Long-term Continuous Siponimod Treatment Reduces Disability Progression, Cognitive Processing in Secondary Progressive MS


Those treated with siponimod (Mayzent; Novartis) for 5 or more years had significant reductions in 6-month disability and cognitive processing speed compared with patients who switched from placebo.

Bruce Cree, MD, PhD, MAS, FAAN, clinical research director of the UCSF Multiple Sclerosis Center

Bruce Cree, MD, PhD, MAS, FAAN

New patient data from the phase 3 EXPAND study extension (NCT01665144), published in the Multiple Sclerosis Journal suggest that treatment of secondary progressive multiple sclerosis (SPMS) with siponimod (Mayzent; Novartis) sustains its efficacy in the long-term, also displaying a consistent safety profile for 5 or more years.1

Compared with a cohort of patients who switched from placebo to siponimod, those treated continuously with a 2-mg/day dose of the selective sphingosine 1-phosphate receptor modulator reduced the risk of 6-month confirmed disability progression (CDP) by 22% (HR, 0.78; 95% CI, 0.66-0.92; P = .0026), as well as the risk of worsening in cognitive processing speed (CPS; HR, 0.77; 95% CI, 0.65-0.92; P = .0047).

Study investigator Bruce Cree, MD, PhD, MAS, FAAN, clinical research director of the UCSF Multiple Sclerosis Center, and colleagues wrote that this “sustained clinical efficacy and consistent safety profile support the clinical utility of siponimod” and that earlier treatment initiation with the therapy is significant, as “persistent treatment differences on both clinical and MRI measures favoring participants on continuous siponimod.”

The core part of EXPAND was a multicenter, 2:1-randomized, double-blind, parallel-group, placebo-controlled study investigating the efficacy and safety of siponimod compared with placebo in 1651 individuals with SPMS. The median study duration was 21 months (range, 0.2–37 months). This extension assessment included 582 patients with active SPMS and 612 with nonactive SPMS. In total, 821 individuals were in the continuous siponimod group and 399 were in the placebo-siponimod group.

“No new, unexpected safety signals for siponimod were identified over the long term,” Cree et al noted. The most common adverse events (AEs) in the extension were consistent with the core portion of the study, with no increases in exposure-adjusted incidence rates (IRs), nor exposure-adjusted IRs of AEs of special interest. Malignancies were reported in 5.1% (n = 78) of participants continuously treated with siponimod (IR, 1.6 per 100 person-years [PYs]; 95% CI, 1.2–2.0) compared with 1.9% (n = 21) of the core cohort (IR, 1.2 per 100 PYs; 95% CI, 0.8–1.9). Basal cell carcinoma IR was increased with long term exposure in the extension, “but other AEs of special interest were in line with the core part,” they wrote, adding that “there were no cases of progressive multifocal leukoencephalopathy, but one case of cryptococcal meningitis in the extension part.”

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In addition to its effects on CDP and CPS, continuous siponimod treatment resulted in a reduction in total brain volume loss, as measured by cumulative percentage change from baseline. After 60 months of follow-up, those treated continuously reported a loss of 1.62% compared with 1.76% in the switch group (P <.05). Thalamic volume loss, measured similarly, was also reduced with continuous use, with a reported loss of 2.68% in the continuous group compared with 3.48% in the switch group (P <.0001).1

“Several studies support a dual mechanism of action for siponimod acting both peripherally and centrally to target inflammation and neurodegeneration/myelination,” Cree et al wrote. “The long-term efficacy observed in participants with SPMS across different clinical measures (including physical and cognitive disability, relapse, and MRI measures related to both inflammatory disease activity and neurodegeneration) seems to be consistent with this dual mechanism of action.”

Siponimod was FDA-approvedal for the treatment of SPMS in March 2019. The approval was granted based on data from EXPAND, the largest phase 3 assessment of its kind, including more than 1600 patients with SPMS. It ultimately showed that 3-month confirmed disability progression was reduced by 21% (= .013).2

Another recent analysis of EXPAND data on siponimod suggests that it significantly reduced the progression of whole-brain and gray matter (GM) atrophy over a 2-year period. Following 12 and 24 months of treatment, siponimod slowed cGM, thalamic, and total brain volume loss relative to placebo, with adjusted mean percentage changes in cGM volume at month 12 were 0.01 for siponimod and –0.60 for placebo (102% relative reduction; <.0001). At month 24, the corresponding changes from baseline were –0.39 for siponimod and –1.04 for placebo (63% relative reduction; <.0001).3

From baseline to months 12 and 24, the adjusted mean percentage changes in thalamic volume were –0.47 and –1.02, for siponimod-treated patients, respectively, representing relative reductions of 63% and 50% in volume loss. Furthermore, the adjusted mean percentage changes in total brain volume from baseline to month 12 were –0.23 for siponimod and –0.45 for placebo (49% relative reduction; <.0001). Corresponding changes from baseline to month 24 were –0.62 for siponimod-treated patients compared with –0.90 for those on placebo (31% relative reduction; <.0001).3

1. Cree BA, Arnold DL, Fox RJ, et al. Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years. Mult Scler J. Published online April 5, 2022. doi:10.1177/13524585221083194
2. Kappos L, Cree B, Fox R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomized, phase 3 study. Lancet. 2018; 391(10127):1263-1273. doi:10.1016/S0140-6736(18)30475-6.
3. Arnold DL, Piani-Meier D, Bar-Or A, et al. Effect of Siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: a gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial. Mult Scler J. Published online March 9, 2022. doi:10.1177/13524585221076717
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