COMMENTARY

From Vancouver, an Update on Multiple Sclerosis

Stephen Krieger, MD; Robert Fox, MD

Disclosures

April 29, 2016

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Long-term Follow-up of Clinical Trials

Stephen Krieger, MD: Hello. I'm Dr Stephen Krieger, associate professor of neurology at the Icahn School of Medicine at Mount Sinai in New York. Today I'm at the American Academy of Neurology 2016 Annual Meeting in Vancouver with Dr Robert Fox, staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic. Welcome, Dr Fox.

Robert Fox, MD: It's great to be here with you.

Dr Krieger: Let's talk about the 2016 Annual Meeting, particularly around multiple sclerosis (MS). What do you think some of the exciting or emerging trends are in MS that we've seen here at the meeting?

Dr Fox: There were a couple different areas. One was long-term follow-up of many of our phase 3 and phase 4 clinical trials. Many of our therapies for relapsing MS are relatively new to people, and we only have a couple of years of experience with them when they come out on the market. It's important for us to get longer-term experience, and we are now getting more of that. Many of the drugs presented long-term data from 5, 7, even upwards of 11 years. Reassuringly, there was very good safety and there weren't many new safety problems that were identified in these long-term follow-ups.

Dr Krieger: For a long time, we've had our old-school injectable medicines and a cohort of new drugs. Now we're starting to see maturing data for all of them—the orals as well as some of the more recent infusion medicines—with extension data showing that the efficacy can be maintained in a great number of people when treated long-term. As you said, safety has to be looked at carefully. We've seen safety signals emerge in clinical practice during these past couple of years, including rare risks of progressive multifocal leukoencephalopathy (PML) with several of our medicines.

Dr Fox: That's true, and fortunately, although we have seen those new safety signals over the past several years, they've remained very rare. For example, PML with dimethyl fumarate and fingolimod remains in the 1:15,000 to 1:20,000 range. It's not zero, but it's certainly reassuring that these are very rare complications.

Risk Stratification

Dr Krieger: Another theme that we're starting to see is better ways of risk-stratifying our patients and better biomarkers in general, like the JC antibody. We'll see more of that to be sure in the coming years, but allowing us to pick medicines better for our patients and ensure their safety in the long term is where I think the MS field is going.

Dr Fox: Yes, we are learning a little bit more about risk stratification. Intriguing data regarding natalizumab and PML suggest that weight is a risk factor; lighter-weight patients who might receive a higher total dose of the drug or dose per kilogram may be at a little bit of an increased risk for PML. It used to be said that you can't be too rich or too skinny, but it may be that you can be too skinny with this drug.

Dr Krieger: It's true. Why are the rates of PML higher in Europe than they are in the United States? Body weight may play a role.

Dr Fox: The more we learn about risk stratification, we can identify patients who are at increased risk and who should consider alternative therapies, and identify those who are at lower risk and who can be more comfortable continuing therapies longer-term. That will really help us guide patients toward the right therapy.

Ocrelizumab

Dr Krieger: The long-term outcomes and long-term benefits of these medicines have informed how our treatment strategies are being designed. One of the emerging therapies that has received a lot of attention this past year and at this meeting plays off of that. Ocrelizumab is dosed by intravenous infusion at 6-month intervals, which is quite different from most of our medications in MS, which have to be dosed virtually continuously in order to maintain efficacy. Let's talk a little bit about ocrelizumab. Tell us a little bit about the data that have captured your attention here.

Dr Fox: Certainly, one of the most exciting things is how highly effective this therapy is. It has a marked reduction in annualized relapse rate, greater than 90% reduction in new lesions on MRI, and a very robust reduction or slowing in the disability progression rate. I view this drug as being similarly effective as natalizumab, which I think is an encouraging addition to our armamentarium.

Dr Krieger: Especially since, in the relapsing-remitting studies (the OPERA studies),[1] ocrelizumab was compared head-to-head against an active comparator, a standard-of-care injectable interferon, and showed impressive reductions in both relapses and new lesions compared with one of the standard medicines that have been used for a long time.

Another aspect of ocrelizumab that I think has been of interest is the ability to achieve no evidence of disease activity (NEDA) in the relapsing-remitting population. This is typically defined as the absence of evidence of disease activity: the absence of relapses and accumulated disability as well as the absence of new enhancing lesions or new T2 lesions. Ocrelizumab was able to achieve that in about 48% of patients at 2 years. That's a pretty good number. We can't really compare between trials, but having a sense of what kind of efficacy to expect is important.

Dr Fox: I agree. To have almost half of the patients treated with this drug with no evidence of relapses, disability progression, or new lesions on MRI is encouraging. An unclear part of the ocrelizumab story is its role in primary progressive MS. We learned a little bit more about that trial. We knew that, overall, there was a slowing of disability progression across the whole patient population. At this meeting, we learned about the subset: the quarter of patients with gadolinium-enhancing lesions at baseline compared with the three quarters of patients without active inflammation or gadolinium-enhancing lesions at baseline.

We learned that most of the benefit of this drug was driven by the quarter of patients with active inflammation. There was a much lower benefit of the drug in the patients who did not have active inflammation. I think it highlights that this is a very effective anti-inflammatory drug. When there is active inflammation, even in progressive MS, one can see a benefit. When there isn't active inflammation, the benefit looks quite reduced. To me, it questions what the real place of this drug will be for patients with progressive MS without evidence of active inflammation.

Dr Krieger: It's going to be interesting to see how the regulatory authorities handle that when this drug comes to approval. We have used phenotypes like "primary progressive MS" for 20 years. However, with increased recognition that some people with the phenotype have active inflammatory disease and some don't, we start to think of MS as more of a mix of factors, not as discrete categories as the way these trials are typically designed.

Dr Fox: You're absolutely right. Another thing about this trial[1] is that it enrolled patients at a very early stage of the progressive disease. They had a maximum of 15 years of disease duration and patient age of 55 years. It leaves completely unknown the benefit of this drug in older patients and those with longer, established disease duration. That's something we'll have to wait for from future trials.

Remyelination and Repair

Dr Krieger: We will, but there is a great focus now on exactly that: identifying signs of progression early (biologically and clinically) and thinking about how to approach not just prevention, but remyelination and repair. There is a big integrated neuroscience session at this 2016 meeting that looked at these topics. What are some of the takeaways or future perspectives that might give us more insight in that regard?

Dr Fox: In the past, remyelination, or putting that myelin sheath back on after the injury, was a bit of a pipe dream. We didn't really know how to encourage it. We knew what happened. We knew that part of the recovery from active inflammation was remyelination, but we didn't know what mediated it. We didn't know how to encourage it. We didn't know how to study it or what biomarkers to use, imaging biomarkers or therapies. There was a 4-hour session that focused on all of the dramatic advances we've had in the past several years. We are understanding remyelination much, much better. In fact, in the laboratory, they can take the myelin-making cells and put myelin sheaths around inert rods, just polymers of nothing, which is a great opportunity for us to learn some of the basic nuts and bolts of how remyelination can occur. And then we can take it into benchtop models and start learning what potential therapies we can use to help encourage remyelination.

Dr Krieger: Right. At the same time that this work is being developed further in the lab, there are agents that have already been moved into human trials and patient trials to have this putative remyelination-type effect. There are several that we've been hearing about. One is anti-LINGO-1, a monoclonal antibody that may work towards helping oligodendrocyte precursors develop new myelin. That has been looked at in clinical trials with optic neuritis, with visual evoked potential as the para-clinical outcome.

Even phenytoin has been looked at as a putative remyelination agent through ion modulation pathways. Whether it is truly remyelinative or otherwise reparative remains to be figured out. However, it has been looked at with similarly positive endpoints on paraclinical measures of visual function with optical coherence tomography. There are others that are being developed in parallel with the emerging understanding of mechanisms of de- and remyelination. I think it is an exciting area in MS research.

Dr Fox: I agree. It's not clear that we're there yet, but we're getting some of the basic tools to understand it and study it at the benchtop—to use biomarkers in clinical trials to study remyelination using focused systems like the visual system, where we can correlate function with some of the electrophysiology. We have some therapies that potentially hold great promise.

High-Dose Biotin

Dr Krieger: The last one, which was something of a surprise in the setting of progressive disease and how we measure impact, is biotin. High-dose biotin was a surprise success in bringing about improvement in a small cohort of progressive patients. We don't talk about improvement all the time; we talk about preventing disability. What do you think about this improvement outcome? And is that something we can achieve?

Dr Fox: We are looking at it more in some of the other trials as well. Can we make patients better? Anti-LINGO is also being looked at in an improvement trial on whether we can take the current function of the brain and not just prevent it from getting worse, but actually help restore function and improve how patients are getting along. I think it's a sign that we are moving forward. We don't have all the answers yet, but we have a much better sense of the direction in which we need to head.

Dr Krieger: One could really imagine an MS treatment paradigm where disease-modifying therapies are used to prevent worsening, and another layer of agents is used to foster remyelination and repair. Then we could have combination strategies that really address multiple needs in MS disease modification.

Dr Fox: I agree. These are exciting times.

Dr Krieger: With that, we'll bring to a close our quick review of some of the trends and outcomes in MS research here at the 2016 meeting of the American Academy of Neurology in Vancouver. Dr Fox, thank you so much for being here.

Dr Fox: It was great to join you.

Dr Krieger: To all of you, thank you very much for tuning in and watching.

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