Siponimod Shows EDSS Subscale Benefits in Secondary Progressive MS

Bruce Cree, MD, PhD, MAS, clinical research director, and George A. Zimmermann Endowed Professor in Multiple Sclerosis, UCSF School of Medicine

Bruce Cree, MD, PhD, MAS

Findings from a new analysis of EXPAND clinical trial (NCT01665144) data suggest that patients with secondary progressive multiple sclerosis (MS) who are treated with siponimod (Mayzent; Novartis) experience a sustained benefit, with a slowing of physical disability progression and addition of cognitive protection.^1,2

Using a pair of new subscales of the Expanded Disability Status Scale (EDSS)—Motor Integration (MI), which measures ambulation and cerebellar/pyramidal functions, and Collateral (C), which measures bowel and bladder, brainstem, cerebral, sensory, and visual functions—the findings were consistent with the earlier analyses of fingolimod (Gilenya; Novartis), thus confirming siponimod’s benefits.

These data were originally accepted for presentation at the now-canceled American Academy of Neurology (AAN) 2020 Annual Meeting.

“These data highlight the critical importance of early treatment intervention with a disease-modifying treatment, such as Mayzent, to ensure the best possible long-term outcomes for patients with MS who are experiencing progression,” Bruce Cree, MD, PhD, MAS, clinical research director, and George A. Zimmermann Endowed Professor in Multiple Sclerosis, UCSF School of Medicine, said in a statement. “It’s never too early to stay ahead of progression in multiple sclerosis, since the early identification of physical and cognitive changes—even subtle ones—can indicate MS disease progression and therefore allow for timely intervention.”

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In total, the analysis included 1645 patients, of which 1099 were administered the sphingosine 1-phosphate (S1P) receptor modulator and 546 given placebo, and showed that significant treatment effects were detected over the 36-month study period for EDSS scores (P = .020), as well as both the MI (P = .014) and C (P = .021) subscales. The effect size favored siponimod from the 6-month mark and onward.

The MI subscale reported a marked effect size as early as Month 9 for all patients (effect size, 0.12; P = .007), as well as a subgroup of relapsing patients (effect size, 0.25; P = .009) and a subgroup of patients without lesions (effect size, 0.13; P = .012). At Month 12, those with lesions also reported a significant effect size (0.22; P = .041).

These treatment effects were observed later on with the C subscale compared with the MI subscale, detecting significant effect size at Month 15 for the relapsing subgroup (0.19; P <.05) and Month 27 for both patients with lesions (0.43; P <.05) and patients without lesions (0.29; P <.05).

Additional data from the 5-year, open-label EXPAND extension study which were scheduled to be presented at AAN 2020 suggest that those who continued on siponimod treatment (n = 878) were less likely to experience both 3-month confirmed disability progression (CDP; P = .0064) and 6-month CDP (P = .0048) compared to those who switched from placebo (n = 346). As well, incidence rates of adverse events per 100 patient-years in the long-term follow-up were consistent with the controlled treatment period, with no new safety findings observed.³

This second assessment included 1124 patients (74% of 1651 randomized patients), all of whom received ≥1 dose of randomized treatment. The efficacy analyses included time-to-3- and 6-month CDP on the Expanded Disability Status Scale (EDSS), time-to-6-month confirmed worsening—defined as ≥4 points on Symbol Digit Modalities Test&mdash;and annualized relapse rate (ARR). A reduction in ARR of 52% was observed for the continuing group (0.054) compared to the switch group (0.097; P <.0001).

As well, a third, post-hoc analysis from EXPAND suggested that siponimod consistently reduced cortical grey matter and thalamic atrophy in those with SPMS. Across all subgroups, the reduction in cortical grey matter atrophy compared to placebo ranged from 48% to 116% (P <.01 at both 1 year and 2 years), and thalamic atrophy was reduced by 30% to 68% (P <.05 at both 1 year and 2 years). Although, thalamic atrophy was not significantly reduced for those with a disease duration >15 years after 1 year (P = .1029).⁴

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REFERENCES

1. Cutter G, Meng X, Bar-Or A, et al. Effect of Siponimod on Disability in EXPAND Re-examined with Two New Subscales of the Expanded Disability Status Scale in Patients with SPMS. Neurology. 2020; 94 (15 Supplement): 4051.

2.Novartis announces new Mayzent® (siponimod) data show sustained effect in delaying disability for up to five years in patients with secondary progressive multiple sclerosis (SPMS) [press release]. Basel, Switzerland: Novartis; Published April 21, 2020. Accessed April 29, 2020. globenewswire.com/news-release/2020/04/21/2019014/0/en/Novartis-announces-new-Mayzent-siponimod-data-show-sustained-effect-in-delaying-disability-for-up-to-five-years-in-patients-with-secondary-progressive-multiple-sclerosis-SPMS.html

3. Kappos L, et al. Long-term Efficacy and Safety of Siponimod in Patients with SPMS: EXPAND Extension Analysis up to 5 Years. Neurology. 2020; 94 (15 Supplement): 4128.

4. Fox R, et al. Siponimod Reduces Grey Matter Atrophy in Patients with Secondary Progressive Multiple Sclerosis: Subgroup Analyses from the EXPAND study. Neurology. 2020; 94 (15 Supplement): 4037