Is siponimod the first cul-de-sac DMT?

Barts-MS rose-tinted-odometer  ★

A big worry for neurologists and pwMS is the sequencing of DMTs. What DMTs can be used before and after each other and does the sequencing of DMTs change the risk profile of the individual DMTs concerned? These have been dealt with many times on this blog and I am in the final stages of completing phase 1 of my app that will address the specific issues around each DMT. 

Another issue relates to the specifics of the label and how we classify patients; this is particularly problematic when it comes to the EMA’s label for siponimod, i.e. “treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity (see section 5.1)”. 

To prescribe siponimod we will have to (1) label the patient concerned as having secondary progressive MS and (2) provide evidence, at least in the UK, that the patient has active disease. The latter would be relapses and/or evidence of MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions). The latest NICE guidance, which is trying to standardise the definition states that MRI activity is “1 T1 gadolinium-enhancing lesion at baseline MRI or a significant increase in T2-lesion load compared with a previous MRI”. Although we haven’t been given a specific time period it is likely to refer to the last 24 months. 

Some questions. If the relapses and MRI activity occurred prior to the diagnosis of SPMS can they still be counted? Or does the diagnosis of SPMS rebaseline patients? I think the answer should be somewhere in between these two extremes. As the diagnosis of SPMS is retrospective the baseline or clock for assessing disease activity should be set when the first objective evidence of worsening was documented. In reality, this is typically 6 or 12 months in the past depending on the frequency of follow-up appointments. The definition of SPMS requires at least 6 months of worsening disability independent of relapse activity. The problem here is that to have active SPMS you also need to have had a relapse and/or MRI activity in this period as well. So it becomes very difficult to untangle worsening from relapses from worsening independent of relapses. These definitions are a mess!

In an ideal world, all the above may make sense, but this does not take into account the reluctance of neurologists and HCPs to document or label their patients as having SPMS. In some countries, a label of SPMS means the current DMTs may need to be stopped. Also the label SPMS has other negative connotations; it is often interpreted as having a second disease, importantly a disease that is not modifiable. I know this happens a lot. When we tried to recruit study subjects for our PROXIMUS study (add-on neuroprotection with oxcarbazepine) my colleagues were reluctant to refer their patients for the trial as it required them to diagnose early SPMS and nobody wanted to do that. 

Another issue that arises is that once someone is labelled as having SPMS can you unlabel them and refer to them as having relapsing MS? Common wisdom says no. In other words, once you have transitioned (and I hate this term) to becoming SPMS you can’t go backwards. This has major implications for patients with active SPMS; once you are on siponimod it may close the door to the other DMTs as they are not licensed, at least in Europe, for SPMS. I suspect this will be one of the biggest hurdles for the widespread adoption of siponimod for active SPMS in the UK. In other words, siponimod will become the cul-de-sac or dead-end DMT until another DMT is licensed for SPMS.  I can already see NHS England making it impossible to switch someone who is failing on siponimod, can’t tolerate it, or develops adverse events that require stopping siponimod, onto another high-cost DMT that is licensed for RRMS.

I think we as an MS community need to make the argument that you can flip-flop between MS subtypes. We have evidence buried in the trial data that a subset of patient labelled as having SPMS behave as having RRMS, i.e. their EDSS scores improve despite superimposed relapses. Similarly, there is a subgroup of patients with ‘inactive’ or ‘smouldering’ SPMS who have not had a relapse for years suddenly become active. The same thing happens with PPMS; approximately 25% of pwPPMS will go onto have superimposed relapses. Surely these people have relapsing MS rather than PPMS? Calling them progressive-relapsing MS does not deal with the biology of the disease in these patients nor their treatment. Leaving them as having a form of PPMS means that are only eligible for ocrelizumab, whereas relabeling them as having RMS opens up many more treatment options for these patients.

These arguments are more than just semantics they have real-life implications for individuals with MS and how we treat their disease.

At the end of the day, we can avoid all these arguments by defining MS as one disease and not two or three diseases (#MS_is_1_not_2_or_3_diseases). Until we do this siponimod, despite the hype and hope around its anticipated launch, is likely to not to be used as much as it should be used to avoid putting patients down a treatment pathway that is a cul-de-sac.

CoI: multiple

3 thoughts on “Is siponimod the first cul-de-sac DMT?”

  1. So, it is mostly an issue that has to do with labelling the disease. But to which extent such labelling is accurate? A doctor cannot know from the very beginning how the disease is going to evolve in every patient, so it is a matter of avoiding MS getting worse? It is really possible that someone with SPMS turns into an RRMS patient? I mean, os it possible that the disease can be somehow reverted?

  2. Never heard of anyone having diagnosis changed back to RRMS once crossed the line. Treatment with steroids and that’s all (until siponimod available).

    As for ‘active’ SPMS and PPMS, kinda crazy waiting for a rare relapse (if lucky and can untangle from background worsening) and then qualifying for treatment. All those wasted years inbetween.

    Regulators seem to love neat little boxes (measured by change in EDSS). Not sure MS in the real world is so simple.

    Thanks for all you are doing to promote the MS is one disease hypothesis.

    1. I have only changed someone’s diagnosis from SPMS or PPSM to relapsing-MS on maybe 10 or so occasions in my career. The reason for doing this has been for access to DMTs. If MS is one disease and not two or three diseases changing labels to describe the disease makes little sense from a philosophical disease. It is not like undiagnosing MS, which is something completely different.

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