Mayzent (siponimod), an approved oral therapy for active secondary progressive multiple sclerosis (SPMS), promotes a more regulatory immune system, which may explain its added benefits for SPMS, new clinical data show.
The study “Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis” was published in the journal JCI Insight.
Novartis’ therapy is approved in Europe, Australia, and in the United States — where it also is approved for treating adults with clinically isolated syndrome (CIS) and relapsing-remitting disease (RRMS) — following the positive results of the Phase 3 EXPAND clinical trial (NCT01665144).
Active SPMS is defined by the presence of evident disease relapses or the detection of inflammatory activity in brain lesions on imaging scans.
Mayzent works by binding to two sphingosine-1-phosphate (S1P) receptors on the surface of immune cells, leading to the internalization and degradation of these receptors. This prevents immune cells in the lymph nodes from reaching the brain and spinal cord, which reduces the inflammatory processes that promote MS development and progression.
The mechanisms underlying Mayzent’s effects on the immune system remain unclear. However, its success in “slowing progression in active SPMS provides the first opportunity to determine the relevance of immune system modulation to disease progression in SPMS,” researchers wrote.
Researchers at the University of Michigan Medical School conducted an observational study, AMS04 (NCT02330965), that enrolled 36 SPMS patients who had participated in the EXPAND trial. Thirteen participants were assigned randomly to receive a placebo, and 23 participants received Mayzent. Participants were followed for up to 12 months.
The team investigated how Mayzent modulated gene levels by analyzing the transcriptome of patient’s blood samples. The transcriptome is the entire set of gene transcripts, meaning messenger RNA molecules constituting copies of the DNA sequence used to create proteins.
The analysis revealed that treatment with Mayzent affected the activity of 1,531 genes. The majority of these genes were involved in the activation of immune T- and B-cells, and they showed decreased activity upon treatment with Mayzent.
In agreement with these gene expression results, immune cell counts showed that treatment with Mayzent led to a reduction in the number of immune CD4- and CD8-positive T-cells, and that of B-cells, compared to the placebo-treated group. Within 12 months, CD4-positive T-cells decreased by 96%, and CD8-positive T-cells by 59%.
Both CD4 and CD8-positive T-cells play an important role in the autoimmune reaction against myelin (the protective coat surrounding neurons), the hallmark of MS. These cells are characterized by high levels of pro-inflammatory molecules that help sustain the immune reaction.
Mayzent led to an overall threefold reduction of the CD4/CD8 T-cell ratio.
Immune B-cells also are a source of pro-inflammatory cytokines, and a known player in MS.
Memory B-cells (identified as CD19-positive B-cells) were reduced by 89% after 12 months. Memory B-cells keep a “memory” of past “foreign” (non-human) proteins and are long-lived, generating a faster and stronger response upon re-stimulation with “foreign” invaders.
Within the remaining subsets of white blood cells, 12-month treatment with Mayzent led to a reduction of CD4- and CD8-naïve T-cells and central memory cells. In contrast, the therapy increased the levels of cells that dampen inflammation, namely anti-inflammatory Th2 cells, and cells that regulate and prevent the immune systems’ over activation, called T regulatory (Treg) cells. Tregs increased by threefold within nine to 12 months after Mayzent treatment.
The therapy boosted the frequency of regulatory B-cells (Bregs), which also work to keep the immune system in check.
No significant changes in other immune cells — natural killer cells, natural killer T (NKT) cells, or other white blood cells — were seen with Mayzent.
“The shift toward more Tregs and Bregs is consistent with a shift toward an overall more pro-regulatory immune environment following siponimod [Mayzent] treatment,” the researchers wrote.
Overall, the findings suggest that the “shift toward an anti-inflammatory and suppressive homeostatic immune system may contribute to the clinical efficacy of siponimod in SPMS,” the team concluded.
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