Management of Progressive Multiple Sclerosis - Episode 5

Siponimod for SPMS Treatment

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Robert Fox, MD, discusses the rationale for using siponimod for the treatment of progressive multiple sclerosis as well as the practical implications of the phase 3 EXPAND trial.

Bruce Cree, MD: I’m going to ask Bob to tell us a little about siponimod and its mechanism of action, as well as the design and results of the clinical trial that led to its approval as a treatment for secondary progressive MS [multiple sclerosis]. Bob, tell us about the EXPAND study in siponimod.

Robert Fox, MD: Sure. Siponimod is an S1P [sphingosine-1-phosphate] modulator, so it’s in a class of medications that we have explored a fair bit in MS. It has a specific affinity for some of the subgroups of S1P receptors. For siponimod, it’s the type 1 and type 5. It was evaluated in a double-blind phase 3 trial. It was a very large trial, with 292 hospital clinics and MS centers in 31 countries around the world participating, with 1651 patients enrolled and randomized. 

Patients were randomized 2:1 to oral siponimod or placebo and followed for up to 3 years or until the occurrence of a number of predefined outcomes, most notably, confirmed disability progression. 

The patients who enrolled in the study had an average disease duration of over 15 years, so they had had MS for quite a period of time. They had secondary progressive MS for on average about 4 years—so these are patients who have longstanding MS and had evolved into secondary progressive MS for quite a period. 

When the data were analyzed, there was a slowing of progression of disability. The 3-month confirmed disability progression was slowed in the siponimod-treated patients by about 21%. That’s not huge, but not small either. That’s a 21% slowing in the hazard ratio, as measured by the Kaplan-Meier curve. 

Adverse effects were somewhat typical and expected for this class of medication, S1P modulators. They included lymphopenia, increased liver enzymes, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, varicella zoster reactivation, and surprisingly, something we hadn’t seen too much before, seizures. All of these were seen more commonly with siponimod compared to placebo. 

Importantly, the initial dose titration seemed to mitigate the cardiac first-dose effects that we’ve seen with other S1P modulators. Those are the main results; it did show a slowing of sustained progression and disability. There was also a decrease in some of the disease activity measures, like the annualized relapse rate and new lesions—T2 lesions and gadolinium-enhancing lesions—in MRI. There was also a slowing of the progression of brain atrophy in the treated group compared to placebo. 

Bruce Cree, MD: Bob, I want you to comment on what you think was going on in this study, because this is a little controversial. Do you think that the impact of siponimod and why this particular study was successful was due to lymphocyte sequestration, which is one of the known effects of siponimod on the body? Or do you think that there were additional effects within the central nervous system that might be targets for siponimod, resulting in a clinically favorable benefit of this drug?

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Transcript Edited for Clarity