Siponimod Reduces Brain Tissue Damage in Secondary Progressive MS, Post Hoc Analysis Suggests

Over 24 months, treatment with siponimod (Mayzent; Novartis) was associated with improvements in brain tissue integrity and myelination within newly formed normalized magnetization transfer ratio lesions.

Recently published data from a post hoc analysis of the phase 3 EXPAND trial (NCT01665144) showed that siponimod (Mayzent; Novartis), a disease-modifying therapy for secondary progressive multiple sclerosis (SPMS), significantly reduced progression of whole-brain and gray matter (GM) atrophy over a 2-year period.

"In summary, these beneficial effects of siponimod on regional brain atrophy and tissue integrity/myelination are consistent with previous preclinical findings and highlight possible direct CNS effects of siponimod, which may be relevant to its effects on disability progression and cognitive processing speed in patients with SPMS," the study investigators concluded.

EXPAND was a phase 3, randomized, double-blind, placebo-controlled, event- and exposure-driven study of up to 37 months duration investigating the efficacy and safety of siponimod in patients with SPMS. Eligible patients were between 18-60 years old, had Expanded Disability Status Scale (EDSS) score of 3.0-6.5 at screening, and had no evidence of relapses in the previous 3 months. The cohort were randomized 2:1 to once-daily siponimod 2 mg (n = 1037) or placebo (n = 523), with end points observed at 12- and 24-months post-baseline.

In addition to whole-brain and GM atrophy, senior author Robert J. Fox, MD, neurologist, Mellen Center for Multiple Sclerosis, and Vice-Chair for Research, Neurological Institute, Cleveland Clinic, and colleagues evaluated MRI measurements such as newly formed normalized magnetization transfer ratio (nMTR) lesions. Additionally, they evaluated nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM).

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Following 12 and 24 months of treatment, siponimod slowed cGM, thalamic, and total brain volume loss relative to placebo. Adjusted mean percentage changes in cGM volume from baseline to month 12 were 0.01 for siponimod and –0.60 for placebo (102% relative reduction; P <.0001). At month 24, the corresponding changes from baseline were –0.39 for siponimod and –1.04 for placebo (63% relative reduction; P <.0001).

From baseline to months 12 and 24, adjusted mean percentage change 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; P <.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; P <.0001).

The rate of thalamic atrophy was more pronounced among those with inflammatory disease activity despite cGM atrophy rates constant/similar across subgroups. Additionally, the reductions from baseline to month 12 and 24 in cGM and thalamic atrophy with Siponimod vs placebo were consistent across subgroups, regardless of baseline age, disease duration, activity, or severity for those in both the per-protocol set (PPS) and the full analysis set (FAS).

On MTR analyses, investigators found no significant differences in mean nMTR change from baseline to month 12 with siponimod vs placebo in NABT (−0.011 vs −0.014; between-treatment difference: 21%; P = .7285), cGM (−0.007 vs −0.009; between-treatment difference: 22%; P = .8308), or NAWM (−0.005 vs −0.018; between-treatment difference: 72%; P = .1550).

By 24 months, mean nMTR continued to increase above baseline levels among siponimod-treated patients, whereas those on placebo demonstrated decreases levels in all tissues (mean nMTR changes for siponimod vs placebo: NABT, 0.001 vs −0.055; between-treatment difference: 102%; P = .0050; cGM, 0.008 vs −0.046; between-treatment difference: 117%; p = 0.0141; NAWM, 0.010 vs −0.056; between-treatment difference: 118%; p = 0.0004). At months 12 and 24, the between-group differences for NABT, cGM, and NAWM were in the range of 85%-105%.

Treatment with siponimod was associated with improved nMTR recovery, as represented by less total decrease in nMTR from stable pre-lesion to stable post-lesion values. Those on siponimod demonstrated decreased values of 1.35 compared with 1.71 for those on placebo, equating to a between-treatment difference of 0.36 (P <.0001). Results from this model were based on the latest pre-lesion and latest post-lesion measurements.

Siponimod, a selective sphingosine 1-phosphate receptor modulator, received FDA approval 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% (P = .013).

1. 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
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.