“We’re going to continue to learn more and more, as more studies are done. In our annual meeting this year, there was sort of a peppering of many of those topics, and I encourage people to take a look because I certainly learned a lot watching some of these presentations.”

Consortium of Multiple Sclerosis Centers (CMSC)

 launched its annual meeting in a virtual format, offering 4 days’ worth of events and presentations covering a plethora of data and information surrounding the treatment and management of multiple sclerosis (MS) and related diseases. Despite it being an unprecedented year, CMSC 2020 continued to offer a focus on multidisciplinary care within these patient populations.

, Scott Newsome, DO, MSCS, FAAN, president, CMSC, and associate professor of neurology, Johns Hopkins Medicine, offered his perspective on this year’s meeting and its topics. He noted that the presentations ranged from updates on the emerging therapies in MS and diseases like neuromyelitis optic spectrum disorder (NMOSD), as well as the latest news on the complementary therapy front.

Newsome also discussed in further detail what the most recent data on disease-modifying therapies and non-pharmacologic interventions suggest about the importance of taking a more holistic approach to the management of patients with MS.

The Multidisciplinary Theme of CMSC 2020

“It was a really fascinating Whitaker presentation that was very dense with information.”

 launched its annual meeting in a virtual format, offering 4 days’ worth of events and presentations covering a plethora of data and information surrounding the treatment and management of multiple sclerosis (MS) and related diseases. One such presentation was the 

, done this year by Peter Calabresi, MD, of Johns Hopkins University School of Medicine.

As Scott Newsome, DO, MSCS, FAAN, president, CMSC, and associate professor of neurology, Johns Hopkins Medicine, detailed in an interview with 

, this year’s talk focused on laying out the punitive mechanisms that play a role in MS disease progression—a particular area of interest in progressive types of MS. Calabresi additionally walked through his own research in remyelination, and the current landscape of MS-related biomarkers.

Newsome offered further detail into each of the objectives of the lecture and shared his perspective on the understanding of MS disease progression, and the role that the induction of—as well as lack of&mdash;remyelination can play in the context of progressive MS.

Progressive MS: The 2020 Whitaker Lecture

Ocrelizumab Compared to Glatiramer Acetate and Dimethyl Fumarate for MS

: The next abstract I was asked to comment on was the post hoc analysis of the combined ASCLEPIOS I and II trials, which compared subcutaneous ofatumumab with the oral formulation of teriflunomide in relapsing disease. In this particular case, they were looking at NEDA-3 [no evidence of disease activity]. Just to remind you what NEDA-3 is, it’s no evidence of disease activity, which means no clinical attack, no new MRI [magnetic resonance imaging] lesion, and no particular EDS [Ehlers-Danlos syndrome] at progression, with a view to try to present ofatumumab as a superior medication to teriflunomide, which was proven in the primary analysis of these 2 drugs.  

I don’t think it was particularly surprising that when you do a post hoc analysis of a study that’s already positive, the chances are you’re going to get another positive result, and that’s true for any kind of post hoc analysis.  

NEDA-3 is something that people are working toward as an outcome measure that is going to be standard today but has not been accepted necessarily by authorities. Hence, the reason for putting it in a post hoc analysis. Most of these studies, to get registered with the FDA, would require a primary analysis, usually based on relapse rates, which it had already proven in both studies individually in the combined analysis. 

At the end of the post hoc analysis, not surprising, ofatumumab showed significant increase in NEDA-3 over the patients who were taking just the teriflunomide.  

Does this add anything to our knowledge regarding the efficacy of ofatumumab? I’m not sure. I think it’s of interest. 

What does this all mean with regard to NEDA-3 as an outcome measure? Our problem is we don’t know what the natural NEDA-3 would be. We know that in some placebo-controlled studies recently that the NEDA-3 rate for even the placebo group was not insignificant, especially if not a lot of MRI studies are done. The rule of thumb is the more you look, the more you find. If you did an MRI every month, the chances of being NEDA-3 at the end of a period of time would be almost 0, since MRI picks up a lot of different new lesions. But if only 1 or 2 MRIs are done and maybe 1 or 2 clinical visits, so there’s not a lot of chance to pick up disease activity, you’re going to see that even a placebo group would probably have a substantial NEDA-3 rate.  

Buried in this study is that group of people who, by natural history, are achieving NEDA. We don’t know that component in either the ofatumumab or teriflunomide group. Regardless, more of the ofatumumab patients achieved NEDA-3 at the end of the time period compared with the teriflunomide group. Keep in mind there’s probably a substantial portion of both of those who did not necessarily benefit from either treatment. 

I don’t think having these outcomes necessarily adds to my confidence that ofatumumab is superior to teriflunomide. The primary outcome told us that. It’s just another way of looking at all the data compiled together. I’m sure we’re going to see other abstracts with subsequent post hoc analysis of the MRI studies and some of the other metrics that were applied in this particular trial, which were not considered the primary or secondary outcomes but the tertiary and exploratory outcomes that one likes to achieve when dealing with a large study like this. They help eventually understand the population that might best benefit from a particular therapy. Although it’s not proof that that population will benefit, it’s the kind of hypothesis-generating results that help guide us to either design new trials or to focus in and enrich a population that would be the best responder to medication X over Y. 

Post Hoc Analysis: Phase 3 ASCLEPIOS I and II Trials in Relapsing MS

: I would like to discuss the ENSEMBLE PLUS study, which is a study on the short infusion time of ocrelizumab. As you know, ocrelizumab is an anti-CD20 monoclonal antibody, which has been approved in the United States and also in Europe and in the rest of the world, for the treatment of relapsing-remitting MS [multiple sclerosis] and also for primary progressive MS. In fact, it is the only drug approved for the treatment of primary progressive MS. 

Typically the infusion duration is about 6 hours in total, which is OK in the sense that it’s a convenient drug; you take that drug IV [intravenously] every 6 months. Six hours is OK, but we would like, of course, to have a shorter infusion period. ENSEMBLE PLUS was a randomized, double-blinded substudy to the single-arm ENSEMBLE study. And if you remember, ENSEMBLE was a trial on early relapsing-remitting MS, naive patients with a disease duration of less than 3 years. In ENSEMBLE PLUS, ocrelizumab, the usual dose of 600 mg was administered over the approved infusion time, which is about 3 to 3.5 hours, and was compared to a shorter infusion period of about 2 hours. 

And at the end, 291 patients and 289 patients were randomized to the conventional and shorter infusion subgroups, respectively. And in fact, we didn’t find big differences at all. In the first randomized infusion, 23% in the conventional, and 24.6% in the shorter infusion group, had some sort of infusion reactions. And most of the infusion reactions were mild to moderate, which is good news. Most of the infusion reactions resulted without any problem at all. 

No infusion reactions in either of the 2 groups were life-threatening, serious or fatal, and we had 1 severe infusion reaction in each of the groups. One in the conventional and the other in the shorter-duration group. So no infusion reaction—related discontinuations occurred, which is also very good news.  

I think the conclusion here is that this primary analysis suggests that the frequency and severity of infusion reactions are comparable between the conventional and shorter infusions, and no new safety signals were detected. And I think this is important. Specifically in the era we are living in now, this COVID-19 [coronavirus disease 2019] era, where we don’t want patients to spend too much time in infusion centers or in the hospital. So the shorter period for the infusion is better for the patient and for the hospital as well. I think from the scientific point of view it’s not an extraordinary trial. But from the practical point of view, I think it’s a very good piece of information. 

Primary Results From the ENSEMBLE PLUS Study

: The next abstract I was requested to comment on was some post hoc analysis from the EXPAND study. This is the siponimod treatment of secondary progressive MS [multiple sclerosis], with the primary outcome being a disability progression measure. The overall outcome of that study was positive but involved the entire population, a substantial subset of which had still been experiencing relapses in the 1 or 2 years prior to coming into the study. They decided to look at this post hoc analysis by separating the patients who had relapses from those who did not have relapses prestudy, because the initial thought was that the patients who were having the relapses were probably driving most of the treatment effect on disability progression.  

By separating them, they looked at confirmed disability progression, or CDP, at sustained periods of either 3 or 6 months. Their own data show that the percentage reduction in the patients who had not experienced relapse was quite small for 3- and 6-month progression, and the numbers they quote for that were 18% and 13%. This is in the patients who had relapses in the prior 2 years. However, their confidence intervals crossed 1, so in that circumstance neither of those numbers was statistically significant.  

When you look at the patients who did have relapses, the reductions were actually quite higher, 33% for 3 months and 37% for 6 months, although we’re not given the statistical significance or the confidence intervals there. Their conclusion that patients who did not have relapses were also benefiting is called into question here. 

The only significant adverse effect in the nonrelapsing patients appears to be the 25% reduction in patients who had attacks in the 1 year prior to the study, since that confidence interval does not cross 1. The relapsing patients look like they had significance in both the 1 and 2 year, but those numbers are not provided.  

In the end, I’m not convinced there’s a treatment effect really in patients who have not experienced relapses, and I believe that is in keeping with the way in which the drug is actually advised to be used by Health Canada. I don’t know if that is the case with the FDA. Patients with active forms of secondary progressive MS and active MS usually means patients who’ve had relapses in the prior 2 years or changes indicative of new lesion formation on an MRI. Those are the ones most likely to benefit from siponimod. 

Post Hoc Analysis: Phase 3 EXPAND Trial in Secondary Progressive MS

: The last abstract was from the virtual American Academy of Neurology Annual Meeting, where long-term data were now being analyzed from patients who were in OPERA I and OPERA II. Those are the 2 relapsing, remitting trials comparing ocrelizumab with subcutaneous interferon-beta-1A [INFBR1A]. In those studies, patients moved over after the 2 years from the interferon to the ocrelizumab arm. In the open-label extension of both these studies, patients were followed and examined at regular intervals. This particular report suggests that after 6 years the patients who reached confirmed disability progression were small in number. But no one knows what the natural history is, so all we can say is those patients who were in the study and took ocrelizumab, especially took it at the beginning rather than crossed over from the interferon arm, seemed to have lower overall progression rates at year 6 compared with those who delayed treatment with the ocrelizumab and were assigned to the interferon arm initially. 

We are not told about the dropout rates and who dropped out of each group. The overall scheme is just that if you stayed in the study, chances are you were probably doing well. The implication is that probably more patients dropped out of the interferon arm, because they were unlikely to have done well. But we have no real comparator here in terms of the natural history of this group that we could rely on, saying, yes, this is a significant effect, and this would not have happened by natural history alone, or that the patients who were randomized from the start on ocrelizumab are that much better.  

But the data can be used to say that this is a higher-efficacy therapy. In terms of ocrelizumab, we know that. That’s what the 2 OPERA studies showed. Moving on to a higher-efficacy therapy from the beginning seems to indicate that that would be the best outcome in the long term, and this is quite intuitive today. Other large studies have also intimated the same, that higher-efficacy therapies from the outset tend to have the best long-term prognosis. 

Open-Label Extension: Phase 3 OPERA I and II Trials in Relapsing MS

: I would like to discuss the paper on the reduction of the risk of secondary progressive multiple sclerosis [MS] in patients who were treated with cladribine in the CLARITY study. As you know very well, cladribine is an oral medication for multiple sclerosis. Cladribine selectively depletes lymphocytes, and it has a minimal effect on the immune cells. 

In the CLARITY study, quite a large number of patients were studied—433 were treated with cladribine, and 437 were treated with placebo. All these patients had relapsing-remitting multiple sclerosis. The progression to secondary progressive MS [SPMS] was not a defined outcome of the trial.  

This paper for the CMSC [Consortium of Multiple Sclerosis Centers] 2020 annual meeting, they used a number of combinations between confirmed disability for progression, and also confirmed progression of functional systems, mainly pyramidal, I guess to define a sort of secondary progressive MS. It’s like a proxy of SPMS. 

Overall, to be brief, the proxy SPMS progression was seen in 6.7% of cladribine-treated patients, versus 13.5% in patients who had placebo. It’s quite a difference, in a statistical and significant way.  

Then if we split the patients into 2 groups, those with a baseline EDSS [Expanded Disability Status Scale score] of 3 or lower, and those who had an EDSS at baseline of 3.5 or higher, the difference are still there. Just to give you some numbers, in patients with a baseline EDSS of 3 or lower, proxy SPMS progression occurred in 3.5% versus 7.7% in the placebo group.  

And in patients with a baseline EDSS of 3.5 or higher, the numbers are 12.2% in patients who had cladribine versus 22.4% in patients who had placebo. You can see that difference between patients treated with cladribine versus placebo in relation to this proxy SPMS concept, or outcome. Also if we look to patients who reached an EDSS of 6, which is quite a high disability, the difference was there.  

I think in conclusion, the risks of progressing to SPMS, using a proxywithin 2 years of treatment for relapsing-remitting MS, cladribine versus placebo, are significantly reduced in comparison to placebo. And this is independent from the baseline EDSS, which I think is positive data, and it’s a good piece of information that, again, transmits to our patients. 

The question here is always the same. We are now using anti-inflammatory drugs to treat patients with relapsed-remitting MS. Only 1 drug has been approved for the treatment of SPMS, and only 1 drug has been approved for general primary progressive MS. 

I think it will be very difficult to run an SPMS trial in many of these drugs. So it’s very nice to analyze in a different way the data we already have, and identify if there is any signal of efficacy in reducing the percentage of patients who develop SPMS. I think that’s the main message coming from this study. 

CMSC Data Release: Abstract DXT58 and MS Risk Reduction

: I was the first author on the paper on efficacy and safety of the BTK [Bruton’s tyrosine kinase] inhibitor evobrutinib in relapsing-remitting multiple sclerosis over 108 weeks. That’s an open-label extension to the phase 2 study.  

You probably remember that BTK plays a role in the B-cell microphage signaling, and evobrutinib has a dual mode of action. One side impacts B cells and myeloid cells, and the CNS [central nervous system]. So from the mechanistic point of view, it is quite an interesting molecule.  

In a phase 2 study that was published last year in The New England Journal of Medicine, in patients with relapsing MS [multiple sclerosis], evobrutinib significantly reduced the cumulative number of patients with T1-weighted gadolinium-enhancing lesions compared to placebo, including weeks 12 to 24 of treatment, and was generally well tolerated. 

Now what we wanted to do is to assess the long-term efficacy and safety in the open-label extension of this study. If you remember the phase 2 study, in the 48-week, double-blinded period, patients received evobrutinib 25 mg or 75 mg once daily. Also we had another group of 75 mg twice daily, and then we had open-label dimethyl fumarate or placebo for the first 24 weeks. 

At 24 weeks, we had our primary end point, it was an MRI primary end point of course, gadolinium-enhancing lesions. All arms continued with the original treatment until 48 weeks, except placebo, who were switched to 25 mg once per day. And then at week 48, and this is the open-label extension part of the study, all patients were initially treated with 75 mg once daily. And then when we realized that 75 mg twice a day was better, we switched all patients to 75 mg twice per day. 

At the end, I think the important data are that 80% of patients completed 108 weeks of treatment, which is very good in my opinion. And for patients who received evobrutinib at 75 mg twice per day in the double-blinded period, the annualized relapse rate was 0.11, which is very low, at week 48, and 0.12 for the 108-week period. 

Evobrutinib after this period was generally well tolerated. The safety profile was maintained during the 60-week observational extension period, and nothing very serious appeared from the safety point of view. 

I think that the data were quite encouraging, and I wouldn’t say there was a lack of safety issues, but in general, it was well tolerated and no serious signals were observed. And the good efficacy prompted us to design 2 phase 3 randomized trials evaluating the efficacy of evobrutinib in patients with relapsing MS against dimethyl fumarate on this occasion. 

I would like to comment that I feel very fortunate. I think we are very lucky. I have been discussing 3 different abstracts using 3 different molecules for the treatment of multiple sclerosis. And 2 out of the 3 are really powerful molecules. They have already demonstrated efficacy in relapsing multiple sclerosis, and 1 of them in progressive multiple sclerosis. The third abstract shows how attractive, how promising a new molecule with a completely different mechanism of action can be. 

I think we all know that we are living in a very special time in the treatment of multiple sclerosis. And I feel very happy knowing how many opportunities our patients with MS have nowadays to treat their condition. 

Rapid Readout: Clinical Updates in Multiple Sclerosis From CMSC 2020

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