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.
Please change the title to 'An interview with me''Interview with MYSELF' suggests that you yourself are interviewing yourself
That is correct; I am interviewing myself. I am asking and answering the questions.
I can see no mention of your EBV ideas or the work of the Charcot Project. Is this not relavant to progressive MS and if so, why not?
Many people have difficulty with the one disease idea and many more have difficulty with the EBV hypothesis.
It is good to read two thoughtful pieces on progressive MS, thank you. I still find it confusing that there are quite different therapeutic offers (however limited) for SPMS and PPMS if you believe they are the same disease. As one who has taken the road ‘less travelled by’ (PPMS), Robert Frost works for me. ‘Yet knowing how way leads on to way, I doubt I should ever come back.’ No doubt there is hope for the future, if not exactly now.
A recent campaign at an assembly by MS Research Australia was #STOP AND REVERSE MS. This should be the goal of all researchers, steering committees, approval committees and governing bodies, journals, MS Societies, etc. If this is not their current goal, they should move aside for some other innovative researcher as the current state of MS treatment after all these years is unacceptable for progressive MS.For almost 10 years now, I have heard some really good ideas on this website about add-on therapies for neuroprotection, remyelination and neurorestoration yet here we sit with "maybe" some neuroinflammatory therapies only that offer no actual clinical improvements in a progressive MS patient's condition.Neuroinflammatory DMDs may offer a patient a minuscule statistically significant slowdown of your disease. This, however, is completely unnoticeable to the patient and eventually will lead to the same clinical outcome. These DMDs function barely above placebo ( <25%) even taking into account therapeutic lag and length dependent axonal hypothesis which are obliterated as a patient ages or in more advanced disease.It is no wonder progressive patients are seeking answers outside their neurologist, even if many times it means being duped, for treatment of progressive MS. There currently is nothing out there and nothing on the horizon. The current state for treatment of progressive MS is pitiful and stagnated.
#STOP AND REVERSE MS. Yes but a hollow slogan does not help us….PROMISE2010..the promise was to start studies not have the answers but it was turned on the researchers that their promise had been broken. We have yet to see reversal except when MS is treated effectively at the beginning of their condition and the natural repair mechanisms do their stuff.Have we seen any compelling experimental evidence that shows that nerve loss is reversed. We know that if the trials have not yet started we are many years away from the reality. We need to keep it real.
Thanks to prof G for this update. I have complete sympathy with Nissan Grifter's post above. if therapeutic lag does occur why does so much money gets spent on more and more anti-inflammatory drugs with similar response levels rather than use the drugs we have which may just take longer to work on those with more advanced disease and use new money on those drugs to help build the pyramid.Does prof G really think that siponimod will be more effective for more advanced disease than the drugs which we already have?
I forgot to add to my last post…. prof G what percentage of neurologists do you think believe in therapeutic leg because I asked my neurologist who definitive said he did not
leg? or lag…
Both ProfG and MD have posted explanations for therapeutic lag. Did your neuro provide rationale and evidence for not giving it any credence Anon?
The data is there, your neuro may read and they may not. I suspect not is the answer
Where is the data exactly so that people can quote that when discussing?
Hugely positive post. Much thanks Prof G.
I don't expect any "restorative" and "protective" pill/chemical better then already existant mechanisms of the body,activated by breathing,exercise/electro stimulation,nutrition and medicinal plants – trial this.It is silly to expect more complex drugs for brain/body health then St. John's wort,rosemary,ginger and many others – those are alien technology. We are wasting our time trying to make some money and be smart.Energy homeostasis is MS future. As soon as neuros change paradigm,sooner we will get right approach for neurodegeneration.Cheers,M
Thanks for refusing to give up on people with progressive MS! and I love that poem, one of the only poems I know by heart. Re modifiable factors, Don't lets forget about the research that shows slower progression of SPMS with lower levels of 'bad fats' in the blood: http://www.msra.org.au/bad-fats-major-culprit-ms-progressionand 66% less brain shrinkage on Lipoic acidhttps://mirandasmsblog.com/2016/12/29/lipoic-acid-for-ms/
Hmm…interviewing yourself, was there a good dialogue? I'm not a mental health specialist but a long vacation away from it all might be in order:-)
I'm amazed he could find him 😉
Vacation… where do you think ProfG has been?:-)