sat with experts and key opinion leaders in the treatment of multiple sclerosis (MS) to discuss the important and innovative topics from the conference. 

Robert Zivadinov, MD, is a professor of neurology at the University of Buffalo and was an author in the TOPIC study, which examined cortical gray matter atrophy in patients with MS. The study was conducted with 618 patients, exploring and comparing the effects of 7 mg and 14 mg teriflunomide to a placebo.

The results showed that teriflunomide significantly reduced the risk of relapse-defining, clinically definite MS with the 14 mg dose (hazard ratio [HR], 0.574; 95% CI, 0.379-0.869; 

= .0087) and at the 7 mg dose (HR, 0.628; 95% CI, 0.416-0.949; 

= .0271). The therapy also reduced the risk of relapse or the development of a new MRI lesion compared with placebo at the 14 mg dose (HR, 0.651; 95% CI, 0.515-0.822; 

= .0003) and at the 7 mg dose (HR, 0.686; 95% CI, 0.540-0.871; 

If you asked me, “Can community neurologists assess the cortical atrophy in the way we did in this clinical trial?” The simple answer is no. Because you really need a high-quality MRI and you need the high-quality analysis to produce this data.

But, what community and academic neurologists should take away as a take-home message from this study is that they should not rely just on the lesion development to lead to the clinically definite MS, but they should think that, even in those people who do not have lesions and develop new lesions, they can develop substantial neurodegeneration in the cortex. As a matter of fact, sub-analysis of this study showed that cortical atrophy developed even in those patients who did not have Gd+ enhancing lesions at baseline. So they didn't have inflammatory activity.

I would say there are 2 messages that should be for the neurologists themselves. First, that the cortical pathology is not a late-stage phenomenon of the disease, it's a very early stage phenomenon, and it’s, in a very short period of 4 years, influencing clinical outcomes like this development of multiple sclerosis. So they have to take it into account. Second, that we have disease-modifying treatments, like Aubagio, which already showed us that from the early stage of the disease we can delay this process. I think by delaying this process, probably, we can delay long-term disability.

This is certainly yet to be shown, but I would suspect that this would be one of the reasons why, in a number of studies and other phase 3 trials like TEMSO, Aubagio showed the ability to delay disability progression in patients with MS. Whether this has an effect on cognition, is also yet to be shown, but just to give you an idea, cortical atrophy in all studies that have been done throughout the years, is the best predictor of cognitive disability in patients with MS.

Robert Zivadinov: The TOPIC Study's Key Takeaways

 sat with experts and key opinion leaders in the treatment of multiple sclerosis (MS) to discuss the important and innovative topics from the conference.

Bruce Cree, MD, PhD, is an associate professor of clinical neurology at the University of California at San Francisco Medical School and a key leader of thought in the MS space. Cree discussed the importance of long-term data collection in MS studies, noting that since MS is a disease that is observed in decades, so should its data. He spoke about the way clinical trials have been conducted in MS over the past few decades.

Cree was part of the EPIC study, involving more than 500 patients with MS that has been ongoing since 2004, and has maintained a high retention rate - something Cree stressed is of utmost importance in MS data collection.

Well, I think the eye is drawn to the features that are most immediately apparent. You put it on an MRI scan and you have got a big white spot in the white matter on the MRI, and your eye is drawn to it. You can't help but notice it, and so we're attracted to the things that are most immediately apparent - relapses, Gd+ enhancing lesions, new lesions - on the MRI. These are things that we see right away and we're drawn to them, but you have to kind of take a step back and ask the question, "Well, are those things the true mediators of long-term worsening?"

You have to do the studies correctly. One of the features of our study, that is, I think, an important component, is we have very little attrition - 91% of our patients were available for assessment after 10 years. Other studies that have been 10-year studies have had 40% or 50% of patients. Patients get lost to follow-up. We demonstrated that it is feasible to get high ascertainment traits.

In 1 of the studies that I described earlier, which was an examination of mortality from the interferon beta-1b pivotal trial - that study had 98% ascertained after 21 years. In a subsequent presentation after mine this morning, there was data from the British Columbia and Red France group that showed exactly the same results. That treatment with interferon beta-1b is associated with a significant reduction in MS-related mortality.

So now we have these 2 independent data sets basically proving the same point. The point being is with really patient ascertainment from either large-scale observational studies or carefully meticulously, deeply, phenotype cohort studies like ours, you can learn a wealth of information that you simply can't obtain from a short-lived, 2-year or 1-year duration randomized control trials.

Bruce Cree: Long-Term Data Collection in MS Studies

Aaron Boster, MD, the systems medical chief of neuroimmunology at OhioHealth, in Columbus, discussed some of the things that excited him from the 7th annual joint ECTRIMS-ACTRIMS conference.

First, the change in dogma related to how and when MS is diagnosed, which greatly impacts the physician's ability to treat patients sooner and more effectively. Second, he expressed excitement about the long-term data that has been collected recently that now allows physicians to show their patients expected outcomes for years down the line.

There are 2 things that I'm really excited about that I'd like to talk about briefly. One is, yesterday, I sat in the audience and watched us change dogma. We have now heard the recommendations for the 2017 revision of the McDonald Criteria. What I'm saying is, we've redefined how we diagnose multiple sclerosis.

As you look at the diagnostic criteria going back from the 1980s and forward, we have become faster, and faster, and faster. Moving from 2010 to 2017 criteria, we have done that yet again. By reintroducing the use of spinal fluid early on, with clinically isolated syndrome (CIS), we can confirm an MS diagnosis much faster. This is very important because the quicker we can make the diagnosis, the faster we can initiate disease-modifying therapy. The data is outstanding, proving the point that the earlier, the better. That was very exciting, to participate in that audience. 

I'm also very excited about some of the long-term follow-up data. When you do a 2-year clinical trial, it is a very short hypoc. MS is measured by decades, and the person is going to live with the condition for 30 to 40 years. As such, a 2-year investigation may be fully inadequate to really have a meaningful conversation in the real world about "what do we expect?"

Some of the posters that I've participated on looked at alemtuzumab, and the 7-year long follow-up data, and it is amazing. Really, in a nutshell, what we are seeing is that going out 7 years, even though over half of patients never got re-treated, there is a durable effect. We are seeing a maintenance of a very, very low annualized relapse rate. Confirmed disability progression diminishes and stays remarkably low. MRI measures, including atrophy, and inflammatory measures remain amazingly low despite re-treatment. Most importantly the side effect profiles are not changing. Having that information at hand, I can now go back to Columbus, Ohio, and treat people and share with them our expectations now going out 7 years. That is really meaningful.

Aaron Boster: Changing Dogma and Long-Term Data in MS

John Corboy, MD, a professor of neurology and the director of the Rocky Mountain MS Center at the University of Colorado, discussed the lack of information in multiple sclerosis research about why or when patients with multiple sclerosis would like to stop using disease-modifying therapies.

, which is currently enrolling patients aged 55 years and older, in order to explore these data over the next 2 to 3 years, expecting results in 2020. The trial will explore how the risk of relapses and new MRI lesions is affected by the halting of DMTs.

The question is, "is there an ongoing benefit of using the medication, and does that benefit outweigh potential risks?" If the benefit is potentially going down as you age, and if the risk is potentially going up as you age, those lines may cross where you do not really see that the benefits outweigh the risks, in which case - especially with extremely expensive medications such as in our world [of MS] - it would at least be the impetus to us to say, "we should try to do a study to figure this out," and that's what we're doing now with DISCOMS.

A. That is true that when they go off, they are no different from people that stay on, or...

B. That maybe they do significantly worse for whatever reason when they go off, or...

C. They might do a little bit worse - maybe there is a slightly increased risk of having a small scan change - and then the patient will have to say, "Well, is that enough for me to continue to use the medication over a prolonged period of time?"

In 3 years, we'll have data that will say 1 thing or another, or perhaps something in between. We may be able to see, in a relatively restricted group of people - because this is people 55 years and older who have been inactive. No scan change or no relapse for at least 5 years while continuously taking 1 of the approved disease-modifying therapies. At least in that group of people who we think are at relatively low risk for recurrence of disease activity, we'll either be able to say:

So we may get sort of an in-between answer, and that is where patient-reported outcomes and that is where other data and asking a simple question: do you feel better, worse, or about the same now as when you started the study with regard to your relationship with the drug? That is, are you happier being on the drug if you are still on it, or off if you are off it, and what is the nature of that relationship now over a 2-year period of time?

It could be that people have a little bit of new disease activity, but they feel so much better being off of the medication. You can look at that as less cost, [fewer] side effects, whatever else it might be, that they are willing to make that trade-off. It is not for us to decide what they should view as a trade-off. None of the drugs we use are perfect. None of them stop all disease activity, so we know there is going to be some level of disease activity with many of these drugs, even as people age. It might well be that we do not hit a perfect no-disease-activity outcome, and yet people still find that is acceptable to them and they would like to stay off medication.

John Corboy: The DISCO-MS Trial and Halting Disease-Modifying Therapy

Francisco Quintana, MD, an associate scientist at Brigham and Women's Hospital and professor at Harvard Medical School, discussed the need for more efficacious therapies in multiple sclerosis (MS), and how the team he leads with the 

Quintana leads 1 of 3 teams that work hand-in-hand with more than 20 institutions around the world to reduce the time and cost of getting therapies ready for clinical trials.

I lead 1 of 3 projects supported by the Progressive MS Alliance, and particularly, what we are trying to do is that we establish a pipeline to identify new candidate drugs to treat progressive multiple sclerosis (MS). We do this basically, by targeting astrocytes and microglia in the central nervous system (CNS), and the idea is to identify new drugs that could target specifically the pathogenic activities and also identify pathways and mechanisms that regulate these cells in the context of progressive MS.

We know that in progressive MS, what we call innate immunity chronic inflammation within the CNS, might be one of the cellular pathological processes. In order to come up with efficacious therapies for progressive MS - which as you know is one of the most important unmet clinical needs for MS - we need to develop drugs that target specifically that chronic CNS restrictive inflammation.

So, hand-in-hand with having therapies for progressive MS, what we need is reliable biomarkers that any neurologist in his or her practice can use, in order to monitor disease progression and response to therapy. We're actually going to need that when we come up with trials to test these new kinds of drugs because, as you know, it's very difficult to run a trial with progressive MS, so the more data we collect from those trials, and the more sensitive a signal we can get from those trials, the better they will be. So our unmet clinical needs are precise therapies for progressive MS and, I would say, reliable biomarkers.

Francisco Quintana: The Need for New Candidate Therapies for MS

Martin Weber, MD, an associate professor of neurology at the University of Göttingen in Germany, discussed what clinical needs are still not being met in the treatment of multiple sclerosis, as well as how much we have learned from looking at neurofilament and other biomarkers.

Weber noted that while much has been learned in the past few years, we are still in the infancy of understanding the later stages of the neurodegenerative disease and that if progress is going to continue to be made, we must focus on finding additional biomarkers and drugs that have neuroprotective effects.

Martin Weber, MD, an associate professor of neurology at the University of Göttingen:

The biggest unmet need, clearly, is drugs that are acting on the central nervous system (CNS) itself. I think we became very efficient in treating the immune system, and preventing relapses, and preventing lesion formation. I think that's that's a really chief goal, so to say, but I think the continuous process in the CNS, for both inflammation and degeneration, is only partly dependent on this de novo infiltration.

That's a process where we are only starting to understand—which is probably really relevant for disability due to atrophy&mdash;for the hard outcomes, so to say, in patients. These probably can only be influenced by identifying and targeting crucial steps within the central nervous system, probably involving microglia, and astrocytes. [These are] new players of CNS resident cells where there is basically no evidence that any of the established MS drugs are affecting these cells at all.

Now, something that gets attention, which I probably would have answered 2 years ago, which is I think very important, is degenerative measures in MS. Meaning neurofilament is probably one of the most important biomarkers for a patient because it is ultimately the one biomarker that is showing you how much CNS, or let's say how much axons, are lost. Meaning that either that's by lesion information or that's by chronic degeneration of NFL. The neurofilament being high is not a good thing, and so for the first time, we have now a measurement of this degenerative process within the central nervous system. We are only starting to understand that the drugs that we have are only partially influencing this process.

Two years ago I would have said exactly that's the marker that everybody needs to go after, and that's fortunately what happened. Right now I don't see that need yet, maybe throughout the conference, we will identifying the next one.

MS Paris 2017 conference

EP 1: Robert Zivadinov: The TOPIC Study's Key Takeaways

EP 2: Bruce Cree: Long-Term Data Collection in MS Studies

EP 3: Aaron Boster: Changing Dogma and Long-Term Data in MS

EP 4: John Corboy: The DISCO-MS Trial and Halting Disease-Modifying Therapy

EP 5: Francisco Quintana: The Need for New Candidate Therapies for MS

EP 6: Martin Weber: Unmet Needs in MS and What We've Learned from NFL