Bret S. Stetka, MD; Stephen Krieger, MD; Michelle Fabian, MD


May 26, 2017

Stephen Krieger, MD, and Michelle Fabian, MD

In just over two decades, multiple sclerosis (MS) has gone from an untreatable disease to one for which clinicians are nearly flummoxed by the options. Since the first MS drug treatment, interferon beta-1b, was approved in 1993, the US Food and Drug Administration (FDA) has greenlighted more than a dozen other therapies. At the recent 2017 American Academy of Neurology (AAN) Annual Meeting in Boston, the progress continued, as evidenced by the numerous clinical trials presented. While onsite at the meeting, Medscape editor Bret Stetka, MD, sat down with Mount Sinai (New York) neurologists Stephen Krieger, MD, and Michelle Fabian, MD, to discuss the bevy of new data.

Medscape: Thanks for joining me today. What presentations on MS have most impressed you this week?

Dr Krieger: I think we've seen some clinical trial results from both core and extension studies that give us more insight into efficacy of different therapies in both relapsing and progressive MS.

Dr Fabian: Everybody is excited about ocrelizumab, and there were a number of exciting studies on this drug presented here in Boston, including the ocrelizumab extension data.[1]The highlights were that it showed a remarkable decrease in the formation of new lesions, both in patients who were already on ocrelizumab and in patients who were switched over from interferon.

Dr Krieger: This is the first year of their extension study, which is going to go on for several years. The extent of the reduction in MRI lesions that we saw in the first year of the extension certainly reassures us that efficacy was maintained, including in those who were originally on interferon in the core trial.

Previously we'd already seen a 95% reduction in gadolinium-enhancing lesions. And in the first year of the extension, looking at 700 patients, zero enhancing lesions were seen—not one.

Dr Fabian: It's really remarkable. It's a number I never thought I'd see in a trial.

Medscape: This is the first approved medication for primary progressive MS (PPMS). Are doctors out there using it yet?

Dr Fabian: I think in the next 6 months or so the uptake will be significant.

Dr Krieger: This is the first drug with both a relapsing MS and progressive MS approval, which I think allows neurologists to have a certain amount of leeway in terms of deciding who the right patients are for this medicine. The kind of data we saw in the extension trials really shows how potent an immune modulator this is at preventing disease activity.

Medscape: Do you think ocrelizumab will be incorporated into relapsing-remitting MS (RRMS) treatment before long?

Dr Krieger: Absolutely. It's there for both types of the disease.

Dr Fabian: Dr Hauser also presented data[2] showing that the onset of action is really quick. And so for patients with RRMS, especially in aggressive cases, he showed that it's effective within the first 8 weeks. Sometimes our older therapies would take 6 months to reach optimal efficacy. So I think we'll be using it a lot.

Medscape: How do you think doctors will incorporate ocrelizumab into RRMS treatment algorithms, especially given the numerous approved therapies for the condition?

Dr Fabian: I think it will be very interesting to see, as the years go on, who starts it, and either as a new start or a switch.

Dr Krieger: I think many people will want to use it for active disease. We'll have to wait and see whether doctors in the United States use it first-line or as a second-line or "breakthrough" medicine. It will be interesting to see.

More Drug Data and Guidance on Sequencing

Medscape: Data also were presented on the drug siponimod in progressive disease. What did these findings show?

Dr Krieger: We've already seen success with ocrelizumab in primary progressive disease, and now the data presented today[3] show success with siponimod in secondary-progressive MS (SPMS); this is a cousin to fingolimod. The results were modest: around a 20% reduction in the risk for disability.

Dr Fabian: This drug is intriguing because it's the only current drug shown to be effective in SPMS, and it has an analog that's already out. So in terms of safety, we have some added comfort here.

Medscape: There were also some exciting data on alemtuzumab, which has been around for a few years now, right?

Dr Fabian: Yes. And I appreciate that these studies are still giving us data 6 years out. It's meaningful that most patients who have been given this drug in trials are still doing well, both clinically and in terms of MRI findings.[4]

Dr Krieger: Ocrelizumab and alemtuzumab are both medicines with a more durable mechanism of action. So we're now seeing later extension data on alemtuzumab—out to 6 years, like Michelle said—and I definitely see a parallel with the ocrelizumab extension data we're now starting to see.

Medscape: Personally speaking, how do you two choose between all of these medications when treating a newly diagnosed patient?

Dr Krieger: We're going to see more and more biomarkers in the next few years that will help us make these decisions on a more rational and biologic basis. But at the moment, I think it comes down to perceived balance of efficacy and safety, as well as the desired risk profile that a patient is willing to take on with their medicines. And then the field of candidate medications is narrowed on the basis of things like a patient's comorbidities, phase of life, and other contraindications.

Dr Fabian: I think that's one of the hardest questions that neurologists and MS specialists face at the moment. There are actually too many good options! So it has to be a decision based on patient factors and on their comfort level. And like Stephen said, we really need biomarkers to help make these decisions—serologic biomarkers, MRI biomarkers, and hopefully others.

Medscape: Like so many areas of medicine, it sounds like personalizing care will be key.

Dr Krieger: Yes. And as the field of MS therapeutics matures, this is a second-generation problem. The first-generation problem is not having treatments, and the second is having an array of them and trying to figure out which is best for which patient.

Medscape: What biomarkers are currently being used in the clinic?

Dr Krieger: If anything, we use safety-risk biomarkers rather than those for efficacy. So I can't yet know which patient is going to respond to which medicine. But I could know which patients are at highest risk for certain adverse events. I think the JC virus antibody is the best example of a risk-stratification biomarker—knowing that with a positive antibody, the risk for progressive multifocal leukoencephalopathy (PML) in a patient on natalizumab increases over the first 2 or 3 years.

There are a few other similar (mostly infectious) biomarkers but not really any drug-specific ones. Soon we might even have microbiome profiles that could help us select treatments. At Mount Sinai we're involved in a microbiome and MS consortium, but it's tricky because the biome can be different in each patient and in different geographic areas.

Real-World Data and Hope for Cognitive Impairment

Medscape: Some data were presented on real-world experience with a few established MS medications. What are your thoughts on these?

Dr Fabian: Research was presented about real clinic experience with dimethyl fumarate (DMF) and fingolimod.[5]They looked at how many patients continue on the agents once they're started and how many discontinue their drug and switch to another agent.

The study showed that DMF was discontinued more frequently due to adverse events in the first year of treatment. Patients on both drugs did about the same in terms of clinical relapses, but the DMF patients had more MRI activity.

Medscape: Can you briefly summarize the data presented on treating cognitive impairment in MS?

Dr Fabian: There was an interesting study[6]done by investigators from Italy, looking at the drug dalfampridine in MS-related cognitive impairment. They used the SDMT—a test for processing speed—and they did show an effect when it was used for 12 weeks. After the dalfampridine was stopped, they tested the patients again after 4 weeks and there was no continued effect. So it was a symptomatic effect while they were on the drug. Also, the treatment did not affect the patient's quality of life. So, even though their cognitive function looked to be improved, their quality of life was the same.

Dr Krieger: This is a medicine that we typically use for ambulatory issues in MS. But now if we have a sense that dalfampridine can improve cognitive function, it's something we can consider when we're treating people with it for gait dysfunction; we can look at it for its effect on cognition, too.

Medscape: How commonly do you see cognitive dysfunction in MS?

Dr Fabian: It's very common—somewhere around 35%-65% of patients.

Dr Krieger: And the closer you look for it, the more you see it. This is one area where the dogma of a generation ago is quite different now. It used to be thought that MS spared cognition, but now we know that often is not true.


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