Siponimod Reduces Disability Progression in Secondary Progressive Multiple Sclerosis

April 21, 2018

The data from the phase III EXPAND study indicated to the researchers that this risk reduction obtained with siponimod was substantially isolated from MS relapse.

Bruce Cree, MD, PhD, MAS

New-post hoc analysis reported that once-daily, oral siponimod (BAF312, Novartis) consistently resulted in disability progression in patients with secondary progressive multiple sclerosis (SPMS).1

Presented at the American Academy of Neurology’s 70th Annual Meeting in Los Angeles, California, the data from the phase III EXPAND study resulted in the researchers noting that they believe this risk reduction obtained with the selective modulator of sphingosine-1-phosphate (S1P) receptor subtypes is substantially isolated from MS relapse.

EXPAND study steering committee member Bruce Cree, MD, PhD, MAS, the clinical research director and associate professor at the University of California, San Francisco, School of Medicine, told NeurologyLive’s sister publication, MD Magazine that a gap in treatment exists for the inflammatory-neurological duality of SPMS—a gap that siponimod has shown its ability to fill.

"Siponimod's beneficial effect on preventing disability progression, independent from its reduction in relapse frequency, demonstrates that patients with secondary progressive MS could benefit from this treatment,” Cree said.

The randomized, double-blind, placebo-controlled trial compared the safety and efficacy of siponimod to placebo in patients with SPMS. The largest of its kind, it included 1651 patients from 31 countries. Patients were a mean of 48 years old, with the average time since first symptoms being 16.8 years (standard deviation [SD], 8.3). All told, 64% (n = 1055) of patients had not relapsed in the prior 2 years, and 56% (n = 918) needed walking assistance.

Patients were randomized 2:1 to intervention of 2 mg siponimod once-daily or placebo. In total, 1099 patients received siponimod and 546 were administered placebo. Of those in the treatment group, 82% (n = 903) and 78% (n = 424) of the siponimod and placebo patients completed the trial, respectively.

Patients treated with siponimod reported a statistically significant reduction in disability progression risk, sustained at both the 3- and 6-month marks. Using a model-based approach in the new analyses, the investigators noted that the estimated risk reduction for disability progression sustained at 3 months ranged from 14% to 20% compared to placebo for non-relapsing patients, with that risk reduction at 6 months developing to 29% to 33%.

In total, 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month confirmed disability progression (hazard ratio [HR], 0.79; 95% CI 0.65 to 0.95; relative risk reduction 21%; P = .013).

The therapy’s effect on cognition was also a noted benefit in the post-hoc analysis. Using the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) for evaluation, those in the siponimod group showed a significant improvement in cognitive processing speed from baseline to month 24 compared to placebo, in all patients when assessed with the SDMT (P = .0004), as well as those who had suffered relapses within 2 years before the trial when assessed with the SDMT and the PASAT (SDMT, P = .0151; PASAT, P = .0275).

Adverse events (AEs) occurred in 89% (n = 975) of patients in the intervention arm compared to 82% (n = 445) of those receiving placebo. Serious AEs occurred in 18% (n = 197) and 15% (n = 83) of the siponimod and placebo groups, respectively. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo.

Siponimod’s ability to treat symptoms evident in about half of all MS patients means it could have a true impact on patients’ daily lives, Danny Bar-Zohar, MD, BSc, the global head of Novartis’ Neuroscience Department, said in a statement.2

“Furthermore, the advanced models used in the new analyses help us to better understand the relationship between relapses and disability and the effect of siponimod on these parameters,” Bar-Zohar said. “We are encouraged by these latest findings, which further solidify the clinical evidence for siponimod as a potential new, much-needed treatment option for SPMS."

EXPAND study steering committee member Bruce Cree, MD, PhD, MAS, clinical research director and associate professor at the University of California, San Francisco, School of Medicine, added that there’s a gap in treating the inflammatory-neurological duality of SPMS that siponimod has clearly shown being able to fill.

"Siponimod's beneficial effect on preventing disability progression, independent from its reduction in relapse frequency, demonstrates that patients with secondary progressive MS could benefit from this treatment,” Cree said.

Novartis has begun the submission process with the US Food and Drug Administration to have siponimod indicated for patients with SPMS in the first half of 2018.

REFERENCES

1. Kappos L, Bar-Or A, Cree BA, et. al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6.

2. New Novartis analyses at AAN show siponimod's efficacy on disability and cognition in secondary progressive MS patients [press release]. Basel, Switzerland: Novartis Media Relations; April 20, 2018. novartis.com/news/media-releases/new-novartis-analyses-aan-show-siponimods-efficacy-disability-and-cognition-secondary-progressive-ms-patients. Accessed April 20, 2018.