Prospects of siponimod in secondary progressive multiplesclerosis

The characterization and treatment of progressive multiple sclerosis has been achallenging area of research. Despite many advances in treatments options forrelapsing–remitting multiple sclerosis (RRMS), there are a paucity of treatment optionsfor progressive MS, either primary progressive MS or secondary progressive MS. Thepathophysiology of progressive MS is unknown, but likely includes the infiltrativeinflammatory damage seen in relapsing MS, along with compartmentalized inflammation andneurodegeneration.^1,2

EXPAND was a randomized double-blind phase III clinical trial comparing siponimod(n = 1099) with a matching placebo (n = 546) inpatients with secondary progressive MS.³ Siponimod is a selective modulator of the sphingosine-1-phosphate (S1P) receptorsSIP1 and SIP5. Other S1P modulator therapies include fingolimod, which is approved forrelapsing forms of MS, and ozanimod and ponesimod, which are under development for usein MS.⁴ One mechanism of action of siponimod is the reduction of lymphocyte egress fromlymphoid tissue, which prevents lymphocytes from circulating to the central nervoussystem. Other hypothesized mechanisms are prevention of synaptic neurodegeneration andpromotion of remyelination due to its ability to cross the blood–brain barrier andpotentially act directly within the brain.

In the EXPAND trial, 1646 patients with secondary progressive MS were randomly assignedto receive either siponimod or placebo. Enrolled patients were typical of those seen inclinical practice, with a mean age of 48 years and disease duration of 16–17 years. Alltrial participants continued the assigned treatment until a target number ofparticipants had sustained progression of disability. As a result, participants had avariable exposure to treatment. A total of 81% of patients completed follow up, whichranged from 11 to 37 months (median 18 months).

The primary outcome was the 3-month confirmed disability progression (CDP), wheresiponimod demonstrated a relative risk reduction of 21% compared with placebo. A similarrelative risk reduction was also seen for the 6-month CDP, where there was a 26%reduction. The rate of clinical relapses also was significantly lower in the siponimodgroup, as was the time to confirmed first relapse. Magnetic resonance imaging outcomesincluded a change in T2 lesion volume from baseline and brain volume, both of which werereduced in siponimod-treated patients compared with placebo. Additionally, siponimodpatients had fewer gadolinium-enhancing lesions and new or enlarging T2 lesions. Theonly key secondary outcome that did not favor siponimod was time to 3-month confirmedworsening of at least 20% in the timed 25 foot walk (T25FW).

Exploratory subgroup analyses suggested that the treatment effect became less pronouncedwith increasing age, disability, baseline disease duration, and diminishing signs ofdisease. This finding is similar to what was seen with ocrelizumab in primaryprogressive MS, where greater benefit was seen in younger patients and those withgadolinium-enhancing lesions at baseline.⁵

These observations raise the question of whether the observed benefits of siponimod maybe attributed to systemic anti-inflammatory properties, as this drug class is well knownto have anti-inflammatory effects in MS. However, there are arguments for othermechanisms of action. Siponimod is known to cross the blood–brain barrier, which mayallow it to affect not only systemic inflammation, but also the compartmentalizedinflammation seen in progressive MS. Additionally, the deceleration of brain atrophyprogression suggests that siponimod could slow down disease progressionvia routes beyond an anti-inflammatory effect. Finally, in a mousemodel, siponimod was shown to modulate biological pathways involved in cell survivalwith subsequent attenuation of demyelination.⁶ A study using another mouse model of brain inflammation reported that siponimodcan prevent loss of GABAergic interneurons, which is thought to contribute to neurodegeneration.⁷

The most common safety events that occurred more frequently with siponimod use werelymphopenia, increased liver transaminase, bradycardia and bradyarrhythmia at treatmentinitiation, macular edema, hypertension, Varicella zoster reactivation,and convulsions. Most of these safety events have been reported with other medicationsin the same class.

In summary, in a large, placebo-controlled trial, siponimod was found to slow thesustained progression of disability in secondary progressive MS and had an acceptablesafety profile. Further analysis of this dataset and additional research is needed tobetter understand whether the benefit was primarily driven by the anti-inflammatoryeffect that is well established by this class of therapies. Nonetheless, siponimod is apromising therapeutic option for secondary progressive MS.