ASSESS Clinical Trial of Fingolimod for Treatment of MS

Fred D. Lublin, MD: Let’s talk about some individual agents that we have available, and we’ll start with fingolimod. Stephen?

Stephen C. Krieger, MD: Sure. Fingolimod—2020 is the 10th year anniversary of when fingolimod was approved for relapsing MS [multiple sclerosis] in 2010. We’ve had the oral treatment era for MS or the second-generation MS treatment for about a decade now. Interestingly, fingolimod was studied at decreasing doses in each of its early trials. And so when it arrived at its phase III studies, it was studied at 0.5 mg pill once a day, which was the lowest dose that had been studied up to that point. And it succeeded in its trials in relapsing MS, both against placebo and versus an active comparator of injectable interferon.

But one of the things that I think Novartis AG was tasked with doing was to see whether a lower dose could be utilized and get a similar degree of benefit. About a year-and-a-half ago, we finally saw data from a trial called ASSESS, which was looking at the standard approved dose of 0.5 mg a day versus a half dose, 0.25 mg a day, versus injectable glatiramer acetate, which was the active comparator that was selected at the time.

This study showed a couple of things. One was that the standard 0.5 mg per day dose of fingolimod was in fact superior to injectable glatiramer, so that was the first head-to-head trial against glatiramer of this agent that showed superiority. But it also showed that the 0.25 mg dose was less effective than the 0.5 mg dose. It was marginally better than glatiramer but not statistically significantly so, which is interesting because it means that we actually arrived at the right dose of the drug when it was studied and put through in its phase III trials.

I do think that it also has a little bit of downstream consequence, at least to how I think about it. In the studies, fingolimod as an S1P [sphingosine 1-phosphate receptor] modulator works by sequestering lymphocytes and probably through other mechanisms as well. But we know that the circulating lymphocyte numbers on someone on fingolimod will be low. In the trials, they held the drug if the level went below 0.2 mg. And so in standard practice I think people deviate from the standard recommendation by giving the drug every other day or less frequently if the lymphocyte count gets too low.

This trial suggests that dropping the effective dose of the drug may actually undermine its efficacy. That to me was a late consequence of interest of that study. The other thing I think worth saying about fingolimod that we’ve learned in the modern era gets at the idea of discontinuation. I think it’s interesting that with our longer-acting durable mechanism agents like anti-CD20s, we can think about stopping them and looking at long-term durable benefit.

But with fingolimod dosed every day, stopping that agent, and probably this applies to the whole class of S1P drugs, runs the risk of rebound disease activity. Because unlike these other agents like the CD20s, the S1P modulators are effectively hiding the lymphocytes but not actually remodeling them. And so letting that drug wash out of the system can re-release into the circulation a lot of the bad actors, if you will, that can potentiate MS disease activity. So we have to be very cautious about not stopping fingolimod even while we’re considering the potential benefits of stopping some of the other agents.

Patricia K. Coyle, MD: And natalizumab.

Stephen C. Krieger, MD: And natalizumab.