Tag: cul-de-sac DMT

Swiss Neurologists Challenge Lublin

Barts-MS rose-tinted-odometer: ★

I have just been chastised by someone from a Swiss Pharma company for suggesting that siponimod is a cul-de-sac DMT. Why can’t someone who is diagnosed and labelled as having SPMS who is started on siponimod be switched to any other DMT? I agree, but the absurdity of the situation arises because of the rigidity of the Lublin classification of MS (see below) and the salami-slicing of MS into multiple disease entities. 

The cul-de-sac is based on the assumption that once you have progressive MS, either primary progressive or secondary progressive MS, you can’t become unprogressive and be subsequently re-diagnosed as having relapsing-remitting MS. This is explicit in the Lublin classification system that defines the clinical course of MS.  According to Lublin progressive MS is a one-way street.

The reason we find ourselves in this ridiculous situation is that MS was salami-sliced up into three and four diseases in the 1990s to allow interferon-beta to get licensed under the US Orphan Drug Act. The Orphan Drug Act states that to be an orphan disease there have to be fewer than 200,000 US citizens with the disease.  There are clearly more than 200,000 people with MS in the US, but there were less than 200,000 people with relapsing-remitting MS, secondary progressive MS or primary progressive MS in the 1990s. Subsequently, a fourth category was added to the classification system of clinically-isolated syndrome (CIS). Fortunately, CIS is gradually disappearing as the McDonald criteria are gradually nibbling away at this pseudo-category of MS.

Few people are aware of the history of MS becoming four diseases, but the consequences of this to the field have been enormous. For one it means that Pharma has had to do trials in all four ‘pseudo-MS disease states’ at great expense to the field. It has had major psychological effects on people with the disease. When you tell people they have SPMS it is like telling them they have a second disease that until recently was unmodifiable. 

The other consequence of MS being three or four diseases is that once you have been diagnosed as having SPMS we are mandated under NHS England guidelines to stop DMTs. This is why most neurologists in the UK avoid labelling their patients as having SPMS. 

The Lublin classification system is based on a clinico-radiological worldview of MS and is not underpinned by biology. If you take a biological worldview of MS, which is the correct philosophy based on our current thinking of what constitutes a disease, then MS is one disease and not three or four diseases. 

Interestingly, I have been asked by the CONY Virtual Conference organisers to give a keynote plenary lecture on this exact topic, which I recorded yesterday. 

The good news is that this Pharma Executive tells me that the Swiss Neurologists have decided that the Lublin classification system is incorrect and that according to the Swiss it will be fine to reverse out of the secondary-progressive cul de sac and to relabel their patients as having relapsing MS and to be able to switch their patients from siponimod to ofatumumab once it is licensed in Switzerland. I sincerely hope the Swiss neurologists publish their new classification system of MS, or MS roadmap, as the Lublin one is out-of-date. More importantly, will the Swiss neurologists be prepared to convince the NHS of their wisdom?  

Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014 Jul 15;83(3):278-86.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

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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