Expert clinicians remark on the significance of the recent approval of ocrelizumab for primary progressive multiple sclerosis and discuss the potential of siponimod for secondary progressive MS.
Fred D. Lublin, MD; James M. Stankiewicz, MD; Thomas P. Leist, MD, PhD; Patricia K. Coyle, MD; Clyde E. Markowitz, MD; Suhayl S. Dhib-Jalbut, MD
PUBLISHED March 12, 2019
Fred D. Lublin, MD: One of the most exciting things for us in the MS [multiple sclerosis] community was, in 2017, when we got our first approved therapy for progressive disease. Tell us a little bit about where we are now with progressive disease.
James M. Stankiewicz, MD: So, it’s true. Ocrelizumab was approved for primary progressive disease based on the strength of a phase 3 randomized controlled trial. In fact, in the approval process, there’s another drug, siponimod, which showed successful trial results in secondary progressive MS. They both had, I would say, a similar reduction in the proportion of patients hitting the progression metric, as we define it by the EDSS, or the Expanded Disability Status Scale, which is reduction of about 24% compared to placebo, which is a start. It’s better than we could do before and so it’s good. Of course, we would like to see better results for our patients than that. And I think that’s sort of a broad overview.
Fred D. Lublin, MD: Tom, let me ask you this. Fingolimod clearly was negative for primary progressive disease. Why do you think siponimod, which is next generation, S1P1 receptor, succeeded, albeit modestly, in secondary progressive disease?
Thomas P. Leist, MD, PhD: That’s an age-old question, right? That goes back to the interferons, where a European trial in secondary progressive MS was positive and a US trial was negative. And some things that we potentially don’t fully understand at this point may actually help us. Obviously, siponimod also has certain receptor specificities that fingolimod doesn’t have. So one argument would be that the distinction in the S1P receptors that are actually targeted could have caused this. The other thing is obviously that what we really control with siponimod is still an inflammatory component of the disease, and with that inflammation drives disability. And that’s really what we are looking at. It also raises the issue that both a S1P receptor agonist, antagonist and an anti-CD20 molecule have some effect in progressive forms of MS. Is it then that the immune mechanisms still play a significant role in this particular condition and also in primary progressive MS?
If I would have to put down my chips today, I think what this controls is the inflammatory component of these states. It’s not what was referred to as a true neuroprotective component, meaning helping previously injured or currently injured neurons to survive longer. I don’t think that either siponimod or ocrelizumab actually do that. I think they control the residual inflammatory activity.
Patricia K. Coyle, MD: But at least siponimod enters the CNS [central nervous system].
Fred D. Lublin, MD: Yes.
Patricia K. Coyle, MD: And the anti-CD20 really doesn’t. It’s less than 0.1%. So if you’re going to have a direct effect, at least siponimod, in theory, gets in there.
Fred D. Lublin, MD: Well, that was the hope for fingolimod.
Patricia K. Coyle, MD: Maybe it is the fact that some of the receptors are bad in the CNS?
Fred D. Lublin, MD: So that would be S1P4, right?
Patricia K. Coyle, MD: Yes.
Clyde E. Markowitz, MD: I have a different take on this whole conversation. If you look at the ocrelizumab clinical trial as primary progressive. And you look at the proportion of patients who had Gad [gadolinium]-enhancing lesions at entry into the trial, and you look at what happened, which had maybe 13%, 14% Gad enhancement, and the ocrelizumab trial had like 25% or 26%. And then you take the group of patients who did not have Gad-enhancing lesions in the ocrelizumab trial. They didn’t do as well as the ones who did have Gad-enhancing lesions. As Tom points out, it’s an inflammation effect. I think the failed trial was really driven by the lack of inflammatory patients in that trial versus the ones who did have inflammation. That’s my take on those.
Fred D. Lublin, MD: But the problem was the subset analyses don’t give us enough information. You’re right, there’s a trend to difference in response between those who had Gad at baseline and those who didn’t. But the numbers were too small to be significant.
Clyde E. Markowitz, MD: They are too small, that’s true.
Fred D. Lublin, MD: And the subset analyses of the siponimod study didn’t give you enough information either. The subsets all showed a therapeutic effect.
James M. Stankiewicz, MD: I would add another thing that I think is interesting. Just published this month was a look in a consortium in Europe that looked at rituximab in a second progressive population. The trial population was similar and showed an effect. So I think that’s an interesting little piece to all this too. And so, I tend to agree that I think it’s more related to inflammation. We don’t really know. Another thing that I think is very complicated about all of this is, the fundamental question is, what is progressive disease? I don’t feel comfortable saying that I could say exactly what’s happening. And, in fact, I would make the argument that it may be a little different for different people. Some patients may have more of an inflammatory component, and others may have less. And so, you may have better opportunity with some than others.
I think this issue about compartmentalization is an interesting one, but I think now we’re starting to understand that B cells are traversing more into the central nervous system than we thought. And so, what you do in the periphery certainly does affect things. So it’s complicated. I’m glad that we’ve had some positive effects. I guess fundamentally I worry that a lot of what you see with progressive disease is dialed in from things that happened long ago, which, again, I think makes an argument for more effective therapies up front.
Suhayl S. Dhib-Jalbut, MD: It could be also that there’s something different about the S1P5 function in siponimod versus fingolimod, particularly in its effect on myelination oligodendrocytes.
Fred D. Lublin, MD: But they both modulate P5.
Suhayl S. Dhib-Jalbut, MD: But there could be more avidity, let’s say, or more S1P5 effect with siponimod. Remember, the clinical effect was in the range of 20%, so maybe a CNS effect could be related to that.