The Ever-Changing MS Treatment Landscape

John Watson


April 25, 2019

Editorial Collaboration

Medscape &

In early March, Jeffrey Cohen, MD, began a 3-year term as president of Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Medscape spoke with Cohen, director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, about his career spent at the forefront of multiple sclerosis (MS) research, which emerging treatments he's excited about, and what makes ACTRIMS unique.

Jeffrey Cohen, MD

Medscape: You were involved in several key studies that began to shift the treatment outlook in MS. How did that involvement begin?

Cohen: The first clinical trial in which I was involved was the US phase III study of glatiramer acetate, while I was at the University of Pennsylvania. I then moved to the Cleveland Clinic in 1994, specifically to develop the clinical trials program here at the Mellen MS Center.

We just had some recent successes with the interferons and glatiramer acetate, and MRI had emerged as a clinical trials outcome, so there was a lot of optimism and enthusiasm in developing new therapeutics. That's what led to the explosion of new medications to treat specifically relapsing-remitting MS over the coming years.

How would you characterize the current treatment landscape for MS in the wake of that explosion of new medications?

Since the first approved therapy for MS became available in 1993, we've now developed quite a broad range of options to treat it, beginning with the injectables, interferons and glatiramer acetate, and then more recently oral agents and infusion therapies.

The increasing number of therapies provides patients and clinicians with the much broader range of options. The therapies have become more effective, better tolerated, and more convenient. The emergence of orals was a big step forward. Most people would prefer to take a pill to giving themselves an injection. And now the more recent emergence of even more highly efficacious therapies has been another big step.

For relapsing MS, we feel like we have a pretty good range of options. The key question there is what our therapeutic strategy should be. The traditional approach has been that you start with a safe but potentially not very efficacious agent, and then change therapy as needed. But more and more people are discussing whether we should start with more potent, more efficacious agents right from the beginning, particularly as those have emerged and been shown to be well tolerated and safe.

Now that we feel like we have a pretty good handle on how to treat most people with relapsing MS, the other big opportunity is finding treatments for progressive MS and to reverse disability that's already developed.

What about treatments on the horizon? Is there anything you find particularly promising?

For the therapies that are on the immediate horizon for MS, I think many of them are improved versions of already available strategies. For example, fingolimod, which was the first orally available therapy, is a sphingosine-1-phosphate receptor modulator. It's nonspecific; it targets four of the five S1P receptors. Soon, there will be several more selective S1P receptor modulators.

Similarly, ocrelizumab, which is an anti-CD20 monoclonal antibody, has proven to be very useful to treat MS. As a result, there are now are several additional anti-CD20 agents under development, which will build upon the success of ocrelizumab, I suspect.

There also are some novel approaches that are being investigated. Those have not yet been proven to work, so we'll see how those studies go. One approach that has gotten a lot of discussion recently is basically cell depletion and repletion, where you kill one component of the immune system thought to be involved in the MS disease process with the hope that as the immune system rebuilds itself, it will function more normally. In some ways, the anti-CD20 monoclonal antibodies alemtuzumab, which also depletes T and B cells, and then cladribine, which is a recently approved medication, work via that mechanism. That's what I see as being the big step forward for relapsing MS.

There have also been discussions about inducing tolerance for specific target antigens in MS.

That's been tried for many years, and in fact that's how glatiramer acetate is thought to work—by inducing tolerance. The goal would be that you affect one selective aspect of the abnormal immune response, which is responsible for causing MS, and leave the other aspects intact. Conceptually, it's really an attractive approach. The problem has been that it's simply not worked up until now.

What trials are you involved in at Cleveland Clinic now that you're most excited about?

I think there are three studies really worth highlighting.

The first study is looking at one particular kind of stem cell for promoting repair. We carried out a small pilot study of mesenchymal stem cells several years back as a potential approach to repairing the damaged nervous system in MS. Our study and those conducted in other institutions had shown pretty good safety and some indication of benefit. But one of things we learned from all of those studies was that how the cells were manipulated, grown in culture, and administered probably were very important factors. So this study that we're just starting will look at cells that have been induced to produce higher levels of neurotrophic factors, and they'll also be administered intrathecally, which we think is a more effective route.

The second that's about to get under way is a multicenter study funded by the National Institute of Allergy and Infectious Disease's Immune Tolerance Network. It's with hematopoietic stem cell bone marrow transplant for patients who have very active disease that has not responded adequately to available therapies. This study will compare immunosuppression followed by hematopoietic stem cell transplant versus our currently best available therapies, the infusion monoclonal antibodies. On the basis of previous studies, we think that's going to show that hematopoietic stem cell transplant is highly effective with very durable efficacy. Although it does have some safety concerns, those are for the most part all front-loaded, occurring at the time of transplant, and then patients frequently have very stable disease without any additional treatment for years after. I'm serving as the overall protocol chair for that, and then will be the site principal investigator here.

The third is a study directed by Dr Daniel Ontaneda, funded by the Patient-Centered Outcomes Research Institute, which is looking at treatment strategy in relapsing MS. It's comparing the traditional escalation approach, where patients start with an injectable or an oral agent and then change therapy if needed for inadequate response, with the newer approach of initiating therapy right from the beginning with one of the highly effective monoclonal antibodies. That will see whether the latter approach helps patients do better in the long run with reasonable safety. I think that's going to be a very important study, because one of the key questions right now is how to treat relapsing MS.

You've been involved in ACTRIMS since its inception in 1995. What has it been able to do for MS research that perhaps wasn't possible with other organizations focused on that indication?

The gap that we hope to fill with ACTRIMS is to provide a scientifically oriented meeting in North America focusing on MS and related diseases, but with the intention of bringing together clinicians, clinical researchers, translational researchers, and basic researchers into a one-on-one setting where they could learn from each other and share knowledge.

Although it's now gotten to be a pretty large meeting—the just-concluded meeting had around 1200 attendees—one thing that's unique about it is that it's a single track; everybody is in the same room for the whole meeting. I don't know of any other meetings except for some of the smaller one-off specialty ones that do it that way.

Usually we focus on a specific topic, and then create a meeting to addresses it from various angles. For example, the focus of this year's meeting was personalized medicine—whether we could tailor MS diagnosis, monitoring, and therapy to individual patients. We try to come at the theme from different clinical, translational, and basic research perspectives. The intent is that no matter what one's personal specific interest is, we can learn from other people who are looking at the same issue through a different lens.

The other emphasis of the organization is to provide an opportunity for young clinicians and investigators to network with more senior people and to present their work. The organization is really trying to develop the next generation of MS clinicians and researchers.

What priorities have you set for your 3-year term as ACTRIMS president?

One is to develop partnerships with other like-minded organizations. We have a longstanding relationship with our counterpart, the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). We also have established partnerships with the National Multiple Sclerosis Society, who present their Barancik Prize for Innovation in Multiple Sclerosis Research at the ACTRIMS meeting, as well as some smaller, more focused organizations, such as the International Multiple Sclerosis Visual System Consortium (IMSVISUAL) and the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative. Cultivating these established partnerships, and developing partnerships with some additional groups, is going to be one of the priorities of my term. We think understanding MS and developing treatments is a worldwide endeavor and want to work with other groups to accomplish that.

Although ACTRIMS was first started in 1995, really the modern history begins in 2014, when we held a combined meeting with ECTRIMS. From that, we decided to develop our own standalone meeting, which first occurred in 2016. Since that time, the annual forum has been very well established. The organization is now financially secure, so the main priority for my term will be to continue to build on that foundation to make sure that the forum is successful each year and that our every-3-year combined meeting with ECTRIMS continues to develop. That's a much bigger meeting that usually has more than 10,000 attendees each year, where four or five or six seminars are going on at the same time.

And then we will continue to further our mission of trying to foster the careers of young investigators and young clinicians. I don't think it'll be any major changes in our focus, but rather further developing the programs we've already established.

For those young investigators and clinicians, what would you say to encourage them to get involved in an organization such as ACTRIMS?

First of all, for me, MS is the most rewarding and interesting field within neurology and clinical neuroscience. We've probably made the most progress in developing therapies compared with almost any other field, and on the other hand, there are a number of very important unanswered questions. There are a lot of advances that we still need to make.

The reason for getting involved in ACTRIMS is that it's a natural community of like-minded people who are all striving for the same goal, but are interested in working together to achieve that.

Thank you for your time, and congratulations on your new role.

Thank you. As my wife says, all my accomplishments require more work.

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