In light of recent changes in the multiple sclerosis treatment paradigm, Clyde E. Markowitz, MD, and Fred D. Lublin, MD, reflect on remaining unmet needs and potential directions for future therapeutic management to take.
Clyde E. Markowitz, MD, and Fred D. Lublin, MD
PUBLISHED December 26, 2018
Clyde E. Markowitz, MD:Multiple sclerosis [MS] in 2018 is very different than it was in 1993, when we had our first injectable interferon treatment. We now have many compounds that suppress disease activity much more effectively than when we started 2 decades ago. But there’s still a significant amount of unmet needs here. We have metrics that we call NEDA, or no evidence of disease activity. Those metrics look at clinical attacks, disability progression, and MRI [magnetic resonance imaging]. But that’s not the whole story of MS because there are pieces that are not measured. There’s this piece regarding progression that occurs independent of everything that we use to treat MS.
One of the problems is when we look at all the drugs that we have available, even the most potent of them, and we’re getting into the 40% NEDA range—40%, 45%, or 48%, whatever it is—but we’re not getting to 100%. That’s not even taking into consideration other metrics that we have not even added to that, such as cognition or other huge issues: fatigue, bladder issues, or spasticity. There’s a lot of disease activity that goes undiagnosed or untreated because we’re focused on those metrics that we can easily see. But all these other ones are going on in that other 50% of NEDA that’s not met. And then there’s the piece regarding how we’ve suppressed the MRI, we’ve suppressed their clinical attacks, and we’re slowing the rate of progression, but we’re not stopping progression. People still get worse.
This phase of progressive MS is a huge unmet need. We need better biomarkers; there’s no question about it. We need the ability to look at individual patients—I may have a blood test that I could get for somebody—and say, “Here’s somebody who’s not going to do well in the next 5 to 10 years, according to this blood test. I’ve got to put you on this treatment because this is going to be the right drug for you.” I may have somebody who doesn’t have that marker and say, “This is somebody who’s going to do OK; we could use other treatments.” But we don’t have those biomarkers.
Right now, there are some ideas that we may have something called neurofilament light chain, which will potentially be a marker to help us in this world. But we need better biomarkers or tests to look at cognitive function and to look at things on MRI that we can’t see so easily right now on conventional imaging. There are new metrics that are being applied. Even tests related to the thickness of the retina with OCT [optical coherence tomography] scans may give us the ability to deal with the slow progressive phase of the disease, and maybe we can start targeting these biologic events. Can we remyelinate? Can we protect the nervous system in a way such that we don’t see loss of neurons and loss of function? That’s ultimately what we need to get to. We’re not there yet. We’ve made tremendous progress over the past 2 decades, but we have a lot more work to do.
Fred D. Lublin, MD: Moving forward, MS continues to be an extremely exciting and interesting therapeutic area. We’ve gotten a great handle on relapsed-remitting disease. It’s not perfect, but we really control it very well. We’ve opened the door for treating progressive disease with 1 agent with modest effects, but it’s available. Another agent going through the approval process now has a modest effect on secondary-progressive MS. Some agents and strategies are in the pipeline to hopefully improve upon that.
There are a number of studies going on. Near-term excitement is for better treatment of progressive disease. It’s interesting in MS that the clinical trials have been directing the science. We learn about the disease through successful clinical trials. We learn about it through basic science and animal research as well, and the 2 come together. But in MS, we’ve really learned a lot by having a successful clinical trial and then asking, “Well, why did that happen?” Sometimes, why it happened is different than what we hypothesized when we started using the drug. That area, the progressive area, is moving along nicely. We have agents in the pipeline now for repairing the damaged nervous system, which is the most exciting that we’re doing short of finding a cure.