We have been beating the combination-therapy drum for so long now we have become bored with the concept. Every time we apply for grants to test the concept, be it with pharma or via other traditional funding routes, we get pushback. Either our targets are questioned or the concept of combination therapies is challenged based on the scientific principles underlying the combination being proposed. Then there is regulatory complexity of doing licensing combination trials that makes most Pharma companies put their heads in the sand.
It is obvious that if we want to achieve our aim of getting pwMS to old age so that they can age normally we are going to have to do more than simply tackle inflammation.
Oncologise is a neologism or new word
I propose oncologising multiple sclerosis and putting in place a national NHS-funded register as part of routine practice, similar to what happens with cancer patients so that everyone can participate in add-on trials of neuroprotectants, remyelination and neurorestoration therapies and any other add-on treatments that we think may work in MS. The latter can include dietary interventions, for example, intermittent-fasting or ketogenic diets.
Making the case for building a treatment sandwich or pyramid
If the NHS doesn’t fund this I would urge Roche and Biogen to do start with the two biggest blockbusters, i.e. ocrelizumab- and DMF-treated patients and to do this as an international initiative. The real-life trial platform could be run like the oncology platforms in that as soon as you find a combination that is better than the monotherapy (plus placebo) the combination then becomes the standard of care. We would have to implement this with more sensitive outcome measures, possibly brain volume loss, rather than the EDSS which has too many warts to survive much longer.
Do you think we can oncologise MS? Would you be interested in participating in add-on studies as proposed above? We have ten or more compounds that we could test right now.
The good news is that I have an ally who works in a large Pharma company who has been chewing the cud with me on this concept and is hopefully going to be able to sell it within his company. If he doesn’t do it I suspect another company may be tempted to take it on.
I gave a talk to general physicians at the Royal College of Physicians (RCP) yesterday afternoon telling them how we have transformed the management of MS. But have we really? To really transform the management of MS we need to cure the disease and then tackle the problem of post-inflammatory neurodegeneration or smouldering MS. The problem we have is that the wider MS community is not necessarily prepared to accept this position and the need for combination therapy add-on studies or the sequential therapy paradigm (induction-maintenance).
CoI: multiple
Sounds like the kind of innovative thinking we need. It’s puzzling to be a year post-DMT, with NEDA but with clinical symptoms that can’t adequately be explained (at least to this patient).
Emma. After 19 years and taking many DMTs and being told NEDA I still had symptoms and gained disability. Personally, I do not see them as the answer as a package, and don’t believe it should be sold as such. I think the add on treatments are interesting. Diets, fasting in particular seems to be showing some small results.
Thanks for this, Helen. I was diagnosed 2 years ago and have had 2 rounds of alemtuzumab. Instead of celebrating NEDA, I am pondering why my legs are killing me every day and old symptoms are coming back. But who knows what I’d be like if I hadn’t had the treatment? I am tackling it by walking up hills in spite of the pain, and limiting my daily intake of chocolate (well, a bit…). The smouldering MS theory really does strike a chord.
If symptoms are returning implying they were not there before, it is important to be sure this is not new disease activity and you may need another ound of treatment speak to your neuro MS nurse.
Saw my neurologist a few weeks ago: no change in MRIs so a third round not on the cards at the moment. Symptoms are being put down to underactive thyroid but I’m not convinced. It’s a ‘watch and wait’ situation for now.
Please read the many blog posts on smouldering MS; for example,
https://multiple-sclerosis-research.org/2019/10/my-smouldering-ms-clinic/
https://multiple-sclerosis-research.org/2019/01/smouldering-ms-does-it-exist/
https://multiple-sclerosis-research.org/2020/01/premature-ageing/
Prof G,
You get 10 out of 10 for effort and the ideas keep on flowing, but the jump between the ideas and real action never makes it.
I would be thrilled to take an add on therapy, but can’t see how this will happen in practice. What add ons would be offered? The recent failed MS Smart trial showed that the three drugs identified by the leading experts as having the best chance of success had no effect. How could a neuro offer a patient an add on therapy without it showing some success in a proper trial?
I’m pretty fed up with the resistance by the establishment – pharma, medics, NHS…. 130k people have this disease in the U.K. (1 in 500) so it’s not that rare. The impact on relatively young people can be devastating – my neuro told me that if you see a young woman in a wheelchair she is more than likely got MS. But efforts to have truly effective treatments always come up against a brick wall.
Please can you let us know (the 130k people in the U.K.) where we can sign up to getting add-on treatments. Most of us would be happy to do so given what MS does. Unfortunately I suspect this won’t be an option as a result of a combination of the conservatism of neurologists, funding issues in the NHS, protests by manufacturers of wheelchairs and walking aids, and protests by the 1000s of MS researchers that there time is up.
Good comment and the best way for this to happen is with an evidence base the community have to get mobilsed to get the people to change the staus quo
“Had no effect”…because they are not effective. Have we asked if they had no effect because the trial design was wrong? Based on neurofilament levels the majority of the influence of CSF neurofilaments is not the incidious neurodegeneration that these drugs aim to target, but the inflammation that can be stopped with current DMT and therefore without dealing with this issue it is very difficult to see a small potentially positive influence. It is important to ask because what comes next is key.
Re: “The recent failed MS Smart trial showed that the three drugs identified by the leading experts as having the best chance of success had no effect.”
We tried to get the MS-SMART and MS-STAT2 trials to be add-on studies, but we were clearly not that convincing in making the argument.
The MS-SMART trial suffered a systematic sampling bias, in the same way FLUOX-PMS did, risking type II error. I’ve published about this if you want to read about it.
You can always leave a link.
For the readers
Type I error: Rejection of a true null hypothesis (There is no difference). So you say there is a difference when there is none.
Type II error: Failure reject a false null hypothesis (There is a difference). So say there is no difference, when there is one.
However, the data does not look different, so if fails the smack you in the eye test.
As a pwMS, with very limited understanding of the illness, it has always seemed a bit odd, since so many of the moderately/very effective treatments have such different ways of acting on the body, that there haven’t been more combination trials. (I do understand it could be insanely expensive, and if so fair enough.)
But from visiting MS websites, it looks to me like a very large percentage of patients are already applying some form of combination therapy. I take ALA, simvastatin and clemastine, have dabbled in fasting etc. Some of these may be helpful; some are presumably voodoo.
So even without pricey pharma, I’m sure it would be fiendishly complex. But would there, at least, be some value in beefing up the ukmsregister.org to include reports of self-administered over-the counter/non-pharma combination therapy?
Where are you getting clemastine from?
That one is actually GP-prescribed, off-label on the advice of neurologist. I made appointment and showed the doctor some info and he was more or less happy to issue the script.
Online pharmacies sell it.
Got my last lot from Pharmacy First
Agree Lindo that there’s a lot of info on MS websites and forums and therefore a lot of us implementing our own version of combination therapies.
I received Alemtuzumab a year after diagnosis for late-onset highly active MS.
I use 16/8 IF and a mainly plant based diet to keep methionine at lower levels. Also drink barely any alcohol.
I exercise, do mindfulness and other activities such as using my non dominant hand to clean teeth etc.
I take metformin, Lipoic acid, Clemastin, Nano Curcumin Plus, Citicoline (CDP Choline), and other supplements supposed to boost cognitive function, alongside the usual VitD3 Though I’m not necessary following the usual dosage but rather ‘play safe’ by adhering to a lower dosage for a number of things.
I know I meet the criteria for a poor prognosis and that age 56 I’m the perfect storm of natural ageing and MS for driving deterioration. Nothing I do has altered the symptoms I live with, however I have had no deterioration in four years since the partial recovery from my last relapse in 2016. My neuro physio whom I see privately every six months has helped confirm this.
I know I will get worse, that this is inevitable, so my focus is to keep the wretched thing slowed up for as long as possible. If the use of DMTs, which we know have limited impact, with combination therapies and life-style choices work the most effectively at slowly up disease progression then it is of vital importance to evidence this and implement appropriate strategies for everyone with MS.
Maybe ProfG you could consider studying those of us who are already living breathing examples of Combination Therapies.
… still need to get the sugar consumption under more control 😏
Re: “…. a very large percentage of patients are already applying some form of combination therapy…”
Yes, I know. But this is a problem as we never get the class 1 evidence that is required for payer to pay for these treatments. This is why we need proper studies to convince not only pwMS but HCPs and payers that these combinations work.
“we never get the class 1 evidence”
CLASSIFICATION OF EVIDENCE:
This study provides Class I evidence that for patients with SPMS, LA reduces the rate of brain atrophy
https://www.ncbi.nlm.nih.gov/pubmed/28680916
This is why there will be more studies I suspect.
That makes sense, yes. But would there be some usefulness in marshalling a large body of muddyish empirical data from something like the msregister to zero in on empirically effective add-ons as a reference when picking a target for more rigorous study?
I guess the empirical sample would need to be huge to be a helpful guide, but some kind of Anglo-American or maybe MSIF self-report resource might deliver something of value?
Prof G, I have always had the greatest respect for new thinking. I’m EDSS 6.5 at best but probably nearer a 7. I am now SPMS but still have the occasional relapse, suggesting that there is still an inflammatory element , For 20 years i have heard the words ‘tantalisingly close’ more times than I can remember.
I have followed the Rituximab issue for over a year since the Basel report was published. So many small studies have since come to light in my research. Sweden has been routinely prescribing for both RR and SPMS. I have a UK private neurologist happy to write a prescription& dosage protocol. and my NHS neurologist is happy to deal with post infusion monitoring. Sadly having no luck finding any private facility/ neurologist/ oncologist that can or is willing administer. I fully understand that the very best i can expect is to slow progression a little, and at worse it do nothing, with possible associated side effects . Is there anywhere you know that can help? A flight to Stockholm every 6 months is the next avenue to explore, crazy as it may sound.
RV
I am afraid we cannot comment on this issue as said before when we were asked this very question by Harvey, I am sure you can find a neurologist that does private work that can do infusions
It seems daclizumab (slide 31) has alot of daclizumab use, is this because it is used for other things and captured by Blue tech or is the data from before 2018 before daclizumab was withdrawn. Would the figures just be for MS or would use of natlaizumab in chronic disease be captued as well
This is legacy data from when the drug was available; there will be no new prescriptions since it was removed from the market.
Great thinking! I’d be in any study aiming for a cure.
Including alemtuzumab or HSCT?
I would happily take part in any trial if i recieved lem or hsct i emailed you a few weeks back 🙂
Prof G, do you think Dr Pender’s immunotherapy could be considered an add on due to it’s safety/efficacy? I understand that it still isn’t available yet, but do you think that is the direction that treatment will go in the near future?
Re: “Dr Pender’s immunotherapy could be considered an add on due to its safety/efficacy?”
Yes and no. The answer depends on the phase 3 trial programme. I suspect it will be a monotherapy trial based on the hypothesis being tested.
Prof G keep up the excellent work you do! Send my thanks to Prof Pender’s and his crew for all the hard work they do! There will be a “self-evident” moment in time!
I would be happy to be in a trial.
Totally support this as a patient, I’d try it it. Should definitely be an option. Just because the status quo is better than it used to be doesn’t mean it’s acceptable or good enough!
Prof G,
If you were paid a £1 for every idea you had, you’d be a millionaire.
But ideas don’t get us stable and / or slightly better.
A friend who was given Alemtuzumab in the mid 2000s also had, as part of the trial, an add on therapy which aimed to (I think) reduce any loss of effectiveness of Alemtuzumab is she needed another dosing. I don’t know what the outcome was, but she signed a form and was happy to do so.
I don’t know how many MSers are treated at Barts, but couldn’t you get together with the other London MS centres and come up with a plan to allow patients receiving treatment X (DMT) to be asked if they wanted to receive an add on therapy (treatment Y). Potentially the add on therapy could be cheap e.g. a statin, metformin… These patients could undergo the usual monitoring (MRI, nfl, EDSS) and after 24 months it should be possible to assess whether the add on has had any additional benefit to just having the DMT. Neuros would use the metrics and their experience to assess whether an add on therapy has been beneficial. Although not rigorous in the usual way, it would allow neuros to potentially identify effective add-on therapies. They would be using their real life experience ie I have 12 patients on Fingolimod + Add on therapy Y who seem to have stabilised (more than would have been expected).
Then there could be a proper blinded trial to come up with a research based answer.
The problem is funding and having the resources to run such an add-on platform. In many oncology subspecialties, it is mandatory and part of the service.
What about neurologising cancer care? Cancer patients would be offered partially effective treatments which were licensed over a quarter of a century ago. The aim would be to not hit the cancer hard as early as possible to give a patient the chance of a cure, but to delay highly effective treatment so the cancer has a chance to metastasise. Cancer patients would not be offered add on therapies to give the cancer a good chance to spread and progress.
Cancer can and does shorten sufferers’ lives. MS can and does shorten sufferer’s lives (and leaves sufferers disabled). Yet cancer sufferers get the latest expensive treatments with the aim of getting the disease under control. MS sufferers are being treated unfairly. Neurologists are a big part of the problem. Oncologists must get great satisfaction from seeing some of their patients defeat cancer and go on to live normal lives. Why don’t neurologists want this?
Re: “neurologising cancer care”
A brilliant point. I am sure to quote you in one of my upcoming lectures 😉
Please do. I don’t include you in the above. But there are still too many ‘bow tie’ neuros who are still fixated with diagnosis than giving MSers the best possible chance of living a near normal life (by offering IRT).
To come to the defense of some neurologists. Many are not neuroimmunologists and therefore rely on pharma, unfortunately, a bit too much. Oncologists are, on the other hand, more knowledgeable on the basic biology of cancer and available therapies. Even dedicated immunologists such as MD 1 and 2 do not have all the answers to MS pathology.
HaHa but the trick is to talk like you think you do….that’s why we don’t have the answers because we don’t know the reality based on the literature
YES. What Ris said!!!!
Some of the most expensive cancer treatments extend patient lives in just a couple of months
Unfortunately
that is perhaps one reason that NICE in UK does not fund them
I can see why this would be appealing to Pharma. The platform itself my drive prescribing of the platform or base therapy so that patients can get the next best add-on treatment. Very clever and a no-brainer to me, but then I am not a Pharma executive.
Hi Lindo,
What dose GP happy to prescribe out of interest? Normal 1mg twice daily or higer?
Same question to Anon?
Hi Judy,
Per the neurologist’s recommendation, and in sync with the current Phase II/III trials, this will be titrated over several months up to 6mg daily (at night!!)
Sounds good to me, but then I have been gradually pushed off any DMT or other MS drugs & now only take very low dose anti-spasticity medication.
Result: When I was taken off Tysabri after a relapse in about 2013 (all tests still JCV negative), my walking with sticks/a frame gradually started to diminish & my arm and hand function definitely deteriorated rapidly.
So now, I just try to maintain as much as possible through exercise (assisted exercise bike), gym at local Therapy Centre (I can stand holding parallel bars for about 60 secs & do knee bends) & use rowing machine at low weights (max 25 lbs). My goal is still to slowly get back to the state where I can stand & take a few steps along the length of parallel bars. Stretch goal: walk a bit with frame and/or crutches.