The Phoenix has risen: the era of disease modification in progressive MS has truly arrived

The EXPAND study is the first positive study in people with secondary progressive MS and marks a new landmark in the treatment of MS.

Please note that I am a co-author on this paper and I sit on the trial steering committee. I am clearly conflicted and therefore you may not want to read or hear what I have to say about the trial's findings. 

Siponimod is the second-in-class of the so-called sphingosine-1-phosphate modulators; the first being fingolimod. The EXPAND phase 3 trial published in today's Lancet is a landmark study in that this is the first positive study in 'non-relapsing SPMS'. Why was this study positive when so many others have failed? It was very large with 1651 subjects included in the study and was a so-called event-driven study, i.e. it went on for a long as necessary to accumulate enough disability progression events to answer the question of whether of not Siponimod can modify the course of SPMS. 

I am aware that many people have and will continue, to pooh-pooh the results as not being meaningful, i.e. the treatment effect is too small. This same pooh-pooh phenomenon occurred with the original interferon-beta studies in RRMS and more recently the ocrelizumab in PPMS study. I must point out that most of the patients in the EXPAND trial required walking aids, hence there was not much reserve in the motor pathway to the legs to see a treatment effect. This also means that therapeutic lag has to be taken into account; therefore, it takes time to see a treatment effect. So a small difference over 3-4 years may translate into big differences over 5 to 10 years. 

Interestingly Siponimod did not have an impact on the 9HPT nor the T25W. It looks as if these two outcome measures were very noisy in this study. This is something that needs to be explored as it challenges our length-dependent axonopathy hypothesis. 

Despite this Siponimod had a very strong effect on focal MRI lesions and brain volume loss. I, therefore, have little doubt about the robustness of these trial results. It is also clear that the SPMSers who were less disabled and younger benefited most. This means that when we treat 'SPMS' we will need to treat as early as possible. I can hear the naysayer saying that you are simply treating relapsing-remitting MS. I would say so what. The pathological processes driving RRMS and SPMS are probably the same and Siponimod will be effective in both the relapsing and more advanced stages of the disease. 

I suspect the EXPAND or Siponimod trial results will rekindle the debate about when SPMS begins and when can SPMS is diagnosed. I personally think that the pathology that drives SPMS is there from the start and that we need to be aware of potential disease worsening/progression even if we don't see a change in physical disability. George Ebers and colleagues used to diagnose SPMS with a median EDSS of 2.0. Their diagnosis was based on a history of clinical worsening in the presence of an abnormal neurological examination. For example, someone may report that their left foot gets weak and drags after 30 minutes walking. They then come back a year later and now report dragging after just 10 minutes. Provided they have abnormal neurological signs in the legs on examination they could be diagnosed as having SPMS. Neurologists, however, have shifted the goalposts and now diagnose SPMS when the patients have an EDSS of 4.0 or higher. Why? Simply because once you label someone with SPMS it excludes them from DMTs that are licensed for relapsing MS and it also tells them they a form of the disease that is not modifiable. The latter is something neurologists have wanted to avoid and patients have wanted to avoid it as well. Why would someone want to be labelled as having a progressive untreatable disease? These results change that for; SPMS is now a modifiable disease and there is now a treatment for this phase of the disease. 

I know people with progressive MS would like a treatment that doesn't just slow down the rate of their worsening disability. They want a treatment that reverses their disability. However, Siponimod can only do what it can do, i.e. as it is an anti-inflammatory it can only stop new focal MS lesions from forming and prevent new damage. Siponimod can't repair existing damage and it can't reverse existing disability. However, it can form the base of the pyramid for add-on therapies for the future, i.e. neuroprotectives, remylienators and neurorestoratives. I would, therefore, urge you all to focus on the positives and to celebrate these results as a milestone in the treatment of MS, i.e. progressive, or as I prefer advanced, MS. 

Why the Phoenix? I couldn't use the eagle, ocrelizumab claimed that bird. We have had so many false starts and hopes dashed in the past in relation to DMTs for SPMS. To me Spinoimod represents the Phoenix rising from the fire of failed SPMS trials to finally offer people with SPMS some hope. We now know how to adequately power and perform SPMS trials. I sincerely hope this trial will act as a catalyst for new SPMS trials. There is no lack of ideas or compounds when it comes to future SPMS trials. We at Barts-MS are pushing forward with our Chariot-MS study and are actively discussing several potential trials in SPMS with Pharmaceutical companies.

Kappos et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet March 2018

Background:  No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS.

Methods: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with, number NCT01665144.

Findings: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.

Interpretation: Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.


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