Case study: managing smouldering MS

Would switching from fingolimod to siponimod make any difference? What about all the other potential treatments for smouldering MS? What would you recommend?

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Case study

She is 42 years of age and has had MS for 16 years. After a relapse in 2016, she was switched from interferon-beta to fingolimod. Despite being NEDA-2 (no relapses or focal MRI activity) since starting fingolimod her disability has worsened with her EDSS going from 4.5 (walking unaided for more than 300m) to 6.0 (needing a walking stick to walk 100m). Clearly, fingolimod is doing what it should do, i.e. keeping relapse and MRI activity at bay. What can we add-on to fingolimod to stop worsening disability? 

Prof G’s opinion

At present we have no licensed disease-modifying therapies to add-on to fingolimod to stop worsening of disability. I am aware that many of you who are in this situation get exasperated with my position and ask me what I would do in this situation. 

Trial participation

My preference would be to suggest you volunteer to participate in any well-designed controlled trials to address add-on treatment to tackle smouldering MS or non-relapsing/inactive SPMS and PPMS. This is why we are running the SIZOMUS trial to test whether or not we can repurpose a drug from oncology to MS. The aim is to scrub the central nervous system clear of plasma cells and B-cells. Hopefully, by getting rid of the oligoclonal antibody response, which may be driving some of the smouldering disease processes we will slow down the worsening disability. 

Other options are the high-dose simvastatin trial, the upcoming clemastine-metformin remyelination therapy trial, the MS Society OCTOPUS trials, etc. 

Again many of you would argue these trials are too far away and you want something now. Could we be more creative and use the so-called “Simon 2-stage, single-centre, phase 2, single-arm futility trial”. The Simon design comes from oncology and allows multiple treatment regimens to be compared. The idea is to screen treatments using an initial futility study and if you pass the initial phase you can then stop for futility but you don’t stop if there is evidence for an overwhelming effect on the outcome. A non-futile treatment can be taken forward for further testing in phase 2b or 3 study. 

The Simon 2-stage design provides initial evidence supporting or opposing a specific treatment, which then requires confirmation. I can see us using this trial design to test the long list of potential repurposed add-on treatments we have to tackle smouldering MS. I see no reason why we can’t use this trial design in a factorial way to test combination therapies, i.e. to build an MS-DMT sandwich. This trial design was recently used to test oral domperidone, an anti-nausea drug, in SPMS (Koch et al. Neurology. 2021 May 4;96(18):e2313-e2322.). The hypothesis was that the increase in the hormone prolactin-induced as a side-effect of domperidone would stimulate remyelination, which will improve or at least slowdown disability progression. Unfortunately, the trial was negative, but it did show that this type of trial design is feasible.

I would love to set up a ‘disruptive Simon-stage-2 trial platform’ for people like you to run your own trials of over-the-counter medications and/or supplements. The platform will screen patients online and assess trial eligibility using PROMs (patient-related outcomes) and then randomise them to different treatment arms. The trial platform will then follow them up via smartphones using the futility design. The primary and secondary outcomes will all be self-monitored using smartphone technology. Wouldn’t it be cool if patients with progressive/smouldering MS took control of their own trials and generated the evidence to support taking some of the supplements or medication a lot of pwMS take anyway; examples could be alpha-lipoic acid, butyric acid, nicotinamide, oral ketone bodies, etc. 

Patients Like-Me,  the world's largest personalised health network that helps people find new treatments, connect with others and take action to improve their outcomes, did something similar with lithium in motor neuron disease a few years ago. The article by Paul Wicks 'Patient Study Thyself' explains the process and is really asking people with the disease to disrupt the status quo (Paul Wicks. BMC Medicine volume 16, Article number: 217 (2018).). 

Switching to siponimod

Several of you would argue even this is not good enough, what can this patient do for herself now. I would suggest she speaks to her MSologist. There may be a case for switching her from fingolimod to siponimod, which has been shown to have some impact in SPMS. Although both fingolimod or siponimod are S1P-modulators, siponimod is an active drug with greater activity within the CNS on the so-called S1P-5 receptor that is expressed in oligodendrocytes and astrocytes. The latter may be responsible for the effects of siponimod on the brains of people with SPMS, i.e. less brain volume loss, improved tissue integrity and slower loss of cognition. 

The problem with the fingolimod to siponimod switch is that it means officially labelling this patient as having SPMS and this means she may not be eligible for switching back to another DMT in the future; SPMS is a cul-de-sac. In addition, in the NHS we can only use siponimod for active SPMS, i.e. patients with a recent history of relapse or new lesions on MRI. I suspect this patient is not eligible for such a switch. 

Lifestyle interventions

What this patient should be doing is optimising her lifestyle to maximise her brain health. This means exercising physically and mentally, getting good quality sleep and making sure all her comorbidities are treated. She should be avoiding medications, such as anticholinergics, that could be making her cognition worse. All attempts should be undertaken to avoid infection, for example, urinary tract infections. When it comes to her diet she should avoid processed and ultra-processed foods and based on scientific principles I would recommend she explores intermittent fasting and/or a ketogenic diet (see MS Selfie Newsletter on ‘Which Diet’). When it comes to supplements I would have no objection to her using alpha-lipoic acid. The latter has reasonable evidence that it may slow down smouldering MS. 

What I can’t sanction for this patient is the off-label prescribing of statins, metformin, sodium channel blockers, antivirals, etc. to treat smouldering MS. We simply don’t have enough good data to support their efficacy in smouldering MS. All these drugs have risks and so until we can establish the benefits of these medications in MS I would urge you to be careful. 

Maybe some of you have additional ideas you could share with us about how you are tackling your smouldering MS. Please share them with us.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.