Post Hoc Analysis: Phase 3 EXPAND Trial in Secondary Progressive MS

Mark Freedman, MD: The next abstract I was requested to comment on was some post hoc analysis from the EXPAND study. This is the siponimod treatment of secondary progressive MS [multiple sclerosis], with the primary outcome being a disability progression measure. The overall outcome of that study was positive but involved the entire population, a substantial subset of which had still been experiencing relapses in the 1 or 2 years prior to coming into the study. They decided to look at this post hoc analysis by separating the patients who had relapses from those who did not have relapses prestudy, because the initial thought was that the patients who were having the relapses were probably driving most of the treatment effect on disability progression.

By separating them, they looked at confirmed disability progression, or CDP, at sustained periods of either 3 or 6 months. Their own data show that the percentage reduction in the patients who had not experienced relapse was quite small for 3- and 6-month progression, and the numbers they quote for that were 18% and 13%. This is in the patients who had relapses in the prior 2 years. However, their confidence intervals crossed 1, so in that circumstance neither of those numbers was statistically significant.

When you look at the patients who did have relapses, the reductions were actually quite higher, 33% for 3 months and 37% for 6 months, although we’re not given the statistical significance or the confidence intervals there. Their conclusion that patients who did not have relapses were also benefiting is called into question here.

The only significant adverse effect in the nonrelapsing patients appears to be the 25% reduction in patients who had attacks in the 1 year prior to the study, since that confidence interval does not cross 1. The relapsing patients look like they had significance in both the 1 and 2 year, but those numbers are not provided.

In the end, I’m not convinced there’s a treatment effect really in patients who have not experienced relapses, and I believe that is in keeping with the way in which the drug is actually advised to be used by Health Canada. I don’t know if that is the case with the FDA. Patients with active forms of secondary progressive MS and active MS usually means patients who’ve had relapses in the prior 2 years or changes indicative of new lesion formation on an MRI. Those are the ones most likely to benefit from siponimod.