Treating Multiple Sclerosis with Disease-Modifying Therapies

Darin Okuda, MD, a professor of neurology and neurotherapeutics, director of the Multiple Sclerosis and Neuroimmunology Imaging Program, director of Neuroinnovation, and deputy director of the Multiple Sclerosis Program and Clinical Center at UT Southwestern Medical Center

Darin Okuda, MD

Currently, more than a dozen disease-modifying therapies (DMTs) are approved by the FDA for use in patients with multiple sclerosis (MS), and currently, they are regarded as the best approach to slowing the natural course of the disease.

However, due to difficulties in attaining comparative data, it is hard to determine which of the available DMTs are more effective than others. Additionally, questions abound regarding the best strategy for treating MS with respect to disease-modification.

To share some insight regarding DMTs, Darin Okuda, MD, a professor of neurology and neurotherapeutics, director of the Multiple Sclerosis and Neuroimmunology Imaging Program, director of Neuroinnovation, and deputy director of the Multiple Sclerosis Program and Clinical Center at UT Southwestern Medical Center, spoke with NeurologyLive about their use, their differences, and what is still missing despite their efficacy.

NeurologyLive: In your experience, out of the available DMTs, what do you find to be the most widely used?

Darin Okuda, MD: From an oral treatment standpoint, all of the orals are used. So, fingolimod (Gilenya, Novartis), teriflumonide (Aubagio, Sanofi Genzyme), and dimethyl fumarate (Tecfidera, Biogen), and the reason being is they have really served as a new path for administration. People are migrating away from the classic parentally administrated treatments. They were all given either intramuscularly or subcutaneously, back in the day, but with the advent of treatments that are available to patients in oral form, there has been some transition to those types of agents.

Now, when it comes to efficacy, classically, the monoclonal antibody-based therapies are viewed as being highly effective agents. So, alemtuzumab (Lemtrada, Sanofi Genzyme), your natalizumabs (Tysabri, Biogen) of the world, and ocrelizumab (Ocrevus). However, the oral therapies are also highly effective as well.

How much have the DMTs progressed?

DO: We’ve really, really progressed. We had therapies, early on, that were more generalized in their approach, meaning that these were therapies aimed at modifying how chemokines are behaving, which, in turn, effects how immune cells behave. Now, we have treatments that allow for resetting, or partial resetting, of the immune system— alemtuzumab being specific to this example—where you’re now giving a therapy that allows for a certain population of B cells and T cells to be removed from the system, and then upon return of the new cells they return with a different set of behaviors. One that is not so pathologic to the central nervous system. Then, we also have therapies, like natalizumab, that are really designed to prevent trafficking of inflammatory cells from the periphery into the central nervous system.

It is really dynamic and eloquent with respect to the different types of therapies we’re able to offer to patients. But know that, for the most part, these therapies are aimed at reducing inflammation and the inflammatory response. They’re not primarily focused on tissue repair, so that’s why there’s a need for this new class of agents.

There’s also a need for agents that can effectively address symptoms. We use treatments for fatigue in an off-label basis for our field. The same holds true for patients with MS with neuropathic pain complaints.

So, I think you have these 3 large buckets. One involves disease-modifying therapies, immune modulators, and chemotherapeutic therapies—meaning they actually destroy cells, ocrelizumab is a cell surface chemotherapeutic, and so is alemtuzumab. Then you also have a path of agents that really are aimed at repairing the central nervous system—rHIgM22 (Acorda) is one, anti-LINGO-1 (opicinumab, Biogen) is the other. Then, we need for other therapies to be developed that really address symptomatic concerns related to MS. That’s your neuropathic pain, fatigue, cognitive difficulties, and the list goes on.

What changed once MS entered the disease-modifying space, and is that where it’s continuing now, or is medicine more focused on trying to repair damage?

DO: The answer really is we have a wealth of therapies that are that serve as wonderful agents that are reducing inflammation, and that’s essentially what all these medications do primarily. Now, the newer therapies—like alemtuzumab, ocrelizumab, and natalizumab—aside from allowing for patients to remain where they’re at neurologically, these drugs are associated with a confirmed disability improvement. So, after receiving the drug, even though the drugs aren’t primarily marketed or even sold to patients as agents that can make them feel better routinely, we see people improve or have improvements in the quality of their life.

I think it’s a combination of having more therapies than we know what to do with. It’s somewhat similar to a shoe salesman trying to sell shoes to someone, and you’re bringing out 3 pairs versus 10 pairs. The chance of having greater success is when you bring out 3 pairs. I think patients are also overwhelmed by the vast majority of offerings that we have, and differing mechanisms of action may only get us so far. What we need beyond that are treatments that really are distinct in their mechanism of action, and these are ones that aim to repair an injured central nervous system.

What’s the approach? Should physicians be treating the disease with DMTs early, then something else later?

DO: The management approach is currently unclear. There are studies that are looking at if starting off with a highly effective therapy—however we want to define that—is that the right approach versus a step-wise approach. Starting with something that’s light if your disease is light, and as it escalates, should we then escalate your therapy?

One of the biggest challenges that we have is understanding which therapy is really more effective than the other, and I think that from a 30,000-foot view, we somewhat can arrive at conclusions in our head on which agent might be better than another, but we know that this list is not going to be uniform in the minds of all clinicians. We really don’t know what the more effective approach is right now. You look at other emerging therapies—oral cladribine is a very exciting therapy. It’s like alemtuzumab, in the sense that it can actually reset the given immune system to a certain degree. Is that approach meaningful? Or this induction approach, where you’re allowing for the resetting of the immune system in hopes that the immune system that reconstitutes is one that’s more hospitable to that individual.

What’s the next step? Is there a need for head-to-head studies?

DO: The head to head studies will never occur because the therapies, when they’re super effective, are so effective you would need over 5000 to 10,000 patients for that study to be appropriately powered. But, I think that the future is not one where we compare therapies—and even if you see an observed result, that may not be the word of God. That may just be the observation in the trial, and if we ran that experiment over and over again, we may have answers that are completely different versus the first observation.

The investment in the future is looking more towards better measures for disease surveillance. It’s looking more towards other agents that are very effective, but also much safer than some of the offerings that we have, and then agents that allow for more than just a reduction in the inflammatory response, but that really help to champion self-myelin repair or myelin repair through the administration of an exsanguinous substance. What’s really happening in our field is we have patients with MS who are advancing in age, and for every 5 or 10 years they’re putting under their belt, the chance of them having acute inflammation is much lower than if they were younger. So, what do we do with that population of patients? They’re growing, and we know that inflammatory treatments are not so robust, and inflammation is not really a robust finding in patients who are more advanced in age with MS.

Transcript edited for clarity.