Fred Lublin, MD: Another new drug: siponimod. Wallace, why don’t you take us through siponimod?
Wallace Brownlee, MBChB, PhD, FRACP: Siponimod is a recently approved medicine from the same family as fingolimod: it’s a sphingosine 1-phosphate [S1P] modulator. Siponimod is exciting for a couple of reasons, particularly because this is a medicine that has been shown to have a positive phase 3 trial in secondary progressive multiple sclerosis [MS]: this was the EXPAND study. In subgroup analyses, it looked like the benefits of siponimod on reducing the risk of confirmed disability worsening were mainly driven by patients who had so-called active secondary progressive multiple sclerosis, so patients who had ongoing relapses or MRI evidence of disease activity. That is the label the medicine has received in Europe for that subgroup of patients with secondary progressive MS. Although I understand that, in the United States, you’ve got a much broader label, even though formal studies in patients with CIS [clinically isolated syndrome] or relapsing-remitting MS haven’t been undertaken.
Fred Lublin, MD: Right. Did you want to say a little bit about how siponimod differs from fingolimod?
Wallace Brownlee, MBChB, PhD, FRACP: There are a number of S1P receptors in the body, and siponimod is more selective than fingolimod. In theory, that may influence both efficacy and potentially [adverse] effect profile. Bradyarrhythmias and bradycardia, which are a concern with fingolimod, seem to be less common in patients treated with siponimod, partly because of a dose titration used to mitigate this first dose effect.
Fred Lublin, MD: Siponimod is selective for S1P1 and S1P5 receptors. Fingolimod hits S1P1, S1P3, S1P4, and S1P5 receptors. That may explain some of the differences there, but you bring up one important point, which is that with the dose escalation, there is no first dose observation with siponimod. Patricia, use of siponimod?
Patricia K. Coyle, MD: Siponimod is a second-generation S1P receptor modulator. It’s beginning to get a crowded field. It was very impressive that they had a phase 3 trial positive in pretty significant secondary progressive MS. You have to give credit: they met the primary outcome. It was critiqued as not being a stunning success in the primary outcome. Nevertheless, it was, and this is a small molecule that penetrates into the CNS [central nervous system], and therefore, it is at least possible—and there are S1P receptors inside the CNS—that it could be having a direct effect on neurodegeneration to have an impact on secondary progressive MS. It was terribly disappointing when that was not recognized by the FDA. However, if you look at the S1P receptor modulators as a class, you might make the argument that siponimod, if it’s effective in relapsing—which is clearly true, you have a phase 2 trial, and look at the other S1P receptors—plus it has a neurodegenerative effect, you could potentially say is that my preferred, go-to S1P receptor modulator? That’s an intriguing question to think about.
Sven Meuth, MD, PhD: I can add that I’m most impressed by the EXPAND trial because of the patient recruitment. If we compare all the different trials in patients with secondary progressive MS [SPMS], I had the impression that the majority of trials tried to also involve patients with late-stage relapsing-remitting MS with a lot of inflammatory activity. This may also be the reason why the beta-interferon trial in SPMS in Europe was positive, while it was negative in the United States. In the European trial, there have been 70% of patients with a relapse while being in the study, and if we compare this to the recruitment strategy of the EXPAND trial where we had over 50% of patients already having an EDSS [Expanded Disability Status Scale] score of 6 or 6.5, this is the first trial recruiting a pure SPMS cohort. This is why I support Patricia’s take on the study.
We saw something in this really progressive cohort, and this is much more meaningful as reflected by the approval of siponimod. In Europe, it is only approved for secondary progressive MS with activity, and this activity has to be shown by clinical relapses or by MRI activity. So far in Europe, we have 2 approved S1P modulators. However, we cannot use them as a first-line therapy because we have fingolimod for active patients and siponimod for active SPMS patients and this is, for me, hard to understand.
Fred Lublin, MD: Wallace?
Wallace Brownlee, MBChB, PhD, FRACP: I don’t have any further comments. We don’t have access to siponimod yet in the United Kingdom, so I haven’t used the drug myself.
Fred Lublin, MD: You highlighted some of the paradoxes with this drug. This was a good study. They set out to get a group of patients for secondary progressive MS, and they succeeded. It’s a population like no other study that’s been done, so I give them a lot of credit for doing that. They had a high EDSS, they had long duration of disease, and it was a good study. As Patricia said, it was a modest effect, but it was an effect that clearly occurred, and now the confusion is in the labeling, both in the expanse of the labeling, which was a leap because of the way this drug was done. For me, more troubling is the lack of understanding of the regulators of what the term “activity” means.
Wallace and I have had this discussion when I visited out in their place at the National Hospital for Neurology and Neurosurgery a year and a half ago, and that is activity must be framed in time. Neither regulatory group on either side of the Atlantic recognized that this must be framed in time. What that does is, if you say secondary progressive with activity, that is every secondary progressive patient because, by definition, they had to have activity at some point. Then the regulators split on how they defined activity.
In the United States, where the regulators don’t accord a lot of respect to MRI, they only talked about clinical activity. The European regulators talk about clinical and MRI activity, but again, neither one specifies the timeframe. One could have done that, but even then, you were looking at a subset analysis of a clinical trial. As scientists, we’re always cautious about what we do with subsets and how we interpret them. This is an interesting situation. We have a paper in press right now in Neurology trying to clarify these issues for the community, so at least they will understand what the concepts are around having activity and not having activity, and most importantly, this issue of timeframe.