EXPAND Clinical Trial of Siponimod for Treatment of MS

Fred D. Lublin, MD: Fingolimod is a modulator of the sphingosine-1 phosphate [S1P] receptor, and it modulates S1P 1, 3, 4, and 5. We have a next-generation [S1P receptor modulator] coming in now, which is more specific, S1P1 with a little bit of 5 and sometimes 3, but more specific. And the first one that’s been approved is called siponimod. You want to talk a little bit about where we are with that?

Amit Bar-Or, MD, FRCP: Yes. It is one of the more selective S1P receptor 1 and 5 modulators. It was studied in the phase III EXPAND trial, which was a secondary progressive MS [multiple sclerosis] trial of siponimod versus placebo. The patient population was a pretty typical secondary progressive MS population. This was an event-driven trial, so an interesting design, not fixed-time duration for each patient but basically calculating in advance the number of events that one would need to achieve, assuming a certain difference between the active versus the placebo. And once that number of events was achieved, basically the trial was stopped and analyzed.

Siponimod was superior to placebo in the primary outcome measure, which was confirmed disability progression at 12 weeks, a modest but statistically significant benefit, and also impacted favorably multiple MRI [magnetic resonance imaging] measures of focal inflammatory disease activity, what one thinks of as relapse biology. And you pointed out the fairly broad label, which I think reflects the FDA’s recognition that the relapse biology is one that exists throughout the spectrum or at least a broad range of the MS spectrum, starting from CIS [clinically isolated syndrome] and through to patients with active SPMS [secondary progressive multiple sclerosis]. Although I agree with the concerns you have about that less than clear definition of activity of SPMS.

Fred D. Lublin, MD: Also it’s a little unusual here to have a drug that was tested in a very different population, just what you said, a really well characterized secondary progressive population. But average, mean EDSS [Expanded Disability Status Scale] I think was 5.

Amit Bar-Or, MD, FRCP: 4.7, yes.

Fred D. Lublin, MD: And it was a very different population. So I’m not quite sure what it meant to cut out the group that, they used different activity. But one could look at activity in multiple different ways. They looked at it because it was part of the study as individuals who had no clinical activity for the 2 years prior. They didn’t look at radiographic activity, and they didn’t look at people who had activity on study, which was a different group than the group that had activity going in 2 years. So I’m just not sure what you do with that information as opposed to taking the study as a whole.

Amit Bar-Or, MD, FRCP: You’re referring to the FDA didn’t look at that.

Fred D. Lublin, MD: Yes.

Amit Bar-Or, MD, FRCP: Yes, because the study of course did look at that. One of the questions going in, preplanned analysis, was is the effect, the benefit of siponimod versus placebo on limiting progression of disability driven by the effect on relapse biology, and accumulating disabilities that’s relapse driven? And so they looked at, leading into the study, the degree of disease activity, as well as on study. And in both cases, although one gets into subgroups and decreases the power, at least the point estimates all seem to be favoring the siponimod, including in the groups that didn’t have overt clinical relapse activity. A caveat, of course, is that as you pointed out, activity measured by relapses only is not going to sensitively pick up subclinical relapse disease biology that of course could be impacted and would be expected to be impacted by this class of drugs.

Stephen C. Krieger, MD: It also troubles me in principle that this trial was designed to look at secondary progressive MS. It was a successful trial. It met its primary end point, and yet the FDA didn’t approve it in that way and instead cut up the data and approved it for subgroups, including groups in which it was never studied, like CIS [clinically isolated syndrome]. We can assume that the drug is likely to be effective there, but I do think it’s hard to sit down with a patient and explain to her why siponimod is an option for her at the time of her CIS when you look at the data, and it was just studied at the entire opposite end of the disease spectrum. I think that poses a real conundrum for us, and it concerns me that it might be a disincentive for other companies to pursue progressive MS trials if even a successful clinical trial doesn’t lead to regulatory approval.

Amit Bar-Or, MD, FRCP: Maybe. As you know, all the other companies were invited by the FDA to extend their labels into the earlier disease spectrum. I think that it is a conundrum and particularly this issue of an SPMS population. It’s not approved for SPMS without obvious activity, although a substantial element of the benefit appeared to be in those who did have that relapse biology. And in some ways, we’ve been encouraging the FDA to accept our view that there’s all this subclinical relapse biology and that it is present throughout the spectrum of MS.

Peter A. Calabresi, MD: I totally agree. I think it was a real step forward recognizing some of the things that you published, Fred, and if you look at the population, the average age was in the late 40s. These are people who had secondary progressive MS or 13 years since duration of diagnosis and 3 years since they’ve had SPMS. These are not the vast majority of patients that I’m seeing with progressive MS, who are late 50s and 60s. And I worry about whether the risk-benefit is necessarily in favor of treating all of those patients.

Patricia K. Coyle, MD: However, the label may be a blessing in disguise because the S1P receptors penetrate into the CNS [central nervous system], so they have the possibility to have a direct effect on neurodegeneration. If siponimod has a direct effect on neurodegeneration, why wouldn’t it be the S1P receptor to use in CIS and early relapsing MS, where there is neurodegeneration? That would be very logical to me.

Fred D. Lublin, MD: At least on the one hand. It doesn’t say what you do with the secondary progressors without activity.

Patricia K. Coyle, MD: They should have gotten a label for SPMS, period, not active versus nonactive, I think, based on their trial.

Amit Bar-Or, MD, FRCP: Or at least include imaging metrics of activity.

Fred D. Lublin, MD: I think it was a very successful trial in the sense of the recruitment population. They really did get a group. If you think of that, you said 3 years after declaring, but it takes 3 to 4 to 5 years before you really declare someone secondary progressive MS. I’ve always thought that’s one of the big challenges in why others have failed in secondary progressive MS because it’s supposed to, even the primary progressive MS, they have this 13-, 14-, 15-year duration of disease. So a lot is going on that we’re not impacting very well.