The effectiveness of Mayzent (siponimod) in both the brain and the body make it an oral therapy tailored for people with early secondary progressive multiple sclerosis (SPMS), according to Dan Bar-Zohar, MD, top executive with Novartis, the treatment’s developer.
Mayzent was recently approved by the U.S. Food and Drug Administration (FDA) for adults with relapsing forms of multiple sclerosis (MS), which, besides “active” SPMS, included clinically isolated syndrome and relapsing-remitting disease (RRMS).
In studies like the pivotal EXPAND Phase 3 clinical trial (NCT01665144), “we saw an effect on brain volume loss reduction which may be indicative for increased remyelination and a decrease in the diffuse damage, and we’re very excited about that,” Bar-Zohar, global head of neuroscience development at Novartis, said in an interview last week with Multiple Sclerosis News Today.
The decision to develop the therapy was based on the efficacy of compounds known as S1P receptor modulators in MS. Gilenya (fingolimod, also marketed by Novartis), is such an example, as it targets the S1P1 subtype found in nerve cells and immune brain cells called microglia.
Mayzent also has very high affinity for another subtype, called S1P5.
“The thinking with siponimod [Mayzent] is that it tickles different subsets of S1P receptors, and the thought was that it could be more effective, particularly in progressive MS than, for example, fingolimod (Gilenya),” Robert Fox, a neurologist at the Cleveland Clinic, said in a separate interview.
That’s because Mayzent enters the brain “avidly,” Fox and Bar-Zohar said, where two cell types implicated in the accumulation of injury contain high levels of S1P5: astrocytes, involved in the formation of the blood-brain barrier, and oligodendrocytes, the cells that form the myelin sheet around nerve fibers.
Preclinical work in animals suggested that Mayzent acts through S1P5 on these cells to ease clinical symptoms of progressive disease. This work “suggests that Mayzent has beneficial effects through these cells, through … astrocyctes and through oligodendrocytes in order to ameliorate clinical symptoms of progressive disease,” Bar-Zohar said.
But Mayzent also acts outside the brain. By targeting S1P receptors, the therapy traps lymphocytes in lymph nodes, preventing these cells from reaching the brain and promote inflammation.
So, considering Mayzent’s actions inside and outside the brain, as well as the findings in animals, “it makes a lot of sense to treat SPMS,” Bar-Zohar said.
Linking clinical benefits to a therapy’s mechanism of action, however, can be quite difficult thing. As noted in Mayzent’s label, “the mechanism by which siponimod [Mayzent] exerts therapeutic effects in multiple sclerosis is [still] unknown.” Added Fox: “In clinical medicine, what we have to do is listen to the mechanism of action, and then shrug our shoulders and look at the empiric data.”
“There’s a lot of things we don’t know,” he added. “For example, dimethyl fumarate, or Tecfidera, has been used for many, many years in MS, and we still don’t know exactly how that drug works.”
Mayzent’s half-life — the time required for its amount in the body to be reduced to half — is considerably shorter than Gilenya’s (30 hours vs. six-to-nine days). According to Bar-Zohar, this aspect of its pharmacological profile enables starting treatment slowly, lessening the risk of a slowed heart rate, which is a well-known side effect of Gilenya mediated via S1P1.
Yet, the common S1P1 targeting makes the two therapies’ safety profile quite similar, Bar-Zohar said, although head-to-head comparisons have not been made. “We know the challenges and we can address them.”
“We must remember that not treating the patient who is transitioning to SPMS is a safety issue in itself,” he said, explaining that delayed treatment means more lost nerve cells. “Time is worth neurons.”
Overall, Mayzent’s attributes make it the right answer for these patients. “This entire package of the efficacy data, the pharmacokinetic profile, the mechanism of action make it [Mayzent] very unique and tailored for the patient population with SPMS,” he said.
Likely future trials
Novartis is planning to test the therapy in pediatric patients after it concludes ongoing discussions with the European Medicines Agency regarding Mayzent’s approval in Europe.
The company is currently conducting a Phase 3 study in the U.S., named EXCHANGE (NCT03623243), assessomg the safety and tolerability of switching patients from other disease-modifying therapies to Mayzent. This trial – currently enrolling (more information is here) – is intended to help patients and physicians better understand the treatment’s safety profile.
A future trial, still in planning phases, aims to look at the benefits of identifying SPMS early and starting treatment with Mayzent compared to keeping patients on their current therapy. According to Bar-Zohar, such study will likely enroll patients transitioning from RRMS.
“The goal will be to show that, in these cases, Mayzent offers, I would say, a much better mid-term and long-term outcome,” he said.
In its effort for earlier SPMS detection, the company is also developing an algorithm to better assess the transition from RRMS, and to promote discussion between patients and physicians. Novartis plans to use this tool in upcoming trials.