Bruce Cree, MD, PhD, MAS, discusses key considerations when selecting one of the four FDA approved sphinogine-1-phospate (S1P) receptor modulators for multiple sclerosis (MS). Dr Cree also highlights a particular adverse event observed in the extension studies of these four S1P receptor modulators.
Bruce Cree, MD, PhD, MAS: The 4 S1P receptor modulators are US FDA approved for relapsing forms of multiple sclerosis. Although they have different activities at different S1P receptor subtypes, they all have therapeutic benefit in terms of reducing relapses, and they have similar [adverse] effect profiles. However, for the first S1P1 receptor modulator, fingolimod, because of its S1P3 receptor activity, there are particular issues with this particular product having to do with cardiac induction that the other S1P receptor modulators do not have. From my point of view, the more selected S1P receptor modulators including siponimod, ozanimod, and ponesimod have an advantage over fingolimod in that they have fewer cardiac issues associated with them. There are other aspects of these products that are important to understand as well; they have different half-lives. Some of them have active metabolites, and these are also features that one has to take into account. However, the most important aspect of all of these drugs in selecting them for patients is their overall efficacy and safety and tolerability profiles. The details as to which of the products binds to a particular subtype of receptor become less important than the aggregate safety, tolerability, and efficacy data. So from my point of view, although we don’t have head-to-head trials comparing ozanimod, siponimod, fingolimod, and ponesimod, you’re left with interpreting the data from the clinical trials, where these drugs are typically either compared against placebo or against an active comparator such as interferon beta-1A or teriflunomide. You have to take that information in aggregate and make decisions about what you think might work best for your patients. In my personal experience, the next-generation versions of the S1P receptor modulators are better tolerated than the original fingolimod product for quite a few different reasons; there’s less need for first-dose observation with these products. For example, with ozanimod, there is no need for a first-dose observation unless the patient has a prior cardiac history. These medications can be taken with gradual dosage escalation, unlike fingolimod, which cannot. This results in fewer first-dose effects with the next-generation products. In general, I think that the next-generation products are, in many ways, somewhat better products for the tolerability and safety perspective.
For all 4 S1P receptor modulators, 1 has both the original clinical trial data as well as long-term follow-up data to consider. [Those] data, of course, do not have the active parallel control arm that clinical trial data [have]. But nonetheless, one can learn a lot about how these products perform over time by looking at their long-term follow-up data. Of course, safety is a critical consideration here, and one wants to understand the safety profile of each of these products over the long term. We need to understand not only if a product is safe over the 1 to 2 years of clinical trial, but whether that continues to be true over the next 5 years or, in the case of fingolimod, after 10 years of data. So that becomes very important to consider as well. Then, one also wants to get a sense of whether the products continue to have efficacy despite long-term usage. I think there’s a general concern that a medication may lose efficacy over time. If that were the case, one might anticipate that for a product that would lose efficacy, that is when we’d start to see relapses occur again, or disability progression, or lesion formation on MRI. The good news for all of these products is that their long-term safety profile in general is very much in keeping with what was observed during the randomized control trials, and that they have low rates of disease activity and low rates of progression, in terms of disability worsening over time. So the long-term data support the randomized controlled trial data. One thing that’s important to understand when one puts these products into clinical practice is that one sees the potential to observe rare adverse events. I think the most important rare adverse event for all of these drugs is the concern about the evolution of progressive multifocal leukoencephalopathy [PML], which, if you’re not familiar with this, is a lethal brain virus infection that is associated with immune suppression, first identified in cancer patients, and now associated with use of immune suppressive medications. In the clinical trial programs with these products, one did not see PML because it is a relatively uncommon event. But then, as these drugs went into their extension studies and into their open label or a general practice use, we began to see cases of PML for the first group, fingolimod. And then with siponimod, now is anabolic. So we do know that PML is associated with these products, albeit rarely, somewhere on the order of about 1 in [9,000] to 1 in 12,000 patients. So it’s an uncommon occurrence, but it can occur with these medications.
Transcript edited for clarity.