Thursday, 22 March 2018

The Phoenix has risen: the era of disease modification in progressive MS has truly arrived

The EXPAND study is the first positive study in people with secondary progressive MS and marks a new landmark in the treatment of MS.


Please note that I am a co-author on this paper and I sit on the trial steering committee. I am clearly conflicted and therefore you may not want to read or hear what I have to say about the trial's findings. 

Siponimod is the second-in-class of the so-called sphingosine-1-phosphate modulators; the first being fingolimod. The EXPAND phase 3 trial published in today's Lancet is a landmark study in that this is the first positive study in 'non-relapsing SPMS'. Why was this study positive when so many others have failed? It was very large with 1651 subjects included in the study and was a so-called event-driven study, i.e. it went on for a long as necessary to accumulate enough disability progression events to answer the question of whether of not Siponimod can modify the course of SPMS. 

I am aware that many people have and will continue, to pooh-pooh the results as not being meaningful, i.e. the treatment effect is too small. This same pooh-pooh phenomenon occurred with the original interferon-beta studies in RRMS and more recently the ocrelizumab in PPMS study. I must point out that most of the patients in the EXPAND trial required walking aids, hence there was not much reserve in the motor pathway to the legs to see a treatment effect. This also means that therapeutic lag has to be taken into account; therefore, it takes time to see a treatment effect. So a small difference over 3-4 years may translate into big differences over 5 to 10 years. 

Interestingly Siponimod did not have an impact on the 9HPT nor the T25W. It looks as if these two outcome measures were very noisy in this study. This is something that needs to be explored as it challenges our length-dependent axonopathy hypothesis. 

Despite this Siponimod had a very strong effect on focal MRI lesions and brain volume loss. I, therefore, have little doubt about the robustness of these trial results. It is also clear that the SPMSers who were less disabled and younger benefited most. This means that when we treat 'SPMS' we will need to treat as early as possible. I can hear the naysayer saying that you are simply treating relapsing-remitting MS. I would say so what. The pathological processes driving RRMS and SPMS are probably the same and Siponimod will be effective in both the relapsing and more advanced stages of the disease. 

I suspect the EXPAND or Siponimod trial results will rekindle the debate about when SPMS begins and when can SPMS is diagnosed. I personally think that the pathology that drives SPMS is there from the start and that we need to be aware of potential disease worsening/progression even if we don't see a change in physical disability. George Ebers and colleagues used to diagnose SPMS with a median EDSS of 2.0. Their diagnosis was based on a history of clinical worsening in the presence of an abnormal neurological examination. For example, someone may report that their left foot gets weak and drags after 30 minutes walking. They then come back a year later and now report dragging after just 10 minutes. Provided they have abnormal neurological signs in the legs on examination they could be diagnosed as having SPMS. Neurologists, however, have shifted the goalposts and now diagnose SPMS when the patients have an EDSS of 4.0 or higher. Why? Simply because once you label someone with SPMS it excludes them from DMTs that are licensed for relapsing MS and it also tells them they a form of the disease that is not modifiable. The latter is something neurologists have wanted to avoid and patients have wanted to avoid it as well. Why would someone want to be labelled as having a progressive untreatable disease? These results change that for; SPMS is now a modifiable disease and there is now a treatment for this phase of the disease. 

I know people with progressive MS would like a treatment that doesn't just slow down the rate of their worsening disability. They want a treatment that reverses their disability. However, Siponimod can only do what it can do, i.e. as it is an anti-inflammatory it can only stop new focal MS lesions from forming and prevent new damage. Siponimod can't repair existing damage and it can't reverse existing disability. However, it can form the base of the pyramid for add-on therapies for the future, i.e. neuroprotectives, remylienators and neurorestoratives. I would, therefore, urge you all to focus on the positives and to celebrate these results as a milestone in the treatment of MS, i.e. progressive, or as I prefer advanced, MS. 



Why the Phoenix? I couldn't use the eagle, ocrelizumab claimed that bird. We have had so many false starts and hopes dashed in the past in relation to DMTs for SPMS. To me Spinoimod represents the Phoenix rising from the fire of failed SPMS trials to finally offer people with SPMS some hope. We now know how to adequately power and perform SPMS trials. I sincerely hope this trial will act as a catalyst for new SPMS trials. There is no lack of ideas or compounds when it comes to future SPMS trials. We at Barts-MS are pushing forward with our Chariot-MS study and are actively discussing several potential trials in SPMS with Pharmaceutical companies.

Kappos et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet March 2018 https://doi.org/10.1016/S0140-6736(18)30475-6

Background:  No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS.

Methods: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144.

Findings: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.

Interpretation: Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.

ProfG    

56 comments:

  1. Mr A again as lead author, maybe profC was on to something:-)

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    1. Yes but Mr A is based in the same place as CompanyN

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    2. Dare I suggest guest authorship?

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    3. No you cant cos we don't know the amount of involvement.


      Were they using DrA,s patented assessment tool.

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  2. "Please note that I am a co-author on this paper and I sit on the trial steering committee. I am clearly conflicted and therefore you may not want to read or hear what I have to say about the trial's findings" erm this is the case for approximately half of the papers on DMTs and trial results...not accusing you of anything and I still think you're brilliant but just saying!

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    1. The only way to deal with conflicts is to declare them and make sure people who read what I say include this in their analysis. In general if someone has an obvious conflict you should ignore what they have to say, for example this post. In MS this excludes a lot of expert opinion.

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    2. I disagree with " In general if someone has an obvious conflict you should ignore what they have to say, for example this post."

      If someone has a conflict, generally you should take their opinion with a grain of salt and realise they have a vested interest in the 'opinion' being correct.

      Having a conflict of itself, however, does not actually invalidate the opinion and ignoring what they actually say is not beneficial for anyone.

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  3. " for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events"

    Study duration.


    "The primary endpoint was time to 3-month CDP"


    "(26%) of 1096 patients on siponimod and 173 (32%) of 545 on placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013)

    You also could read 74% on the treatment group add LESS than 21%

    relative risk reduction of cdp

    SO BASICALY THOSE ON PLACEBO DID BETTER (32%)

    Does this give Pwms reasons to celebrate?

    Does this pass the smack you in the eye the test?

    Why do a study for 3 years and setting the end point at 3 months?

    Would like to see if those 21% would hold at 1 ,2 or 3 year mark?

    What about brain atrophy?

    Obrigado

    Luis

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    1. Brain atrophy data is in the paper. Siponimod subjects had less brain volume loss.

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    2. I guess that trial design needs justification.

      But can Siponimod be used jointly with Tysabri or straight after Lemtrada?

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    3. How accurately can brain volume be measured? If I remember right, I thought there was a margin of error of about 5%. BTW, thanks for your work on this study Gavin!

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    4. I doubt it would be sensible to use straight after lemtrada as people will be made very lymphopenic

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    5. Re: How accurately can brain volume be measured?

      Error rate is less than 1%, but this is not an issue with large group comparisons as the errors cancel themselves out with randomisation.

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  4. Re: "The pathological processes driving RRMS and SPMS are probably the same..."

    Huh? Alright, then why as someone with advance MS in England can I not be treated? Why is the nothing licensed? What are you actively doing about it? Why should we be thankful for empty conjectures?

    "I would, therefore, urge you all to focus on the positives and to celebrate these results as a milestone in the treatment of MS, i.e. progressive, or as I prefer advanced, MS."

    Are you taking the Mickey, Prof G. We're dying here! I have lost the use of my legs and right hand. I lose control of my bladder and sometimes my defecation organ.

    You are out of touch, sir.

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    1. Sorry. Science takes time, a lot of time.

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    2. Sadly, this is time that none of us have today. In continuously pushing these very minimal statistically significant neuroinflammatory medications, these DMDs are standing in the way of possible successful remyelination, protective neurodegenerative products and neurorestoration.

      Current DMDs, which treat the MRI and are of questionable clinical statistical significance do not do anything to improve the patient's clinical situation. They promise us to worsen just slightly less worse than placebo with the same endpoint. This is unacceptable.

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    3. Pharma has all the time in the world. At least until their patents run out.

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  5. Why are we still on the bottom rung of four? Will we get up to rung two by the end of the careers of Profs B and G?

    Prof G - you seem very happy with mediocrity. This drug trial has minimal benefits for people with progressive MS. If you had SPMS would you be happy with the treatment options available?

    Imagine going to one of your fancy restaurants and ordering the best Argentinian steak with a selection of vegetables. The waiter arrives with two peas on the plate and says "it's better than nothing". Would you still have a smile on your face?

    Those with progressive disease want one thing above all else - to be stabilised (no further progressive). I can live with EDSS 5.5, but find it difficult to live a life knowing that next year I'll be 6 or 6.5. Until there is a treatment for progressive MSers that stops any more profession I can't say that I'm grateful for the work of the MS research world.

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    1. We are glass half empty people, profG is glass half full.

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    2. It's easy being a half glass full person when you haven't go a progressive neurological condition and have witnessed countless failures in trials for progressive MS. I'm not the only one to consider these results to be a complete cowpat. The BBC website covers the story and an expert considers that the results are pretty much useless.

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    3. Re: "Prof G - you seem very happy with mediocrity."

      I am afraid when it comes to advanced MS and anti-inflammatory DMTs a 20-25% treatment effect on EDSS is what to expect. Most of the progression is driven by previous damage from before the trial. Anti-inflammatories will however get better with time due to therapeutic lag.

      What is need to get better results are add-on neuroprotectives, remyelinating and restorative therapies.

      Haven't we learnt anything from the last 20 years?

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    4. In addition to the expert on the BBC so does Dr Metz from Canada think these results are worthless. Her critique in the Lancet is scathing.

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    5. 1/5th full that is. And 4/5th empty.

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    6. This post would be insulting to our intelligence if it wasn't so embarrassing. Pompous graphic (firework bird), pompous phrases (Phoenix has risen, era of disease modification, new landmark), clearly unjustified enthusiasm, all in the service of a rubbish drug. This thing is overblown to the point that even "progressive MS" sounds positive in context, and as we fail to comprehend its point of view even in the light of conflict of interests, one word comes to mind: immodesty.

      But then, seeing MS that way is essential in keeping the funding flowing for the next decade. Research teams come at a cost and prof GG is responsible for the longevity of such a team.

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    7. This is why I state "Please note that I am a co-author on this paper and I sit on the trial steering committee. I am clearly conflicted and therefore you may not want to read or hear what I have to say about the trial's findings".

      I am conflicted, but I do think the findings are meaningful.

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    8. So, it has similar effects to Tysabri and Ocrevus at progressive MS but they just set the right trial endpoints, so that it would turn out successful. Smart guys (twice smart since the drug is a Gilenya copy). Bravo.

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    9. Re: "Smart guys (twice smart since the drug is a Gilenya copy). Bravo."

      Is it not better than having nothing? Is it not a start? The expectation that a DMT is going to result in a 50% or greater treatment effect and/or reverse disability in people with advanced MS is simply not going to happen.

      I am still not sure what point you are trying to make.

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    10. Meaningful?

      You say,"a 20-25% treatment effect on EDSS is what to expect" which is not an overstatement but a pure and double lie:

      Stop using relative percentages to make them look bigger. The truth is 32%-26%= 6% more patients had 3 month CDP. The denominator is the set of people involved, the future pool of recipients.

      Then why 3 month? Why not 4? 5? 6? Even CDP is just a subjective opinion of an external investigator. Highly volatile and calibration resistant.

      As for adverse events: "Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo."

      And so elegantly put: "Initial dose titration mitigated cardiac first-dose effects."

      I am sure that none of the drug recipients understood that it was the real drug they were given! So, it is beyond speculation that the aforementioned 6%, in all its magnitude, is the result of the placebo effect of the recipients suffering from side effects (89%-82%=7%)!

      Of course not. The results are meaningful and elephants fly.

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    11. "I am still not sure what point you are trying to make. "

      My point is that this is mostly a smart management tactic to create a market for an new drug that otherwise would not be needed. We already had drugs that could deliver these results to progressive MS patients, so this celebration is not about the progressive MS and their need to be on a DMT (a thing that I agree, even if its not that inovative or gamechanging), this is a celebration that Novartis has good market strategy.

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  6. EDSS >4 = SPMS = no treatment in the UK.
    As the increase in EDSS must be caused by further MS activity and DMT is reducing MS activity then it follows that DMT can help to hold back the increase in EDSS of people with ‘SPMS’. However no treatment and in fact now I know at least 5 people with different classifications of MS and none of them are on any treatment. Essentially NICE is saying ‘please go away and die slowly but quietly’. Can I get a private prescription? - No. Can I get on a trial - No. Can I get treatment abroad - No. Just die slowly but quietly please as we don’t want to hear your whining.

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    1. Then you need to support the study by DrK, he has not given up on anybody and has offered treatment

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    2. We are trying to challenge the NHS England stopping criteria; they don't make sense in terms of the new data that has emerged. Yes, we treat people with active MS regardless of their disease stage.

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    3. I have not been offered any treatment. As I said I know many people with MS and none of them are on any treatment. There is no doubt the "MS Establishment" does not wish to offer treatment and uses any angle on diagnosis to deny treatment. Whether this is down to cost or a genuine belief that none of the available treatments has the slightest effect on PMS, I don't know. If the MouseDoctor would be kind enough to inform us of the treatment offered then I would take it up like a shot. It's hard to slowly fall apart and lose one faculty after another; the wall of silence from the NHS just adds to the anxiety. I will be dead of this within 10 years and the platitudes just add insult to injury.

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  7. What would be the perceived cut off point for any benefit if edss was the scale ?

    Regards as always.

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    1. Re: "What would be the perceived cut off point for any benefit if edss was the scale?"

      The upper EDSS cut-off in this study was 6.5.

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  8. Does the fact that fingolimod did not seem to have activity for PMS temper your optimism about siponimod? How do we explain the difference vs. why not think of this as a second (and discordant) result of the same hypothesis?

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  9. Prof G in Greek mythology, a phoenix is a long-lived bird that cyclically regenerates or is otherwise born again. This is very apt and describes fingolimod rising again as Siponimod.

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    1. Actually theres a big difference. In action and side effectd. Fingolimod acts on SP1 to SP5. Where as Siponimod acts on SP1. Same with ozanimod and posinimod are alsonvery selective in thw action hence higher efficacy amd lower side effects. Its good to be cynically with anything pharma does but the drugs are the same class but different in efficacy

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    2. Not sure why I chose the Phoenix, but now that you point the cyclical regeneration is a good analogy for how Pharma works within the patent environment.

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  10. Genentech’s Ocrevus Begins to Move the Needle on the Treatment Rate for Primary Progressive Multiple Sclerosis but May Not Be the Only Disease-Modifying Therapy in Play

    https://www.spherixglobalinsights.com/genentechs-ocrevus-begins-to-move-the-needle-on-the-treatment-rate-for-primary-progressive-multiple-sclerosis-but-may-not-be-the-only-disease-modifying-therapy-in-play/

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  11. Any guest authors on this paper? Prof G has been very quiet on this issue.

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    1. No guest authors. I will pen some of my thoughts on the guest authorship issue when I have had time to think about and analyse the issues in detail.

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  12. "I am clearly conflicted and therefore you may not want to read or hear what I have to say about the trial's findings."

    Right enough, the BBC's article on this sounded a lot more realistic.
    http://www.bbc.co.uk/news/health-43502845

    Why can't you put more backing on your blog of what Dr Luanne Metz is
    saying; "Trials of other novel treatments that target non-inflammatory mechanisms are still needed."

    ...instead of repeatedly over-egging this pretty awful "anti-inflammatories for progression" pudding?

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    1. She said: "Although siponimod seems to reduce the time to confirmed disability in secondary-progressive MS, the treatment effect was small.

      "In our opinion... the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for secondary-progressive MS."

      She added: "Trials of other novel treatments that target non-inflammatory mechanisms are still needed."

      http://www.bbc.co.uk/news/health-43502845

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  13. Frankly gob smacked by the negativity coming from the people you are trying to help! Please continue looking for treatments that will help people w MS, whatever stage they're at, thanks for the work you and your team are doing

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    1. If we'd listened to our regular naysayers here, we'd have packed it in years ago. As it is, we'll keep on keepin' on.

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    2. Oh, come on, it's just the reinvention of the wheel most of the time, not true progress.

      No-one's been successful in developing any drugs in the other layers of the treatment pyramid, it's just more anti-inflammatories - which are no good to those of us without inflammation.

      Do you wonder at our despondency, twice in a week the BBC et al have trumpeted breakthroughs in MS - but they're not for us pwPPMS - doesn't stop the general public thinking we're all cured now though, does it?

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    3. I am not aware of any PPMSer or SPMSer coming to post-mortem without inflammation in their brains and spinal cords.

      It is dogma, and incorrect, to say that non-relapsing progressive MS is not inflammatory. Please read the pathology papers and stop viewing MS through Gd-enhancing MRI spectacles.

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    4. Pathology papers emphatically state that neuron damage precedes inflammation in the spinal cord. You don't seem to contemplate on that.

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    5. They aren't my spectacles, Prof G, but I seem to have to share the view through them. It may be dogma, but I'm still left deteriorating with untreated PPMS whilst my mobility disappears practically as I watch.

      Either anti-inflammatories are for all pwMS, in which case, please can I have some too, or they aren't, in which case, my point still stands - there are only anti-inflammatories available and they are not available to pwPMS.

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    6. In a large number of countries ocrelizumab is available to people with early PPMS. Similarly, a large number of people with PMS are being treated in Europe with mitoxantrone and in some centres HSCT. At Barts-MS we are using off-label cladribine to treat people with active advanced MS. The latter is on compassionate grounds, which we will have to stop if the Chariot-MS trial gets funded.

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    7. This is my situation, please can I be treated under this regime?

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    8. As I mentioned earlier no one in the UK is being treated for MS. I’m going to have to bankrupt myself to get the money together and see if I can buy a course of DMT somewhere in the World. Harsh but fair.

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  14. Positive multi-center, double blind, randomised, CLINICAL trials are necessary, prior to any administration to patients.
    Biochemical markers are not enough, we saw that in cholesterol studies, total mortality was not eventually reduced.

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    1. You say this but the new head of the FDA wants to license drugs based on biomarkers only with the clinical outcomes coming later. Interesting times ahead.

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