Fred Lublin, MD: Let’s move on to the last agent we’re going to discuss with you, Sven: that’s ozanimod.
Sven Meuth, MD, PhD: Ozanimod. Now it’s getting difficult to get a differentiation between the different sphingosine 1-phosphate [S1P] modulators because ozanimod is also claiming to be very specific on S1P1 and S1P5 receptors, and therefore, the profile looks quite comparable to siponimod, which we discussed a minute ago. However, there have been several trials, phase 2, phase 3…. In the phase 2 study, RADIANCE, it could be shown that ozanimod reduces the activity on MRI compared to placebo, and this was then the reason to continue with the phase 3 trial, the SUNBEAM trial, a multicenter randomized trial. There, they compared ozanimod versus interferon beta-1a, and they could show that, if patients are treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate compared to interferon beta-1a.
The safety profile seems to be as expected for this class of agents, and the study was further supported by a second phase 3 trial, the RADIANCE Part B trial, where the patients were randomized and treated over 24 months. For Europe, the approval makes a difference. As mentioned before, we have this specific approval for fingolimod and siponimod, so ozanimod would be the first S1P modulator entering the market in our hands for first-line therapy. The study was significant when it comes to MRI and annualized relapse rate. However, the effect on disease progression was not significant, and this started a whole discussion. My opinion on this is that, even in the interferon beta-1a group, there was not much of a progression, so concerning the secondary endpoint of the study, the study might be underpowered.
Fred Lublin, MD: Has it been approved in Europe as well as in the United States?
Sven Meuth, MD, PhD: Not yet.
Fred Lublin, MD: Not yet, but you’re hopeful that it will be approved for relapsing-remitting MS [RRMS]?
Sven Meuth, MD, PhD: Yes.
Fred Lublin, MD: You think it’ll be treated differently than the fingolimod because it won’t have a first-dose observation?
Sven Meuth, MD, PhD: Yes, because maybe the safety profile is a bit in favor of ozanimod because we don’t have the first-line observation, and the study is clearly targeting a cohort of early MS [multiple sclerosis] patients. It’s recruiting-relapsing remitting patients aged between 18 and 55, and they are starting with a EDSS [Expanded Disability Status Scale score] between 0 and 5, so this is, in my opinion, an early RRMS cohort. But you are right, maybe they have the idea that it should be approved comparable to fingolimod or siponimod. This is not necessarily, as discussed before, based on the available data, so I’d be surprised.
Fred Lublin, MD: Wallace?
Wallace Brownlee, MBChB, PhD, FRACP: There are some nice MRI data that have come out from the phase 3 trial program of ozanimod. One of the things that’s concerned us has been that it didn’t appear to be a reduction in disability progression, and that’s probably because this is a tough end point to make in patients with very early MS when you’ve got an active comparator. What was impressive were some of the MRI data that came out of the phase 3 trial program where they looked at some pretty advanced MRI, in particular, not just whole brain atrophy but gray matter atrophy, which may be better correlated with later physical disability and particularly cognition. They showed an 80%-plus reduction in grey matter atrophy in the ozanimod treated patients. This is potentially exciting, and in Europe if this has a first-line license, it’ll be a particularly useful addition.
Fred Lublin, MD: Patricia, how are we going to decide which S1P to use?
Patricia K. Coyle, MD: It’s interesting. Ozanimod breaks down to 2 major metabolites that make up 88% of the active drug. Their half-life is 11 days, so this needs a washout at 3 months. It’s a longer washout than fingolimod, and way longer than siponimod. And if you think about the S1P receptor modulators as a whole cohort and you’re going to choose 1, I’d choose the 1 that had an effect on your degeneration plus the relapsing form of MS. You’d have to give me a good argument to not choose that 1.