair-bound in short periods of time. It’s very difficult to predict who is going to have that particular outcome. Perhaps we’re doing better. Maybe some biomarkers will help us. We certainly have prognostic factors that we’ve employed, such as the lesion burden in the spinal cord, but it’s extremely difficult to predict.

I would posit that whatever drives relapsing-remitting disease is probably quite different than whatever drives progressive disease. We certainly don’t find that the drugs that are so effective for relapsing-remitting disease have much of an effect in individuals with progressive disease.

Diagnosing SPMS

Before we talk about medications, I want to dig a little bit deeper into SPMS [secondary progressive multiple sclerosis] and some of the work that’s being done in terms of further characterizing it. I’m going to ask Fred to comment on this because this is some of his seminal work in trying to understand the relationship between disease activity and progression, and the utility of providing further classifications. Fred, do you want to take this one?

Let’s look at the disease courses that Joe outlined earlier, which we published in I believe 1996. We looked at them again in 2012 or 2013 to see if they needed to be updated. We decided that the courses had served us well in the clinic, in clinical trials, and the regulators had used them and used them well. But we thought there were some changes that we needed to make. 

One was that we wanted to have a way of assessing, in a dynamic way, where someone was at any given point. To do that, we added 2 subclasses, modifiers, on the courses. One was whether they were active or not active; because once you diagnose someone as having MS [multiple sclerosis], they have it for the rest of their lives until somebody takes the diagnosis away.

When you say someone has relapsing-remitting MS, they have it unless something changes. But over the years, especially with treated patients, you want to know how they’re doing. This is important for figuring out what you’re going to do with them—maintain a therapy, stop a therapy, or change a therapy.

We said, “Let’s characterize them as whether they’re active or not active.” In doing that, we said active meant having had either a relapse or new MRI activity. One of the important points that perhaps we didn’t stress enough because it’s caused considerable confusion, especially among regulators, is that that determination had to be framed in time. We said that you could pick whatever timeframe you want when you see your patient and characterize their activity, but that it should be annually at a minimum. That meant that you should have it assessed annually, whether there had been a relapse or a change in the MRI in the last year. 

The second characterization was for progressive patients—primary progressive or secondary progressive—whether they were progressing or not progressing, and again, framed in time. We all know that there are patients with progressive disease who go long periods without changing as we’re measuring them. We said that you should assess progression at least annually on a clinical basis. We could not come to agreement as to any MRI requirement for progressive patients to assess progression because there is no MRI equivalent for progression. So that, too, had to be framed in time. 

You end up having 4 possible characterizations for someone with progressive disease, which is what we’re talking about today. They could be active and progressing. They could be active, meaning they’ve had a relapse or a new MRI lesion, and not progressing. They could be progressing and not active. That’s a group that we’ll spend some more time discussing because that’s the one that’s probably of greatest interest to us. It certainly meets our most pressing therapeutic need. Then there are people who are not active and not progressing, meaning they are stable.

After you get done doing these things, there are all sorts of consequences, intended and unintended, that you think about after the fact. One of them was that by defining activity as either a clinical event or an MRI event, we equated those. Biologically, I think that makes sense. Because if you have an MRI that causes a lesion but it doesn’t hit clinical threshold, is that biologically less important than one that does? That may be more a matter of the stochastic choice of where the lesion occurred. We also codify the idea that there should be at least an annual MRI in patients who have a relapsing form of MS. That was useful for clinicians for dealing with insurance companies.

Fred, I’m going to follow up with that. You very nicely described the subclassifications of progressive MS in terms of active and not active, with and without progression. Would you say the same set of criteria apply regardless of whether a particular patient is classified as having secondary progressive or primary progressive MS?

Yes. They’re both important in somewhat different ways. There’s some older literature that had suggested that once you hit a progressive phase, it doesn’t matter whether you have any relapses. More recent literature suggested that’s not right; that for example, secondary progressive patients who are having relapses develop disability milestones faster than those who are not. 

It turns out that there’s more activity going on in primary progressive disease than we would have thought a decade or more ago. They also have activity. How much that is contributing to their underlying cause is not as clear-cut because there’s less activity there, but it still occurs.

 Bob, what criteria do you use to diagnose primary progressive MS [PPMS]? It seems like the distinction between PP [primary progressive] and SP [secondary progressive] might have to do with an event that occurred in the distant past that may or may not have been adequately characterized medically. What criteria do you use for PPMS?

 To me, PPMS looks exactly like SPMS. There’s a gradually progressive decline in neurologic function, most often manifested as a walking difficulty. So there’s a progressive myelopathy in walking function, but sometimes an arm function instead, or in addition. The MRI findings are typical of demyelination, but the absence of a clinical episode. As we mentioned, that clinical episode may be a little bit fuzzy, and so sometimes we’re left unsure as to whether the patient has primary or secondary progressive MS. 

At the end of the day, the neurologist has to decide. Do they think there is a history consistent with the demyelinating clinical event? If the answer is no, then primary progressive MS is the diagnosis that one is left with. The bottom line is that it looks exactly like secondary progressive MS, except that a neurologist, in the best judgment of his or her experience and clinical judgment, says, “No, there’s no history of a clinical relapse.”

Bruce Cree, MD: Is MS just 1 disease, or is it all these different subgroups? This is a question for everybody. Should we be thinking of MS as just MS, or should we be thinking about it in these different ways?

Classification and Diagnosis of SPMS

We’re going to move on to talk more about PPMS [primary progressive multiple sclerosis] and SPMS [secondary progressive multiple sclerosis] and their treatments. Joe, I’m going to send this topic over to you. Would you compare the treatment for PPMS and SPMS?

Sure. Why don’t we talk a little about the treatment of progressive disease in general? Up until the ORATORIO study, we didn’t have a treatment for progressive disease, be it PPMS or SPMS. The use of ocrelizumab in patients with primary progressive MS was shown to have a modest effect: a 20% or 30% reduction in disability progression at 3 months in 20% to 30% of individuals. 

There was perhaps some effect from an anti-CD20 monoclonal antibody in individuals with primary progressive MS. That drug and others like it have not been used in SPMS. At least there are no data available yet to suggest that the anti-CD20s are as effective. But there’s no reason to think not. 

There have been studies that have subsequently come out that have looked at SPMS with S1P1 receptor modulators like siponimod, which again shows a modest reduction in the progression of the disease as well as an effect on relapses. My sense is that none of the drugs that we have available for us in the treatment of progressive disease are home runs by any stretch of the imagination. At best, they’re singles or doubles if you want to analogize it to baseball. But at least we’re seeing some effect. 

In my mind and in reading the literature, where they seem to be most effective, at least in individuals with secondary progressive MS, are in those individuals who are in that transition phase where they still have superimposed relapses and active disease. These drugs are most effective in that context. Unfortunately, we still have a poor understanding of what drives progressive disease and the drugs that target those elements of the immune system that are driving it. What we have available to us is a bit disappointing, but at least we have something.

Now that we have something, I’m going to ask Dr Krysko, what do you do when you consider a patient who’s coming in with PPMS or SPMS? How do you determine which of these products to use?

The first factor is whether to start them on a disease-modifying therapy. That comes to what Dr Berger just mentioned. The benefits are there. They’re statistically significantly better than placebo in the trials, but they also have risks. I think especially in progressive MS, where the benefits are not as good as in relapsing-remitting MS, we really need to consider the risk-benefit ratio. 

First, I think age is an important factor because younger individuals in the trials have tended to show a better response to therapy. If we have someone presenting with primary progressive MS or converting to SPMS at a young age, that would be a factor that leaves me more likely to recommend treatment. Younger individuals also have more activity. The patients who have gadolinium-enhancing lesions or relapses recently are more likely to benefit as well. That’s been shown in a number of the trials in progressive MS.

Younger age, recent onset of disease, evidence of new lesions, enhancing lesions, or relapses are factors that make me more likely to treat someone with MS who is in a progressive phase. The rate of progression is also something to consider. Even if someone’s not having activity, if you see them getting worse at each clinic visit, it’s hard not to recommend a therapy that may provide some benefit. Whereas if someone’s stable, it’s hard to know if you’re providing any benefit of the treatment. 

Other factors I consider are the level of disability and comorbidities. Those increase the risks; some of these medications have risk of infection. If someone is already wheelchair-bound, that risk is even higher and makes me hesitate to start a disease-modifying therapy that’s immunosuppressive. 

It’s the same with comorbidities in patients who have diabetes, hypertension, or cardiac disease. They may not tolerate these medications as well, so you need to consider the potential risks and whether you’re causing more harm than good by starting a disease-modifying therapy. Those are some general thoughts about when to start a treatment in someone with progressive MS. I think we’re going to talk about the specific treatments coming up.

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Treating PPMS Versus SPMS 

I’m going to ask Bob to tell us a little about siponimod and its mechanism of action, as well as the design and results of the clinical trial that led to its approval as a treatment for secondary progressive MS [multiple sclerosis]. Bob, tell us about the EXPAND study in siponimod.

Sure. Siponimod is an S1P [sphingosine-1-phosphate] modulator, so it’s in a class of medications that we have explored a fair bit in MS. It has a specific affinity for some of the subgroups of S1P receptors. For siponimod, it’s the type 1 and type 5. It was evaluated in a double-blind phase 3 trial. It was a very large trial, with 292 hospital clinics and MS centers in 31 countries around the world participating, with 1651 patients enrolled and randomized. 

Patients were randomized 2:1 to oral siponimod or placebo and followed for up to 3 years or until the occurrence of a number of predefined outcomes, most notably, confirmed disability progression. 

The patients who enrolled in the study had an average disease duration of over 15 years, so they had had MS for quite a period of time. They had secondary progressive MS for on average about 4 years—so these are patients who have longstanding MS and had evolved into secondary progressive MS for quite a period. 

When the data were analyzed, there was a slowing of progression of disability. The 3-month confirmed disability progression was slowed in the siponimod-treated patients by about 21%. That’s not huge, but not small either. That’s a 21% slowing in the hazard ratio, as measured by the Kaplan-Meier curve. 

Adverse effects were somewhat typical and expected for this class of medication, S1P modulators. They included lymphopenia, increased liver enzymes, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, varicella zoster reactivation, and surprisingly, something we hadn’t seen too much before, seizures. All of these were seen more commonly with siponimod compared to placebo. 

Importantly, the initial dose titration seemed to mitigate the cardiac first-dose effects that we’ve seen with other S1P modulators. Those are the main results; it did show a slowing of sustained progression and disability. There was also a decrease in some of the disease activity measures, like the annualized relapse rate and new lesions—T2 lesions and gadolinium-enhancing lesions—in MRI. There was also a slowing of the progression of brain atrophy in the treated group compared to placebo. 

Bob, I want you to comment on what you think was going on in this study, because this is a little controversial. Do you think that the impact of siponimod and why this particular study was successful was due to lymphocyte sequestration, which is one of the known effects of siponimod on the body? Or do you think that there were additional effects within the central nervous system that might be targets for siponimod, resulting in a clinically favorable benefit of this drug?

Siponimod for SPMS Treatment  

 I want you to contextualize this a little bit further for us by comparing the results of the EXPAND study to the results of the ASCEND study. 

We don’t know for sure how siponimod works in progressive MS [multiple sclerosis]. There was a subgroup analysis that was published with the primary paper. I commend the sponsor for conducting this deep-dive subgroup analysis to help understand the types of patients who benefited more vs the ones who may have benefited a little less. 

What was clear was that the patients who were more toward the relapsing end of the spectrum seemed to benefit more, meaning the younger patients, patients with lower disability at baseline, patients with a shorter disease duration, and patients with gadolinium-enhancing lesions at baseline. All of those types of patients were more likely to benefit from siponimod than the opposite end of the spectrum: those without gadolinium-enhancing lesions, with an older age at baseline, with a higher disability as measured by EDSS [Expanded Disability Status Scale], and those with a longer disease duration. 

It does raise the question of whether, probably not all, but at least a lot of the benefit may have been mediated through the anti-inflammatory effect that we know this class of drug has in relapsing MS. Whether there is additional benefit on the progressive aspects, whatever is driving that in secondary progressive MS, is a little bit less clear at this point. 

Compare that to the ASCEND trial, which studied natalizumab in secondary progressive MS. They did not see a slowing of disability in the natalizumab-treated placebo patients, but did see a reduction in the annualized relapse rate and a reduction in new lesions on MRI. It’s a little less clear, but I think the patients in the EXPAND trial had more active inflammation at baseline, were a little bit more to the left side—the relapsing side—of the secondary progressive spectrum, so they may have had a better opportunity to have a beneficial impact from this therapy, which we know has anti-inflammatory activity. 

 That’s possible. Certainly, one possibility is differences in patient populations at baseline. Another could be pharmacological aspects of the drugs that are different. Lymphocyte sequestration and blockade of lymphocyte access to the central nervous system [CNS] share some similarities. Both mechanisms are preventing the lymphocytes from entering the CNS. 

Bruce, there were some technical issues, though, between the 2 studies. 

ASCEND had a tougher job because, if I remember correctly, they had to show sustained disability, meaning that it wasn’t just confirmed at 3 months or 6 months, but sustained through the entire course of the study. I believe that was at the FDA’s request. That is the correct way to do it, because if you’re affecting progression, it should never get better. That’s a tougher metric. I don’t know why they haven’t insisted on that in subsequent studies, because they should, but that makes it harder to do. 

That’s a great point, Fred. What you’re really talking about when you refer to sustained disability progression, which you defined as confirmed and then sustained to the end of the study, is irreversible disability progression. Right?

And disability progression that’s not driven by relapses. The EXPAND study did take a look at some of this in a post hoc analysis and try to determine whether there was an effect of the drug in that subgroup of patients who never had relapses. They did a number of statistical models around that and tried to show an effect. The effect was consistent, so there may well be a property of siponimod that is somewhat different from natalizumab in this regard. But in the absence of a head-to-head comparator, and with potential differences in baseline characteristics as well as end points of the study, you make a really good point, that making a cross-trial comparison of this sort is very challenging.

MS Treatment: EXPAND Study Versus ASCEND Study 

 I want to get into ocrelizumab, and I’m going to ask Dr Krysko to discuss the ocrelizumab study. Dr Krysko, could you get into the details of ORATORIO for us?

 ORATORIO was the phase 3 trial that led to the approval of the first disease-modifying therapy for primary progressive MS [multiple sclerosis]. It was a study of ocrelizumab, an anti-CD20 monoclonal therapy, which depletes B cells, for primary progressive MS. We didn’t include any patients with secondary progressive MS in this study.

Prior to that, rituximab had been studied for primary progressive MS in the OLYMPUS trial. In that study, they found that, overall, the results were not statistically significant. But interestingly, the younger patients, under the age of 51, and those with gadolinium-enhancing lesions tended to benefit. 

That was followed by the ORATORIO study, where they tended to include a younger group and more had some disease activity on MRI at baseline. In the ORATORIO trial, they had a placebo-controlled comparison of 732 patients who were randomized to 600 mg of IV [intravenous] ocrelizumab or placebo every 24 weeks. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks. In that study, the patient population was between the ages of 18 and 55, with a mean study population age of 45 years old, EDSS [Expanded Disability Status Scale] of up to 6.5, and within 10 to 15 years from disease onset, depending on their EDSS at baseline. About 30% of the patients had gadolinium-enhancing lesions at baseline.

The mean study results showed a statistically significant reduction in confirmed disability progression at both the 12-week and the 24-week time points. They had seen disability progression in about 33% of patients on ocrelizumab and 39% on placebo, so the hazard ratio was a 24% reduction in disability progression. That was exciting because it was the first study that showed benefit in primary progressive MS. As discussed before, it was a fairly modest benefit. They also found benefit on brain volume loss metrics in the study.

Many of us are aware of the main adverse events and use ocrelizumab in relapsing MS as well. The same adverse events were described in this study, with infusion reactions and infections being the most common. The infections primarily included upper respiratory tract infections and herpes virus infections, such as reactivation of cold sores. This is the one trial that had a breast cancer signal as well, with 4 cases of breast cancer on ocrelizumab compared to none on placebo. That wasn’t seen in other studies of ocrelizumab.

This trial included a more active group of people with primary progressive MS who were younger and more likely to have gadolinium-enhancing lesions compared to the rituximab study, which led to this demonstration of benefit and the approval of ocrelizumab for primary progressive MS in most countries. It is not approved for secondary progressive MS, though, at least in Canada.

Progressive MS Treatment: Ocrelizumab

 I’m now going to ask the panel a question about the selection of patients. Bob and Kristen provided excellent summaries of the clinical trials. They’ve highlighted a couple of features, which I believe are commonly shared for both studies. Younger patients who have evidence of disease activity, ie, either gadolinium-enhancing lesions at baseline for both studies, or a recent history of relapses for the secondary progressive MS [multiple sclerosis] clinical trial, meaning relapses within 2 years prior to entry into the study, tended to do quite well on these therapies.

I’ll open this up to panel discussion, but I’m going to ask Joe first. How do you select these treatments for your patients with SPMS [secondary progressive multiple sclerosis] and PPMS [primary progressive multiple sclerosis], knowing that some of them have disease activity and others simply don’t?

 It’s an extremely difficult question to answer. I tend to default in my patients with primary progressive MS, particularly those who are younger. We certainly see people in their late 70s and 80s when they first present, and I’m not sure about the wisdom of starting them on any medication. 

But with younger patients, I generally default to ocrelizumab because the data were generated for PPMS with ocrelizumab. As I mentioned earlier, I can’t say that I’m bowled over by the effects of the drug. Sometimes it’s extremely difficult to determine what effect you’re having on the course of the illness because every patient is so unique.

Since we are able to use anti-CD20 antibodies, at least in the United States, and the mechanism of action is similar in the patients with PPMS as in the SPMS group, I often, not invariably, default to an anti-CD20 with patients who have SPMS. I’ll occasionally use an S1P [sphingosine-1-phosphate modulator], depending on what the patient is interested in. There are a fair number of patients who simply don’t get treated. They get treated symptomatically, and I don’t feel as if there’s a particular therapy that’s going to be particularly helpful for them. 

That’s generally what I do, but I depend as much on the patient preferences, which we’ll talk about a little later. There are some patients who come in and insist on being treated. In some instances, I’ve tried both drugs sequentially. When one doesn’t appear to be working, I try another. 

Bob, I’m going to pick on you to follow up on this idea that Joe just mentioned about sequential therapy. Do you do sequential therapy between these products? If so, how do you select which one to begin with? What kind of patient do you begin it in?

There are 2 main things that I’m now wrestling with in the middle of a pandemic, and hopefully we will be in a post-pandemic period soon. We know that older patients have a decreased benefit from these therapies and may have an increased risk of complications. Keep in mind that the siponimod secondary progressive trial enrolled no one over than the age of 50, and the ocrelizumab primary progressive trial enrolled no one over the age of 55. 

We don’t know what the risk-benefit trade-off is in patients who are older than those ages. We have lots of patients, as Joe alluded to, who are over age 60 with primary and secondary progressive MS, and we don’t have trial data to guide us. I am worried that the risk-benefit trade-off may not be positive for patients who don’t have evidence of active inflammation and do have risks of complications from these rather strong immune-modulating therapies. Adding to that, we know the response to vaccines is decreased in patients treated with anti-CD20s, and with S1P modulators. 

We would expect that the response to, for example, a COVID-19 vaccine will be diminished. We know that the complications of COVID-19 in anti-CD20–treated patients are higher than the complications of COVID-19 in the patients not treated with anti-CD20 antibodies. 

We’re now getting a better sense of balancing the risks and benefits, and realizing that there are some risks, risks of other complications and of insufficient response to a vaccine. That has made me quite cautious before I put a patient, particularly those aged over the mid-50s to 60, without evidence of active inflammation, on these drugs. 

In terms of sequential therapy, it’s a little tricky. I’m more comfortable going from an S1P, which washes out quickly, to an anti-CD20. It’s a little bit hard to know when the anti-CD20 is no longer effective, and I don’t have the potential additive complication risk of an anti-CD20 plus an S1P modulator. That makes it much more complicated to go from an anti-CD20 to S1P than the reverse. 

You touched upon an excellent point, which has to do with safety considerations with the potential for sequential therapy use.

Patient Selection in MS Treatment 

 Fred, what do you do with your patients who have nonactive progressive forms of multiple sclerosis [MS]? Do you offer these patients treatment based on the results of these trials, or do you just offer symptom management in that setting?

Following up on what Dr Fox just said, it depends on their age. If it’s a young person who’s progressing, I will try one of these. In an older individual, I actually take the paradoxical view that I do MRIs on them and hope we see some activity, which is of course the opposite of what you want for the younger relapsing population. If I at least see some activity on the MRI, it makes me think I could maybe do something for these people.

When you look at all these studies, including some that failed, like the INFoRm study, if you have activity, you’re more likely to do better. The problem here, which Joe partially addressed, is that even in these studies, we’re treating inflammatory activity, so we have this paradox of how much of what we see in progressive disease is from the underlying inflammation. We know from the pathologist that there’s inflammation there all along the course of MS. We’re not sure how much is underlying inflammation vs neurodegeneration that we’re probably not touching. 

These studies were designed where you couldn’t separate it enough to be sure. People have either shown that they were negative, like the INFoRm study—so even there because the amount of inflammation was sufficiently low. Even though when you dig into it, you can see a therapeutic effect on the inflammation, it didn’t affect the underlying progressive metric in that population.

In the ocrelizumab studies and the siponimod studies, there was enough turning off of inflammatory activity to say, “Maybe that’s what’s going on in here.” But you don’t know for sure because, with ocrelizumab, when you did the subset analysis, there wasn’t enough power to answer the question of whether people had activity or not. 

I’ll raise one other issue: it really depends on how you want to look at activity. Do you want to look at what the activity was when people came into the study, going back a year or 2 years, which is what was done in the unfortunate subset analysis done in siponimod? Or do you want to look at the activity on study, which has been looked at in EXPAND? Nevertheless, that’s actually the population that’s telling you something that’s different between those who do and those who don’t. 

 There’s another component to this: what the patient wants. It’s sometimes very hard to talk patients out of some form of treatment. They come in and have read about these drugs. They know they’re available and they say, “I would like you to treat me with something.” Very often, I feel compelled to do so. It’s hard to talk them out of being treated, even when you describe the risk-benefit analysis.

Joe, I’m not sure our job is to talk patients in or out of a therapy. Our job is to explain the potential benefits and the potential risks before they help choose. I have a lot of patients who make what I think is an incorrect decision, either starting a therapy or not starting a therapy, but it’s a decision that’s in their purview to make. Our job is to give them the data and the information. As long as we’ve given them the proper information, then I think it’s OK for them to say, “I hear you. That drug may not help me much and has some risk, but by jove, I’m going to jump in and try it,” and I say, “OK.” 

 Yes. Well, that’s precisely what I was meaning.

 Shared decision-making is of course what we do in clinical practice today. That’s I have to say entirely different from when I was a first-year medical student and things were done in a very different style. But I think this is a much better way of practicing medicine today.

Nonactive MS: Treatment Therapies

Bob, I’m going to ask you to summarize the ibudilast study that you were the principal investigator on, and comment on neuroprotection. I want you to define what neuroprotection is. Tell us whether you think ibudilast is a neuroprotective drug and whether we’ll ever see application of this in progressive forms of MS [multiple sclerosis].

 Sure. What we’ve been getting at throughout this program is that progressive MS can have active inflammation, relapses, and new lesions on MRI, but a lot, if not the majority, of the progressive aspects of progressive MS are not that. It is something else. It is this gradually insidious pathophysiology that’s leading to a gradual decline in our patient’s function. The therapies we’ve talked about today have been certainly able to target the inflammation. It’s a little less clear whether they target that other aspect. 

Ibudilast is a therapy that tried to target that other aspect. It is an orally absorbed medication. It’s approved in many countries in Asia to treat asthma and post-stroke symptoms. The mechanism of action is a little unclear in the central nervous system, but it does have an inhibitory effect on several cyclic nucleotide phosphodiesterases. Also, macrophage migration inhibitory factor and toll-like receptor 4. These are different cellular pathways that may be related to neurodegenerative processes that may be going on in progressive MS. 

SPRINT-MS was a placebo-controlled trial that randomized patients to up to 100 mg a day of ibudilast compared to placebo. It followed patients over 2 years. The primary outcome was progression of whole-brain atrophy with secondary outcomes, including cortical atrophy, advanced MRI measures such as MTR [magnetization transfer ratio] and diffusion tensor imaging, and retinal nerve fiber layer thickness, as measured by OCT [optical coherence tomography].

The primary outcome was met, in that ibudilast-treated patients had about a 50% slowing in progression of whole-brain atrophy. There was also a slowing in progression of cortical atrophy and a decline in magnetization transfer ratio. There were trends seen in OCT and diffusion tensor imaging consistent with a protective effect, although not statistically significant.

Importantly, there was no reduction in the few relapses seen in these progressive patients, and there was no reduction in the new T2 lesions seen on MRI. This is one of the few therapies that were targeting that other aspect. Even though it did not slow the number of new lesions or disease activity, it did reduce or slow the evidence of neurodegeneration, as measured by things like atrophy and MTR. 

As for its next steps, that was a phase 2 trial. You can’t get regulatory approval based on just MRI outcomes. It is waiting to go into a phase 3 trial. I have not heard any further updates regarding the company that has the IP [investigational product] interest in ibudilast in terms of moving forward into a phase 3 trial. We’re still waiting for that next step: the definitive phase 3 trial for that drug.

Ibudilast for Progressive Treatment 

Management of Progressive Multiple Sclerosis

Experts discuss the diagnosis and treatment of progressive multiple sclerosis.