I did a post-ECTRIMS interview with a Portuguese health magazine last week. The interview has helped me reflect and formalise some of my many ideas about secondary progressive MS that have been fermenting in my cortex for some months. I have therefore put pen to paper using a new format the self-interview.
Q: Prof G what was your main highlight at ECTRIMS 2018?
Without a doubt the acceptance by the wider MS community that progressive, or more advanced, MS is modifiable. Until quite recently most people thought that once someone with MS loses the ability to walk it is over for them from a treatment perspective. The two-stage MS hypothesis has been responsible for entrenching this worldview, i.e. an early modifiable inflammatory phase that is then followed by a secondary neurodegenerative phase.
Q: You say MS is #1_not_2_or_3_diseases; how does this position sit with the positive siponimod in secondary progressive (EXPAND) trial results and negative fingolimod in primary progressive (INFORMS) trial results?
Firstly, these were very different studies. The PPMS, or INFORMS, study was much smaller study and hence potentially underpowered for the question it was asking. The INFORMS population had less ‘inflammatory’ activity and was more advanced in terms of the biology of MS than the EXPAND population. More importantly, the SPMS or EXPAND study was event-driven and continued until there were enough events to get a result. I don’t think the discordance of these results supports MS being more than one disease. Another aspect that has been ignored is the obvious fact that fingolimod and siponimod are different drugs and may differ in their mode of actions, i.e. siponimod may have subtle effects within the CNS or potentially off-target effects that explain some of its efficacy.
Q: Do you think the EXPAND trial results are clinically meaningful?
Yes, I do think they are clinically meaningful because if you have SPMS having a drug that will slow down your disease progression is better than having no drug. The unmet need in SPMS is enormous. I agree that the effect on disease progression may seem small in terms of numbers, but this treatment effect will get bigger with time, because of therapeutic lag. It takes time for anti-inflammatory therapies to have an effect in more advanced MS because disease worsening in the next year or two is driven by damage sustained in the past. It takes time for this damage to work through the system, hence switching off inflammation now will take years to manifest as a treatment response.
It is also important to understand that siponimod will become a platform therapy on which we can build more effective combinations. It is clear that an anti-inflammatory therapy on it own is unlikely to make a big difference in more advanced MS. We need to build a therapeutic pyramid and add-on neuroprotectives, remyelination therapies and in the future neurorestoratives therapies. Regulators don’t like combination therapies unless one of them is a licensed product; siponimod could be that licensed product.
Q: What are you going to tell your patients about siponimod?
I am going to spread the hope. The ocrelizumab in PPMS (ORATORIO) and siponimod in SPMS (EXPAND) results are just the beginning of a new treatment era in MS. We need to celebrate the results of these trials and build on them. These trial results have challenged and killed the dogma of MS is a two-stage disease and that once you become disabled you are beyond hope.
It is also important to manage expectations in that these treatments are going to slow down and not reverse disability, hence many people with MS may not notice a treatment effect. However, we need these treatments as a platform to add on other therapies I refer to above.
I am definitely going to tell them about the effect siponimod has on cognition. Trial subjects treated with siponimod were more likely to have their cognition stabilise or improve compared to subjects on placebo. I am sure people with secondary progressive MS value their cognition and this bit of information may help them in making a decision about going onto this treatment or not. Please don’t forget MS is a cause of dementia and siponimod is one way of slowing down the development of MS dementia.
Q: In addition to being treated with siponimod is there anything else people with SPMS can do t help?
Yes, there is a lot they can do. This is about the holistic management of MS. If they smoke and they want to stop smoking they should seek professional advice about stopping smoking. The need to optimise their diets, exercise and sleep. The should review their medications and see if any medications that could be making their MS worse can be stopped. They should be screened for comorbidities or other diseases and have these treated. If they are having recurrent infections, particularly urinary tract infections, this should be addressed and treated. There is a lot that can now be done to reduce the risk of bladder infections.
People with MS should use it or lose it. If MS is affecting some function you should seek advice on what you can do to improve or stabilise function in that particular part of the nervous system. Don’t underestimate the value of rehabilitation and focused exercise programmes to help maintain function.
Q: Any final comments?
Don’t shoot the messenger. Although progressive, or more advanced, MS seems to have been neglected for many years these positive studies are catalysing many more studies in progressive MS. We need to reflect and celebrate these successes. Stopping to contemplate where we have come from and were are going to does not mean we have reached the end. One of my favourite poems makes this point very well.
Stopping by Woods on a Snowy Evening
BY ROBERT FROST
Whose woods these are I think I know.
His house is in the village though;
He will not see me stopping here
To watch his woods fill up with snow.
My little horse must think it queer
To stop without a farmhouse near
Between the woods and frozen lake
The darkest evening of the year.
He gives his harness bells a shake
To ask if there is some mistake.
The only other sound’s the sweep
Of easy wind and downy flake.
The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep..
CoI: multiple. I am an active steering committee member on both the EXPAND and ORATORIO studies.