Patricia K. Coyle, MD: There were 2 interesting presentations on the CLARITY trial. CLARITY was the pivotal phase 3 trial for relapsing multiple sclerosis where they looked at oral cladribine in 2 different doses—3.5 mg/kg and 5.25 mg/kg&mdash;compared to placebo. In the first study they looked at 2 very important markers, the first being transition from relapsing to secondary progressive MS [multiple sclerosis]. They had worked out some parameters that made that very likely. The second was transition to a well-documented disability marker, EDSS [Expanded Disability Status Scale] 6, where you need to use a unilateral cane to get around. They broke down the groups by lower EDSS, EDSS 3 or less or EDSS 3.5 or less, and they focused on the 3.5 mg/kg cladribine dosing group&mdash;which is the proven dose&mdash;and the placebo arm. Indeed, statistically significantly fewer patients, less than half as many, transitioned to secondary progressive MS with cladribine treatment versus placebo, whether their EDSS scores were low or high. In addition, significantly fewer went on to reach EDSS 6, that bad disability marker. 

I think transition to secondary progressive MS is something we really want to prevent from happening because it means inevitable disability, so I thought that was very reassuring. In addition, they also looked at the cohort that had received the 3.5 mg/kg cladribine dose in the 2 years of the pivotal CLARITY trial, and then they went into an extension period. Some of those patients received a whole second course of oral cladribine, whereas another group did not, they received placebo. They looked at time to first relapse, and what they found was that there was no difference between the 2 groups. In other words, the cladribine, which is a very durable induction or immune reconstitution strategy, kept its benefit in years 3 and 4 without further treatment. There was no added benefit to getting the extra cladribine doses, so it really confirmed the label approval, and it confirmed the durability of taking this oral agent—it has a long-lasting effect. 

The significance of this data for the real world is that we have a hard parameter decreasing relapsing to secondary progressive MS. We want to be able to tell our patients that the treatment, the expectation is that it can do that, and the EDSS 6 is a very pragmatic hard marker. The patient needs an assistive device to walk. That's significantly less likely to occur on treatment. It's very reassuring to discuss those very practical take-home lessons for our patients with MS. This is the expectation that the treatment will hopefully prevent this from happening. 

ACTRIMS 2020 News Network: CLARITY Study on Relapsing Multiple Sclerosis

Clyde E. Markowitz, MD: The CLARITY trial was an interesting study. It was performed over a decade ago. We are now looking at those data again because cladribine got approved last year in 2019. What is interesting is that the study was designed as a relapsing-remitting multiple sclerosis trial. It was not designed as a secondary-progressive multiple sclerosis trial. In clinical trials these days, you can actually come up with surrogate markers that could be used as markers of patients with secondary-progressive disease. That could include a certain level of EDSS [Expanded Disability Status Scale]. So you can use maybe an EDSS score greater than 3 or 3.5 with a functional score of at least 2 on the pyramidal, or you could use an EDSS score of 6, which requires somebody to use a cane. Those are defined metrics that you could actually use to make the determination: Is the patient in the trial hitting those milestones?  

As part of the design of the study, patients are followed by their EDSS scores. If they were at a score less than 3, you would have a baseline score, and then you could measure them over time. If they increase their disability progression, you could say they hit a milestone of greater than 3.5, confirmed for greater than 3 or 6 months. They would have met that disability progression. You could have people who had an EDSS score greater than 4 who might progress up to an EDSS score of 6, and you could actually look at these metrics and use those as proxies for secondary-progressive disease. 

In the trial, they looked at this and actually found about a 50% reduction in patients who were treated with oral cladribine compared with the placebo group of those metrics of going by these proxies to hit this secondary-progressive end point. Overall it gives us comfort to say that a medication like this can reduce the risk to go on to develop secondary-progressive disease.   

In the real world, you’re going to ask the question: If I put my patient on this medication, am I going to be able to prevent them from hitting the secondary-progressive proxy end points that we just talked about? The reality is yes, you might actually have this as a very comfortable place to think, “I have somebody who’s maybe on the edge of that conversation, who’s maybe starting to have some ambulatory difficulty. If I start them on this medication at this point, I might actually have an impact in the long term hitting those secondary-progressive metrics.” 

What’s interesting about the CLARITY trial and how the drug is administered is that it’s a very short course of treatment. You’re really using it for 5 days, then the next month for another 5 days, and the following year you use it for 5 days, and follow in the next month with another 5 days. Then you’re essentially done with the treatment. They’re short courses of treatment, and you’re asking the question: How good and long term is the benefit? If you follow these patients—and that’s what they did in the extension trial&mdash;they looked to see what proportion of patients was relapse-free and how patients did in the long term. Is it maintained? 

What was nice is at least from the standpoint of looking at the relapse metrics, there were data to suggest that it is maintained over time. If you were concerned that somebody was going to have a relapse in a short amount of time and the medication may not be very effective at 2, 3, or 4 years, these data would suggest that it’s maintained throughout the entire period of that extension, so that you can feel comfortable putting your patients on a treatment like this and it’s going to have a durable effect that’s going to last for much longer than the duration of the treatment itself. 

ACTRIMS 2020 News Network: Updated Data From the CLARITY Study

Patricia K. Coyle, MD: The EXPAND study was the phase 3 trial in secondary progressive MS [multiple sclerosis] that validated siponimod, a second-generation S1P [sphingosine 1-phosphate] receptor modulator, an oral agent, versus placebo. What they looked at in this study was active secondary progressive MS, those who had had a relapse in the prior 2 years or had a contrast enhancing lesion on their entry MRI [magnetic resonance imaging] scan because that was the ultimate approval, for active secondary progressive MS. Here they were looking at duration of MS. They broke it down into those who were less than 16 years into their disease process and those that were 16 years or longer into their MS process. This is important because in general the longer you're in the MS stage, the less well you respond to treatment because you've had that much more time to develop permanent injury damage to the central nervous system. 

They looked at confirmed disability progression at 3 months and at 6 months—3 months had been the primary outcome and 6 months was a secondary outcome. What they saw were in the patients with active secondary progressive MS, patients under 16 years in disease duration, they had significantly fewer going onto confirmed disability progression either 3 months or 6 months with siponimod versus placebo, even more dramatic changes than in the entire trial. They saw a trend, a clear trend in favor of less progression at 3 months and 6 months in those who had the disease duration greater than 16 years, but it did not reach statistical significance. However, they had fewer patients in the study. So is that an element of fewer patients statistically, or was it that they had longer disease? Obviously, we can't rule out that that was a factor. But still there was a clear trend in less confirmed progression in the siponimod versus the placebo group. 

The real-world significance of this study is that we can say that even if you’ve had very long-standing MS and you’re active secondary progressive, I think the expectation is that you're going to get a benefit from siponimod treatment. It's somewhat arguing to treat as early as possible. You saw even better progression disability lowering in the active secondary progressive MS cohort, so it's certainly an encouraging feature to talk about this as a valid therapy for these patients. 

ACTRIMS 2020 News Network: EXPAND Study on Relapsing MS

: The EXPAND trial, which was a secondary-progressive multiple sclerosis [MS] clinical trial, was really asking the question, “If you have patients who have secondary-progressive disease, would a medication like siponimod make a difference?” What we found in the trial was that it hit on the end points of slowing the rate of disability progression, but the question was, “Is the secondary-progressive population more active?” More active could be having had relapses in the last 2 years or MRI [magnetic resonance imaging] activity, etc. If that is the population we’re going to study, and you ask the question, “Does disease duration play into that?” they broke it out into if patients had disease duration less than 16 years or more than 16 years. 

They were able to show that the population that was active with disease duration less than 16 years had a more robust effect on slowing the rate of disability progression both in the 3- and 6-month time points, somewhere in the range of 35% to 40%. That was compared with people who had a longer disease duration, greater than 16 years, which also was quite impressive but maybe not as robust—in the 24% to 30% range&mdash;in slowing the disability progression. 

To me, the way I view that is in your population of patients who are earlier in the course of secondary-progressive disease, you’re going to have a more robust effect than waiting for them later in the disease. It’s important to identify those patients as early as possible and get them on treatment as early as possible. 

In the clinical practice of MS, it’s really important for us to be able to identify which patients are in that category of progression. Right now, it’s really difficult for us to find a defined point to say, “You are now in secondary-progressive disease.” It’s very slow and indolent. I think we have to start asking these questions, something we were not able to do previously in part because we didn’t really have any treatments that would be able to address the secondary-progressive population, but now we do. We have data now even from a study like this that show the earlier you identify these patients, you may have a greater effect. This becomes very practical to us, being able to figure out how to identify them and asking the questions about progression in the early secondary-progressive setting. 

ACTRIMS 2020 News Network: Effect of Disease Duration in the EXPAND Study 

: There was an interesting abstract that reported on the OPERA study. Recall that these were the phase 3 trials for relapsing multiple sclerosis where patients were randomized to ocrelizumab 600 mg IV [intravenous] every 6 months or subq [subcutaneous] interferon beta-1a, 44 mcg 3 times a week. So, the pivotal trial was 2 years. There was then an extension study, and we're now looking at 6-year data. This is important because you want to be assured that over 6 years you continue to see good safety and you continue to see some efficacy. What they looked at was the group that was randomized to ocrelizumab initially and then had an additional 4 years of study—so 6 years of ocrelizumab study versus those who were on the comparator, the interferon beta, the first 2 years and then went on ocrelizumab in years 3 through 6. They looked at the annualized relapse rate. The annualized relapse rate was higher initially in the interferon beta arm&mdash;it went down when they were switched to ocrelizumab. In the ocrelizumab arm, they continued to have very low annualized relapse rates. In fact, by year 6 we were in the 0.04 to 0.05 range. It was really amazing. They also looked at confirmed disability worsening, and this was the interesting feature. The group that was delayed, that didn't go on ocrelizumab immediately, that had 2 years of a good interferon beta, didn't catch up. There was still a difference. The lowest confirmed disability worsening was in the group that had been on the ocrelizumab for the entire 6-year period compared to the group that had delayed treatment, who were on the interferon beta and then switched over for the last 4 years. 

The real-world application is that ocrelizumab is a high efficacy agent, interferon beta is not. It's additional documentation that there seems to be a benefit in starting early with optimized high efficacy treatment. 

ACTRIMS 2020 News Network: OPERA I/II Trials on Relapsing MS

: In the ocrelizumab extension trial, they looked at patients who were originally on the OPERA I and OPERA II trials. These were the relapsing-remitting multiple sclerosis studies, and they followed patients out after they either converted over from the interferon cohort onto active treatment with ocrelizumab or stayed on ocrelizumab from the beginning. They followed them out to 6 years. 

The question we’ve always been asking about these patients is, “Do the patients who switch over gain a benefit like the patients who originally started on ocrelizumab from the beginning, or is it not really going to help?” The reality is you follow these people out, you look at the patients who remain on ocrelizumab from the beginning, you see how their relapse rate numbers look, and then you look at the patients who switched over and what happened to them. Do they ever catch up? How do things go? 

They looked at both relapse-rate reduction and disability progression. The results that came out of this are that the patients who converted over from interferon gained the benefit of relapse-rate reduction similar to the population you start on ocrelizumab from the beginning, but they never seem to catch up. You don’t get to the level of disability progression reduction as the patients who started ocrelizumab from the beginning.  

I think the take-home message for us—we’ve seen this with many different clinical trials&mdash;is that whatever the more effective therapy is from the beginning, if it started the earliest, it’s going to have the greatest outcome in suppressing disease activity and ultimately in slowing the disability progression that we’re most concerned about. These data really confirmed that as well. 

From a practical standpoint you have to ask the question, “Am I going to start a patient on a more effective therapy from the beginning, or am I going to put them on something that may have a more tolerable safety profile or something that’s a little milder. Overall, after we’ve done so many clinical trials with the different agents that have a higher efficacy, we have learned that you’re best off starting with the most effective therapies. Even though there could be a safety question that you are worried about, those are manageable at this point.  

We know what the safety concerns are. We know how to identify patients at greatest risk, and we’re able to figure out how to manage that. The bottom line is that the field overall is saying we need to be starting with a more aggressive therapy from the beginning. Because you aren’t going to catch up if you wait. 

ACTRIMS 2020 News Network: 6-Year Data With Ocrelizumab

: There was an interesting late-breaking study on ofatumumab. Ofatumumab is a human anti-CD20 monoclonal antibody. It's given subq [subcutaneous] monthly, 20 mg. They give it weekly 3 times initially, and this is an anti-CD20 that lowers B-cell count. It lyses B cells. They actually looked at how quickly it lowered the B-cell count, which was very quickly. You're talking about within 2 or 3 weeks, and the B-cell count remained low throughout the course of treatment. In addition, it didn't seem to matter what part of your body was getting the subq injections, you had a very complete lowering of the B-cell count. They also did do an analysis of injection issues because this is going to be a subq home delivery, and the injection reactions seem to be very mild. They were most pronounced with the very first subq injection of the ofatumumab product and then didn't really seem very bad at all. 

Ofatumumab is not yet approved, but it's going to be approved. It's going to give us an alternative high efficacy anti-CD20 that can be given at home subq. It's reassuring that you saw an excellent lowering of the B-cell count throughout. It is also somewhat reassuring that the subq injection seemed to be extremely well tolerated. 

ACTRIMS 2020 News Network: APLIOS Bioequivalence Study on Relapsing MS

: In the APLIOS trial, the ofatumumab study, we know from the original phase 3 study that the data looked very impressive with regard to B-cell depletion. It was very effective on the metrics of relapse-rate reduction, MRI [magnetic resonance imaging], and disability progression, so it all looks good. The question we’re asking is whether a subcutaneous administration at the frequency that it is administered—which is at baseline, 7 days later, 14 days later, 28 days later, and then every month&mdash;at what point and how deep is the B-cell depletion? That’s really the question of this trial.  

They looked at patients with multiple sclerosis [MS] and they were able to find that by 14 days, you had a quite impressive depletion to the point of having a minimal number of B cells. Essentially, everyone was depleted by 28 days. That was maintained. Since you’re administering every 28 days, that was maintained quite impressively to the level of a 1—B-cell conversation. This is a blood test that we’re doing to measure their B cells. What we never know is what the tissue B-cell numbers are looking like with any treatment. This is what ocrelizumab or ofatumumab. It doesn’t really matter. We know that there are different doses that are being administered. This is a 20-mg once-a-month dosage versus 600 mg every-6-months dosage for ocrelizumab.  

We just don’t know what the tissue B-cell distribution is. We can at least say if we’re just measuring the blood, it’s quite effective in doing this. It mirrors what you see with ocrelizumab as well. Again, we just don’t have the ability to measure it in the tissue, so that’s going to be an unknown. At least from our standpoint, taking these data and applying them to the real world, we’re going to say it’s a very effective B-cell depleter. If you look at the data from the phase 3 clinical trial, you’ve got all the metrics of relapse-rate reduction, disability progression, and MRI that look very similar to what you get with ocrelizumab as well. I think there’s going to be a big added benefit to our MS treatment algorithms. 

ACTRIMS 2020 News Network: B-Cell Depletion in the Phase 2 APLIOS Study  

: There was a very important late-breaking abstract that presented the most recent recommendations on standardized MRI [magnetic resonance imaging] for the brain and the spinal cord in MS [multiple sclerosis]. This has gone through several revisions. The good news is that they coalesce the recommendations of the Consortium of Multiple Sclerosis Centers, or CMSC, and MAGNIMS [Magnetic Resonance Imaging in Multiple Sclerosis], which is the big MRI group from Europe. They've had somewhat different recommended protocols. They coalesced them, so they've united together. They've also made them extremely practical. They talk about using 3D with no gap whatsoever. They put some suggested limitations on the use of gadolinium contrast, saying that it should be used for the diagnosis of MS and if there is suspected worsening, but saying that if it is going to be at the same center and you can make a direct comparison, you probably don't need to do it at other times. This is very important because we need to standardize how we do MRI scans in patients with MS or suspected patients with MS. This gives the state of the art compilation of experts from the United States and Europe who have now agreed on what they think are the best protocols. 

There is a very important feature here. This needs to be accepted. This needs to be taken up, and they really have built in a program where there will be webinars to try to get that done. We need the buy-in of radiology and neuroradiology as well as neurologists, and they're also going to have cards that actually outline the protocols, which they have tried to simplify and make it as straightforward as possible. I think you're going to see a big push to really get people to accept this, and I think this will be a huge movement forward in taking care of MS if we can get everybody to agree on this protocol. 

There were a few other things that were very interesting at the ACTRIMS [Americas Committee for Treatment and Research in Multiple Sclerosis Forum] 2020, but this had a big push on talking about various types of networks, including social networks. I was shocked to learn that social isolation, which means you have 5 or fewer close friends whom you deal with, is associated with a 29% increased risk for mortality. Being socially isolated is the equivalent of smoking ¾ of a pack per day of cigarettes as a negative health outcome. That really surprised me. 

In addition, there was a very interesting discussion about epigenetics and methylation in MS. Their data is suggesting that patients with MS are phenotypically aging, show greater aging than matched controls, and I think this will be something very important to look at further.  

There was also a very interesting preliminary report—the study is still blinded&mdash;of a nanotechnology study for chronic optic nerve and vision loss in patients with MS, where they're looking at crystal gold nanoparticles to boost CNS [central nervous system] repair. Believe it or not you have a quadzillion particles that you drink, take by mouth, 60 mL daily, that get into your brain, and they're looking to see if it actually promotes CNS repair. This is a small study, but it's expanding. It's still in the blinded stage, but I thought that was really very interesting. So, stay tuned. 

ACTRIMS 2020 News Network: Updated Recommendations for Standardized MRI Protocol in MS

: The standardized MRI [magnetic resonance imaging] protocol that has been evolving over the last decade for the most part has given us the capability to try to get patients close to standardized sequences that are used. Because 1 of the things we use MRI for these days is not just the diagnosis of MS [multiple sclerosis] but as a marker of disease activity over time.  

We want to be able to say that if we’re going to use it for purely the purpose of a diagnosis, you need to have sequences for that. At least for that you must have an axial and sagittal FLAIR [fluid attenuated inversion recovery] image. You want to be able to do this with very thin slices. It used to be 3-mm requirements, and now we’d like to get it down to 1 mm with no gaps and be able to have continuous information, so you’re able to see and not miss lesions that could be in important areas like the corpus callosum, for instance.  

That is a requirement. They have core requirements, and they have some supplemental things you could add to this. Another thing that is particularly important is the use of gadolinium. I think overall, the use of gadolinium has generated a concern for potential toxicities, both the renal toxicity, which we had known about, and now there may be a toxicity with deposition in certain areas of the brain. 

Because of that, it’s really more important to use gadolinium as a diagnostic piece, but maybe not so much as a monitoring piece over time, unless indicated. We’re trying to reduce the amount of gadolinium use in that setting. In addition to that, now we’re going to go ahead and use it to monitor for disease activity. We know that clinical activity may show up at a much smaller frequency than MRI activity, so we want to be able to capture any disease activity as soon as possible. In doing so, we want to have a standardized protocol for that.  

The challenge we have in the MS community is that they’re upgrading machines all the time, software packages are different, the strength of the magnets are always an issue, and patients’ insurance coverage changes from 1 day to the next. You can use this place, or you can use that place. It makes it really hard to be able to follow an individual patient over time because of these differences in all these pieces that move around.  

Make sure patients get the proper sequences for follow-up and alignment. The alignment is key because if you’re going to say you need to align the patient’s head between these 2 points, no matter where you get that scan done—and make sure you have them done with no gaps, thin slices&mdash;you might actually be able to use it from other sites. But everybody has to get on board with that because in 1 person’s scan if they made an alignment like this and another 1 is like this and there’s a lesion that’s missed within that conversation, that could be important. Coming up with the most updated protocols for standardizing MRI scans across multiple radiology facilities is going to be really important for us to be able to monitor our patients adequately. 

I would love to be able to have radiologists adhere to this. I think that there has to be a strong enough statement coming out from the MS community that this is a requirement. It is not just a good idea. If you’re going to have a standardized protocol such that this is how we use this information to monitor our patients on treatment, you’ve got to follow these guidelines. It’s just the way it is. There’s no wiggle room in that conversation. It’s standardized and you’re going to have to follow this. It’s not that difficult. It’s just that we have to get that message to all the radiology sites, to the radiologist, that this is what is required and needed by the MS community to adequately follow patients. 

ACTRIMS 2020 News Network: Standardized MRI Protocol for MS 

: This meeting was really quite intriguing. There were a number of basic science ideas that are coming out. Over the next 5 years, I will guarantee that we’re going to see a shift in our emphasis on certain pathology or pathophysiology of the disease that’s going to really help us with the questions of remyelination and neuroprotection.  

Overall, the field over the last decade has been moving toward a more aggressive stance. We have B cells that are now being treated. We’re going to start entering conversations about microglia in the central nervous system. I think there are a number of targets and agents that are currently looking to target microglia. The BTK [Bruton tyrosine kinase] inhibitors are a whole area that I think would really make a difference here in hitting the microglia, the microglia being the antigen-presenting cells in the central nervous system.  

I think you’re going to hear more about how the microbiome that lives in our gut is contributing to what’s happening in the central nervous system. There are a lot of very nice data being presented at this meeting [Americas Committee for Treatment and Research in Multiple Sclerosis Forum 2020] about small molecules that are being released, whether it is by the gut microbiome or the immune cells that are resonant in the gut, and how these can travel up to the central nervous system and activate blood-brain barrier disruption and migrate into the central nervous system. I think this is an area we’ll be spending the next 5 years really investigating. There are some very intriguing targets that were presented on as well. 

ACTRIMS 2020: Post-Conference Perspectives