Robert J. Fox, MD: Siponimod is a member of the S1P [sphingosine 1-phosphate] class of medications. This is the same class as fingolimod, which we have been using for over a decade for treating relapsing MS [multiple sclerosis]. Siponimod is a little bit different in that it doesn't activate all of the S1P receptors, but only activates the S1P1 and the S1P5 subsets. By modulating those receptors, it has a bit of a different effect within the body and on the immune system.
Nonetheless, it probably works in a relatively similar fashion, in that it sequesters white blood cells into the lymph nodes, preventing them from getting into the brain to induce inflammation and injury. Siponimod also probably crosses, at least to some extent, into the brain, and may have some direct activity within the brain.
Siponimod was studied in a large phase 3 trial in secondary progressive MS. This was secondary progressive MS patients who had relapses in the short time prior to the trial and those who didn't have relapses shortly before the trial. These patients were randomized to either siponimod or placebo. They were followed over time with a primary outcome of sustained progression of disability. At the end of the study, the investigators found that, indeed, siponimod was associated with a slowing of progression of disability of about 21%.
When there was further evaluation of the patient characteristics that tended to respond better, what was found was that the patients who had active inflammation, who were younger, who had less disability—all of the things pointing toward an earlier stage of the disease—were more likely to respond to siponimod than the other types of patients—those who didn't have active inflammation at the start of the disease, those who were older, those who had more disability.
It has raised the question of, “OK, it’s helpful in secondary progressive MS, but is it clearly more helpful in that left end of the secondary progressive MS spectrum, in those who had active inflammation and were younger? Indeed, this study didn't enroll secondary progressive patients who were much older—those who are in their late 60s or 70s—which is a very common patient that we see in clinic with secondary progressive MS.
Fred D. Lublin, MD: The EXPAND trial succeeded. They had a statistically significant reduction in disability accumulation in the siponimod-treated group as compared to the placebo group. On subset analysis, it turned out that the majority of the effect that was seen was seen in individuals who had some activity, clinical activity, in the 2 years prior to entering the trial. So there's some thought, although not really tested because it's a subset analysis, that the primary effect was on the inflammatory aspect of the disease. That may be correct, but one can't assume that by doing subset analyses of the study.
The group that was studied in the EXPAND trial was a very well-characterized, secondary progressive MS group, chosen having had entered a progressive phase, and they did. So, they succeeded in that. The drug's approval labeling was for clinically isolated syndrome, relapsing-remitting MS, and secondary progressive MS with activity. However, the drug wasn't tested in either clinically isolated syndrome or relapsing-remitting MS. It was only tested in secondary progressive MS. As I mentioned, the group with activity showed more of a therapeutic effect than the group that didn't have activity. There are several different ways of defining activity. The one that they're talking about there was a clinical attack in the 2 years prior to entry into the study.
I think it's a fair assumption, based on the earlier fingolimod studies, that the drug would have an effect on relapsing-remitting disease and clinically isolated syndrome, because it looks to have an effect on inflammatory activity. But those populations weren't tested.
Robert J. Fox, MD: The findings of the phase 3 siponimod trial have helped guide us in clinical practice. It is pretty clear that patients with active inflammation in secondary progressive MS are more likely to respond favorably to this therapy. Patients who don't have active inflammation, who are much further along in the disease and are much older, appear to be less likely to respond.
Indeed, some of the safety issues that were found—the increased rates of respiratory infections, and things like that—may outweigh the potential benefits. Those at higher risk of infections may outweigh the relatively smaller rate of slowing of disability progression. In clinical practice, I've been using it more in patients who are younger with active inflammation, and using it less in patients who are older without evidence of active inflammation.