Wednesday, 10 February 2016

ThinkSpeak: do we really need a wrecking ball to crack a nut?

Wrecking-ball or molecular tweezers; choose your poison. #ThinkSpeak #MSBlog #MSResearch

ThinkSpeak = thinking aloud

"I have said many time before the autoimmune hypothesis of multiple sclerosis may be wrong. This is why I refer to black swans, field hypotheses and viral causes of MS. I am not alone in the world when it comes to taking an alternative view of MS. Many of you will argue that I am wrong and that this position, or hypothesis, is incongruent with the effectiveness of induction treatment strategies such as HSCT, alemtuzumab, cladribine/fludarabine, etc. When you look at all the highly-effective therapies common to them all is an anti-B-cell effect, except for daclizumab which is an outlier. In other words HSCT may be simply be working via its effect on B-cells. If this is the case then the T-cell depletion, general bone marrow suppression and other off-target toxicities are simply collateral damage. Do we really need a wrecking-ball to crack a nut? Likewise, if alemtuzumab is working via B-cell depletion do we really need to collateral damage that comes with alemtuzumab's depletion and immunological changes that come from  its specific immune system reconstitution pattern (secondary autoimmunity). Do we really need a sledgehammer to crack a nut? Cladribine and fludarabine may be safer to use than either HSCT or alemtuzumab, but we would still be using a hammer to crack a nut."



"With a short-term efficacy profile that is looking very good anti-CD20 therapies must be the way to go; they work like heat-seeking missiles to take-out their target and the collateral damage from depleting B-cells seems relatively contained. This view may change with longer follow-up. What population of B cell is anti-CD20 therapies targeting? Could it be the EBV infected pool? If this is the case then we need better drugs; drugs that target EBV hence the need for the Charcot Project. More importantly, are anti-CD20 therapies enough? I suspect not. Stephen Hauser mentioned to me at ECTRIMS that many of his patients with active RRMS treated on rituximab for many years have gone onto to develop secondary progressive MS. Why? It may be that anti-CD20 therapies do not target long-lived plasma cells within the central nervous system and these plasma cells, which produce OCBs may be driving progressive disease. This is why I am so disappointed that MedImmune have put their anti-CD19 MS programme on ice; CD19 is at least expressed on plasma cells and anti-CD19 may be one way of targeting this population of long-lived plasma cells."

"People are often surprised  that I am so interested in daclizumab as a treatment for MS. Why? Daclizumab is one highly-effective DMT  that does not have an obvious upstream impact on B-cell biology. If I am right about the B-cell depletion hypothesis then how is daclizumab working in MS? If we can work out daclizumab's exact mode of action in MS we will be much further along the path of finding out the cause of MS. At present we know that daclizumab as a monotherapy seems not to be immunosuppressive in the classic sense and appears to working as IL-2 modulator. By directing IL-2 away from its high-affinity receptor to its intermediate affinity receptor it expands the population of CD56-bright NK cells. The expansion of this population of cells correlates with daclizumab's efficacy. The function of CD56-bright NK cells is complex; they are part of the innate immune response and have regulatory functions in relation to activated effector T-cells. The latter fits with the autoimmune dogma. Their other role is anti-viral. Could CD56-bright NK cells be controlling the virus that causes MS? I therefore can't wait to study the impact of daclizumab on HERV and EBV biology in pwMS. This is why I am hoping the FDA and EMA, and NICE,  give daclizumab a greenlight. Not only will it provide people with MS another option to treat their MS, but it will allow us to test the daclizumab antiviral hypothesis."

"I am sure many readers will disagree with me on many of the points above. If you do lets have a conversation or debate about the issues. I really don't believe we need wrecking balls, sledgehammers, hammers or heat-seeking missiles to treat MS. I would prefer a precision tool; a set of molecular tweezers that cause no collateral damage."


CoI: multiple

46 comments:

  1. I don't normally "shout", but I LOVE THIS POST! Simply wonderful.

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  2. Replies
    1. Re: "Do the NK cells have any effect on B cells?"

      Yes, they can kill B cells. They can also secrete soluble factors that can activate and promote B cell division. I suspect it is the former function that is more interesting. We know that pwMS on daclizumab have fewer lymphocytes in their CSF; this is likely to be non-specific and secondary to anti-inflammatory effects.

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  3. What is your opinion on the effect of the anti-CD20 therapies on immunosenescence?

    I think the problem with the wrecking ball aproach is that it effects your T-cells and regeneration will be dependent on the thymus which becomes less efficient starting in early adulthood.

    I would assume the anti-CD20 therapies would not have this issues because b-cells can be regenerated without a dependancy on the thymic efficiency.

    I would appreciate your view.

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    1. Re: "What is your opinion on the effect of the anti-CD20 therapies on immunosenescence?"

      I would need to look-up what happens to patients with rheumatoid arthritis on rituximab long-term. I suspect it would have an impact on B-cell function down the road and may reduce antibody levels and response to infectious agents. This can be dealt with by giving hyperimmune globulin to patients; we do this for patients with immunodeficiencies. So in short yes, I suspect anti-CD20 therapy will cause premature senescence of B cell memory. I would be surprised if it didn't.

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    2. Rheumatoid arthritis data will be very useful

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  4. Name me a CD_19 therapy? Is there a licensed drug? What are you fellows doing about it?

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    1. https://clinicaltrials.gov/ct2/show/NCT01585766?term=Medimmune+AND+%22multiple+sclerosis%22&rank=1
      Not licensed and trial on ice sadly.

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    2. MedImmune are pursuing their anti-CD19 therapy in neuromyelitis optica.

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    3. Why was the trial put on ice, out of interest?

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    4. I am not privy to this but maybe they be for commercial reasons, the MS space is crowded,

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  5. Until we (scientific community) can figure out what the h*** is going on with this disease, I say use a sledgehammer approach. I would much prefer a scalpel and a fine incision but the varying opinions justify a "napalm" the immune system tactic. This is one tough nut to crack. Whew, lots of metaphors.

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    1. The metaphors make it an interesting read.

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  6. This seems to make a lot of sense to me as a novice MSer. Any ideas of the possible waiting time for the green light on daclizumab?

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  7. "Stephen Hauser dropped a bomb on the stage at ECTRIMS when he mentioned that many of their patients with active RRMS treated on rituximab for many years have gone onto to develop secondary progressive MS."

    What were the baseline features of the rituximab-treated patients who became SPMS? It's impossible to interpret the claim without this baseline information. Were the patients already EDSS 4 when they started rituximab? If so, then this is not surprising -- and if it took those patients 10 years from baseline to become SPMS, the fact that it took so long would be the remarkable result.

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    1. "......and if it took those patients 10 years from baseline to become SPMS, the fact that it took so long would be the remarkable result." The question is : What is the time to SPMS from diagnosis without treatment? Yes, the goal of DMTs and induction therapies should be to extend this time frame. The researchers from the University of British Columbia have published on this controversial topic of "Do the treatments delay the onset of SPMS?"

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    2. Re: ".. What were the baseline features of the rituximab-treated patients who became SPMS?"

      I am not sure, but we know already from the rituximab PPMS trial that rituximab's impact on non-relapsing progressive MS is very small and seems to be limited to active and young subjects.

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    3. "we know already from the rituximab PPMS trial that rituximab's impact on non-relapsing progressive MS is very small and seems to be limited to active and young subjects."

      Yes, I am wondering why the data from Hauser's patients tell us anything new. Ten years ago, prior to the anti-CD20 clinical trials, it is very unlikely that an insurance company in the US would have approved rituximab as a first or second line treatment. If these were patients with multiple prior drug failures, on the threshold of SPMS, then it is not surprising that many of them would have transitioned within 10 years. As far as I know, it's still challenging today to get first or second-line approval for off-label rituximab.

      These data *may* be very interesting, if these patients had low EDSS when they started rituximab treatment -- but that's precisely what's unknown!

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    4. Re: ".. These data *may* be very interesting, if these patients had low EDSS when they started rituximab treatment -- but that's precisely what's unknown!"

      It is the now old story of early and hard, or early and effective, and let's hope in 15-20 years time there are no problem. It's the hypothesis that the alemtuzumab extension studies are testing and no doubt the ocrelizumab extension studies will do as well. I still think we need to clear the OCBs to be confident that we have cured MS. I kind of put OCBs down as NEDA-8. NED-4 in brain atrophy, NEDA-5 CSF neurofilament levels, NEDA-6 cognition, NEDA-7 a PROM and NEDA-8 disappearance of OCBs. What do you think?

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    5. Dear Prof G,

      I really like all the NEDAs listed out. I think it is very useful to set a good bar and have that bar mean the same thing to everyone.

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    6. "What do you think?"

      The hypothesis that curing MS will require eliminating OCBs is perfectly reasonable. It would be great to discover whether this is true. However, without baseline information, Hauser's data do not provide evidence for it.

      Why not just try to get the baseline information? Bruce Cree, Hauser, and other UCSF people had an ECTRIMS poster showing 10 year follow up of patients who enrolled at UCSF in 2004. It may have included many patients who started rituximab around that time: http://onlinelibrary.ectrims-congress.eu/ectrims/2015/31st/115416/bruce.cree.multiple.sclerosis.in.the.treatment.era.long-term.evolution.of.html?f=m3

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  8. XoRXoR 13.47
    Can't post your recent comment (for obvious reasons), sorry.

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  9. I agree with several points of this publication.

    I think I've asked here on the blog if Daclizumab have an action on anti-viral true...

    Every time I read a clinical trial of a genetic locus for MS, I think I have read studies citing at least about 50 different SPN...It is as if they were looking for a needle in a haystack. For example now I read a study linking 11 SPN linked to other autoimmune diseases, particularly type 1 diabetes, autoimmune thyroid and celiac disease. But it's something I always wonder also what makes me so my immune system "attacks" oligodendrocytes, and others who share the same genetic affinity attack the pancreatic cells? There's something so beyond the gene regulating all this?

    Could EBV hiding in the lymph nodes and thymus? Have they thought about verify the presence of EBV before and after those who undergo the HSTC? I know some people who have done HSTC in Brazil and MS returned. Most had MS and active and could already be making the transition to SPMS...

    And that is another question I have: is the patients of Dr. Hause who were treated with Rituximab already had EDSS 4? I ask this because I know a guy who began to express IN to 16 years. She began treatment with Rebif but failed, ended up having a very strong surge with quadriplegia. So your neuro was "innovative" by Brazilian standards: began to treat him with MabThera and now at 19 he's fine, fully recovered from the bout without sequelae.
    So does the very early treatment with anti-CD20 as Rituximab or Ocrelizumabe prevent the transition to SPMS?

    Another question I have is why, beyond the amazing effect of daclizumab, do not observe deeper into MS juvenile?
    I think this very early presentation of MS can give several answers ...

    So many, many questions

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  10. Does anyone know what happens to MS patients treated for B cell lymphomas, does the MS go into remission?

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    1. Re: "Does anyone know what happens to MS patients treated for B cell lymphomas, does the MS go into remission?"

      Variable. I have two patients one who have developed lymphoma after having developed MS who did very well after their lymphoma treatment and one patient who did very badly because of her lymphoma. This type of question can only be answered by interrogating large country-wide databases, e.g. Denmark or Sweden.

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  11. Fingolimod sequesters both B and T cells in lymph nodes thereby reducing "autoimmune" attacks on the MS brain. If this is so, then why did it fail so miserably in progressive MS trials if it has "halted" B cell activity. Also, why does it have such a pathetic effect of around 30% on stopping progression of the disease in RRMS. If MS was just a "B-cell" driven disease, or a T-cell driven disease for that matter, would you not expect a better effect than the paltry numbers of the current medications on the market on disease progression? Even Ocrelizumab numbers in their trial on PPMS patients on disease progression are barely statistically significant above placebo. If Biotin is proven to be true in delaying progression in its trials then does it not make sense to your team that MS progression is not a B-cell (or T-cell driven) phenomenon and is probably something that is triggered directly at a cellular level. Also, if it is true that the anti-seizure meds slow down progression, they also have no effect at all on B or T-cells whatsoever. The work by potentiating GABA receptors or blocking influx of sodium into neurons. I think that the T and B cell theories in MS progression are "circling" the drain because of their lack of effectiveness through existing drugs on the market in preventing disease disability.

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  12. Prof G

    I think the obvious answer to your question is that molecular tweezers would be infinitely preferable to a wrecking ball. Except that these molecular tweezers you speak of don't exist. So it's a bit of a false hope/non-question really.

    It's a little bit like dangling a carrot in front of a cancer patient and saying, "Do you really want chemo/radiation, or would it be better to just pop a medicated fruit pastille to cure your cancer and not have any side effects at all?". And then they say, “ooh yes please”. To which you reply, “Ah, sorry – just a hypothetical question”. Slightly irresponsible?

    The reason people opt for the wrecking ball approach is that nobody really has a clue about what, specifically, causes MS. Seeing as we only live once, some of us therefore opt for a treatment to cover as many bases as possible to stack the odds in their favour.

    If we take the last year on this blog, we may need to address T cells, B cells, microglia, microorganisms, EBV, HERVs, unknown viruses, plasma cells, field hypothesis, OCBs, neurodegeneration, peripheral activation, genetics, Vitamin D, etc, etc, etc.

    Even you, as a leading expert in the field, really can't say with any reasonable degree of certainty what the cause is, or how to cure it.

    As a patient, what are we supposed to do? Pick one of these theoretical routes and take a punt (gambling our life on a narrow, unproven theory - e.g. the EBV hypothesis), or do you go for a wrecking ball that improves the odds by hitting multiple targets and which has some decent evidence behind it of stopping whatever it is that's causing it (Lemtrada, HSCT) - but accept some collateral damage.

    It's like having a virus on your computer. Nobody wants to wipe their hard drive and lose all their stuff as collateral damage. But if your Antivirus can't fix it, what are you gonna do? Pick one document to delete and hope the virus was in that one?

    I'd love it to be as simple as a targeted therapy with zero collateral damage, but to go down that route, we need you guys (medical community) to work out what the problem is. I appreciate you're working hard to get to that point, but I don't really see much point in stating the obvious/dangling a carrot in the meantime, that you're not even close to inventing (and would be years to a decade away from availability, even if you knew what to do).

    It's just getting everyone hyped over nothing and suggesting that there's an equally effective and available option to the wrecking ball that is available to them to choose - which is just not true. Ocrelizumab is not available yet, good luck accessing Rituximab as a first line, and there is zero evidence so far to make an assessment of whether B cell therapies impact transition to SPMS (with, if anything, Dr Hausers evidence suggesting perhaps they do not).

    Not getting at you – I know you have the best of intentions and I agree this is the future of treatment. I just think we need to be real in saying it’s not here yet. So, if you have MS right now, and we follow your advice that early effective intervention is vital to long term outcomes, you’ve got to play the hand you’ve been dealt. Which is a choice between the relatively ineffective CRABs, or a wrecking ball.

    Sucks, right?

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    1. It is pretty clear he is discussing anti-CD20 therapies as a pontential surgical approach. It quite far from a "hypothetical" suggestions.

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    2. "Do we really need a wrecking ball to crack a nut?"

      Of course not, no one wants unnecessary collateral damage! But what's the alternative? Take a less effective drug & hope you get lucky, all the while risking acquiring more irreversible damage?

      If we had a reliable & proven alternative offering better efficacy that the current 'wrecking ball/s', of course people with MS would take that option!

      Agree entirely with Matt, until there is a comparible or better alternative in terms of efficacy, why even pose such a question?

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    3. The HSCT chearleaders are crawling out of the woodwork again.

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    4. Excellent post Matt - your cancer analogy is spot on. No cancer patient wants the effects of chemo/radiation but to wipe out hidden cancer cells it must be done. No MS patient wants to wipe out their immune system but "time is brain" and the questions of what to target in the complex immune system are not answered. As to anon 11:44:00 "HSCT cheerleaders...." Is a cheap shot. No one wants a wrecking ball but it is a viable option for some patients.

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    5. To Steve s,

      If HSCT overseas treatment is your only option I guess you are either confused or ignorant. The reason why HSCT is so popular is because it has been promoted as a treatment for progressive MS, so if it works in people with progressive disease, surely it will work in RRMS.

      But all of the established researchers have abandoned this treatment for PPMS because they realized it has no benefit, not because they are in the back pocket of Big Pharma.
      All that is left is the anecdotes on Facebook, not considerably different from the CCSVI fanatism a few years ago.

      I cannot fault people with progressive disease putting their hopes on this treatment, but those newly diagnosed with a low level of disability going for medical tourism is a pretty extreme measure. Maybe they would have been better off trying to get an off label prescription for Rituximab or travel to a country where they can obtain this drug for treatment.

      HSCT is the ultimate wrecking ball and it's refreshing to hear feedback from researchers and clinicians about the future of viable treatments for MS.

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    6. No, HSCT has not been promoted as a treatment for progressive disease. RRMS patients who are non-responders to the conventional drugs are candidates for this more aggressive stem cell therapy. Neural stem cell progenitors are being studied for possible repair in progressive disease. Tisch MS Center in NYC is planning a study using NPCs.

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    7. Great post Matt, but I think they simply try to do their best to find a cure to MS and to inform us. They try to manage expectations as much as they can meanwhile.

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    8. Slightly pathetic. You're not worth addressing directly, so I'll just stick to the facts.

      The reason HSCT is "popular" is nothing to do with progressive MS. It's because, on the balance of data to date, it shows extremely positive efficacy in RRMS - which is where all the trials are focused.

      The MIST Phase II trial suggests a NEDA-3 rate for HSCT of c.70%, versus 39% for Lemtrada in the equivalent trial (CARE-MS1). And, furthermore, the patient cohort for CAREMS-1 was massively more favourable to Lemtrada than the comparative cohort for MIST II.

      CAREMS-1 recruited only treatment naive patients with relatively recent disease onset and low EDSS, whereas in MIST (HSCT) Phase 2, nearly 20% of patients had SPMS, and all had failed previous therapy with no limit on EDSS or disease duration (many with high EDSS/long disease duration). Also, by nature of the procedure (chemo), it naturally selects for those with more severe disease.

      Yet, despite trialling in a cohort of patients who were fundamentally less likely to respond than the respective cohort for Lemtrada, and where 1 in every 5 patients had SPMS, HSCT achieved essentially double the NEDA rate of the most effective treatment on the market, in Lemtrada - which makes the results more impressive or, to quote Prof G when the HSCT studies were shared on this blog, "remarkable".

      Reported EDSS improvements were also higher in HSCT than Lemtrada (though we have to consider the lack of blinding in the HSCT trial may have influenced that).

      You could argue one is a Phase II and the other a Phase III, and there are legitimate concerns re lack of blinding in the MIST trial (albeit very difficult to resolve where chemo is involved), so that should be considered. However, equally, these studies have been replicated with near identical results, around the world (including now in the uk) - and consistently the experts conclude this to be a highly promising and feasible therapy.

      It also crosses the BBB (unlike the mab drugs) which may or may not be important, depending on your viewpoint and the studies show that the effect is not merely immune suppression, but profound reconfiguration. Prof G has himself said on this blog that the immune system which reconstitutes post-HSCT is healthier than that post-Lemtrada.

      There is a risk involved clearly, and some docs feel the mortality rate at 0.5% is too high. Some patients feel the benefits warrant the risk and make their choice accordingly.

      I'm supportive of balanced facts, and free choice to patients - and wish you the best of luck whatever you choose to go for.

      I'll leave it to the readers on the blog as to whether they should take the condescending and deliberate misinformation of a spiteful and increasingly pathetic anonymous troll slinging insults from behind his keyboard, or the peer reviewed trials published in respected journals.

      Think I'll leave it at that.

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    9. XoR - Agree completely. Fully appreciate the work they do, and the blog. :)

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    10. "Neural stem cell progenitors are being studied for possible repair in progressive disease."

      This really has nothing to do with HSCT, extreme immunosuppression or using a wrecking ball to swat a fly.

      It is a method to restore damage and may well be used in the future but is not pertinent to this discussion.

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    11. So I'm curious...

      Given Octelizumab is not licensed (and has issues aplenty of it's own) how do YOU propose we "swat this fly", Anon?

      You're not just trolling, right? You do have a better solution?

      P.S. I'd wager most people on this blog would find your view that MS is merely "a fly" to be swatted as pretty insulting given the disease impact.

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  13. To go back to the original metaphor, isn't the nutcracker in this case simply using anti-vitals to suppress the Epstein Barr virus? I know this is probably a stupid question, but could you explain why, just briefly?

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  14. I cannot add to to the science, the highly intelligent and independent-minded content and reasoning of Prof. Giovannoni's post - of course not. The only thing I can possibly add to this discussion are my personal feelings about the prospect of taking a drug with potentially very severe side effects, which may - given that I have shown progression since the onset of MS symptoms nearly 16 years ago - not do me much good at all in the end. I wish for more understanding or certainty of the pathology of MS, and that there were drugs which do no more damage than necessary, which target the core of MS. Until then, I'll take what MS throws at me on the chin as best I can. It can only ever be a personal choice. This, for me, has to do with the knowledge of my own body and psyche: I have reactions even to most shampoos and make up, and I didn't even get my ears pierced because I felt it would be self mutilation. My MRI scans gave me horrific nightmares. Maybe I'm a coward, maybe I would need to be made of sterner stuff to contemplate the drugs currently on offer. I don't know, but I am certainly so very happy that Professor Giovannoni has the vision to strive for something better - something far more refined than the drugs the pharmaceutical industry so gladly churn out.

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  15. What about Tecfidera? Cladribine? Given the small side effects (compare to the other) they look less like wrecking balls.

    BTW "Highly effective" is neither scientific nor true. Science deals with comparison not absolute judgement call like "Highly". I agree that existing MS drugs can be "effective" and even more than Beta interferon. But still I will call something "Highly effective" or even "effective" if it can cure something. Meanwhile "highly effective" sounds to me like cheap big pharma marketing.

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  16. Well it does strike me that it depends on whether it is a hazelnut, a coconut or a macadamia.
    The same treatment is offered to people with rapidly progressive MS as to people with less aggressive but still relapsing MS on say Tecfidera. Is just the fact we have active disease enough? Are there others ways to stratify us, get an idea of our particular type of MS and outlook? Are there genetic differences that matter? Or is it just that treatment options are limited and active is disease is active disease and needs treating (if you want). How long do you wait for something better and maybe a bit more selective? I am very grateful that there are at least treatment options now but it is still hard to go for the wrecking ball when I am probably just a walnut.

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  17. This kind of question makes me think of the scene from star trek 4 when they travel back in time and Dr Bones McCoy cures a patient with a single pill. That would be a wonderful feeling. There are solutions so tantalizingly close, it sometimes feels like the cause of the MS puzzle is on the tip of my tongue. This is of course an illusion.

    We do however need to live our lives today, and today we live in a time of wonderful discovery. Just a generation ago, with my Mother's MS there was no hope; we went to see a statue that had allegedly moved and held a relic from a saint that had stigmata. We tried what desperate and ill people have tried for millennia, to no avail. Today it is different, there is real hope and progress, with people that take the time to share with us their discoveries, Knights and heavy metal.

    I try to take solace in the fact that our time is a golden age of medical discovery and we get a front row seat in the discovery process. I know that is no consolation to many but it works for me. The DNA tweezers are coming, but in the mean time a hammer is better than no tool at all. Oh and when we do get these DNA tweezers, I've got a couple of 'electives' that I'll get done at the same time please.

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