The most recent data continue to support Mayzent‘s (siponimod) benefits and provide more insights on how this therapy can make a difference for those with relapsing forms of multiple sclerosis (MS) — in particular, data showing the therapy lowers the risk of becoming wheelchair-dependent.
New results from the pivotal Phase 3 EXPAND trial were presented at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held Sept. 11–13 in Stockholm.
Approved by the U.S. Food and Drug Administration (FDA) in March this year, Novartis‘ Mayzent is a new sphingosine-1-phosphate (S1P) receptor modulator, indicated for the treatment of people with relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS).
Data from the EXPAND study (NCT01665144) was one of the key pieces of evidence for Mayzent’s approval. Involving 1,651 patients with SPMS (both active and non-active), the study showed that taking 2 mg tablets of Mayzent once per day reduced the risk of disability progression at three months by 33% in those with active, relapsing disease, and by 13% in those with non-active SPMS.
The therapy also decreased the annualized relapse rate by 55%, reduced the progression of brain lesions, and lessened whole-brain volume loss (brain atrophy), measured in the overall population (active and non-active SPMS); a further analysis demonstrated an additional benefit for improving cognitive processing speed.
“Patients with active SPMS benefit from Mayzent to a greater extent; however, this benefit is not restricted to active SPMS patients,” Douglas Arnold, MD, from McGill University in Canada, said at a Novartis media briefing held during ECTRIMS.
He believes that this increased benefit in these patients is a general phenomenon possibly related to the fact that they have more lesion formation and more inflammation, which worsens the degenerative process. So this could explain why they respond better and have a slower disease progression with anti-inflammatory therapies like Mayzent.
On that note, a post-hoc analysis presented by Arnold at ECTRIMS showed that Mayzent significantly slows the loss of both cortical grey matter and thalamic volume — two measures of brain atrophy — at two years, compared with placebo, in SPMS patients.
Overall, the data suggest that Mayzent offers a benefit in terms of physical and cognitive ability. But from a patient perspective, what does this mean? Are SPMS patients receiving Mayzent more “functional?”
“That’s, of course, a key question,” Ludwig Kappos, MD, principal investigator of the EXPAND trial, said in an interview with Multiple Sclerosis News Today.
“The analysis that we are now presenting at this meeting addresses this question. So is this difference, which is not a complete effect and is still quite far away from what we would like to have, something important for people?”
Different outcome measures can be used to judge the benefits of a therapy such as Mayzent, explained Kappos, who is a professor and researcher at University Hospital Basel in Switzerland.
“One way is to look at so-called milestones, so things that everyone would believe … make a difference,” such as “the transition from being able to walk with aid into not being able to walk and needing a wheelchair for every movement.” This is defined by an EDSS disability score of 7 or higher, he said.
“The number of patients [on Mayzent treatment] who reach this endpoint was significantly lower, approximately 30% lower,” so with Mayzent, “you also progress to some extent, but slower,” said Kappos, referring to the new findings shared at the conference.
Results also suggested that Mayzent can delay the time to wheelchair dependence by approximately 4.3 years, compared with placebo. These estimates were based on a data extrapolation model, which assumed the therapy has a stable effect over time.
“We use a somewhat sophisticated statistical method where we included the whole trajectory of the patient during the study in order to project in the future — so for those who are not there yet — how long is the delay. This was calculated at approximately four years,” Kappos said.
“Of course, we don’t know if this prediction will be true, but up to now … what is happening in the treated group looks quite similar, so these four years are realistic, and we will have a long-term follow-up of this study,” he added.
As to how reliable these type of estimates are, Kappos believes “it’s justified [to assume Mayzent’s effect is constant over time], because we have been seeing it also in similar substances as S1P immunomodulators; we also have not seen a wane off of the effect over time; it’s at the same level.”
When asked if any differences between patients with active and non-active SPMS in this study stood out, or if an analysis was done to look specifically at patient subgroups, Kappos answered, “No, we didn’t [analyze that], because then you come down to lower numbers, so for this subgroup analysis, it’s not so easy.
“In general, the effects of so-called active disease were somewhat stronger, but the positive finding was that we saw the effect also in those without activity,” Kappos noted. “Therefore, this was reassuring; of course, the effect is not as big, but it is there, and up to now, we didn’t have anything to offer to these patients.”
Kappos also stressed that Mayzent “is quite well-tolerated,” and is not associated with side effects that may make “life difficult. Usually, you take a pill and you don’t realize anything in addition to that.”
About Mayzent’s acceptance by the medical and patient communities, after its approval in March, Kappos noted that although he is not practicing in the U.S., “I talk to my colleagues, and I think it’s really coming slowly into that, because there’s no alternative at the moment of regular use.”
At the same time Mayzent was approved, another oral therapy called Mavenclad (cladribine; marketed by EMD Serono) was also approved by the FDA for the same indication — the treatment of adults with RRMS and active SPMS.
No head-to-head study has compared these two oral therapies, and Kappos is quick to point out the differences between the two treatments that may affect how doctors and patients choose one over the other.
“The mode of action is completely different because siponimod [Mayzent] is not affecting the immune cells directly; it just sequestrates them into the lymph nodes, so they’re out of the circulation — some of them, not all — and they can, as soon as you stop the drug, within one or two weeks, they can come back again in their function,” Kappos explained.
“With cladribine [Mavenclad], you kill immune cells, so it’s a cytostatic agent. The advantage, as compared to most former cancer drugs that are also cytostatic, is that it is specific for immune cells, so it interacts with the metabolism of the genome of the immune cells, and it has very little effect in other cells. And this makes it tolerated with less burden of side effects, but there is an immunosuppressive effect,” he added.
As final notes, Kappos mentioned two other studies he is involved with that were also presented at ECTRIMS. One is a study showing that Actelion’s ponesimod, an investigational oral treatment, is superior to Sanofi’s Aubagio (teriflunomide) in lessening the frequency of relapses and easing fatigue symptoms in adults with active, relapsing MS.
The second study highlighted by Kappos is focused on ofatumumab, an investigational under-the-skin injection, that was found to be superior to Aubagio in reducing relapse rates and active brain lesions in patients with relapsing MS.
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