Monday, 23 January 2017

Understarters Orders...whats the plan to ensure the race ends in a good outcome

This weekend's post about alemtuzumab not working in some people after fingolimod begs the question "How we should transition people from fingolimod onto something else?"

We have had this debate about natalizumab already. Look for the posts on this aspect.

HIGHLIGHT
  • Fingolimod and Natalizumab are "racehorse" drugs
  • They keep cells trapped to stop them entering the brain
  • As they are not killing drugs, disease forming cells can accumulate over time

  •  They are "under starters orders" to race to the brain.
  • Stop drugs and disease "rebounds" in some people
  •  There are many *****LIMOD trials ongoing to take on fingolimod and Siponimod.
  •  What measures are in place for me when the drug supply stops at the end of the trial. How is rebound going to be prevented, even if it is a progressive (or what every you want to call it) MS trial?



These drugs are not killing drugs... they are trapping drugs and for fingolimod they trap disease-causing cells in lymphoid tissue and for natalizumab they trap-disease causing cells in the blood. 

They do not stop the disease process and so the disease causing cells can accumulate and are trapped, whilst drug treatment is in place.

However, see these cells as racehorses waiting to run into your brain, and they are "under starters orders" waiting to go. The gates open and "they're off"

Remove drugs and the cells escape, get into the brain and disease activity occurs.

Whilst some people view progressive MS, as a different disease, this I think is a dumb view and importantly a dangerous view. It is very clear than there are many people with active lesions that come and go as the progressive course carries on. If you look in the pathology of people with progressive MS there are active lesions.

It is clear that some people with progressive MS benefit from immune-inhibition.

However, I think it is also the case that the "racehorse drugs" allow the accumulation of damaging cells in people with progressive MS to such an extent that the drugs convert their subclinical relapsing pathology into relapsing-active MS, with a time-bomb ticking once drugs are stopped.

This is because the horses are all lined up and waiting to go.

Stop drugs and relapse occurs...this is sometimes called Rebound. 
Call it "resumed (synchronized) relapse" in case you don't like the word rebound...but they are damaging by what ever name you call them and it need to be avoided.

Does this happen? Sure it does! DrK a case report please

DrK says "Here you are MD: Davion JB, et al. Two cases of relapses in primary progressive multiple sclerosis after fingolimod withdrawal. J Neurol 2016;263: 1361–3.

However, how do you treat somebody with PPMS and rebound with no licensed options available?  We will hopefully see soon..."

Thanks DrK!

We are in the race for the "Mod me toos" and "Mods in progressive MS" and there are loads and loads of trials in relapsing MS and we will see them in progressive MS too if siponimod gets a green light. 

If deemed a success companies may contiune to supply drug as this gives them important safety data, but if the study is deems to have failed drug supply may be stopped, or if it is a small company a failure means they are gone and drug supply will be stopped

If it clear to me, that you need to ask "Once the trial ( I am volunteering for) finishes, what are the plans after the trial if it is a success or a failure? What happens when the drug stops and what is in place to limit rebound?

Rebounds won't have happen in everybody but if they do, people can not afford to loose more brain, because we haven't thought of a solution and got a plan in place. This goes out to pharma and the neuros.

18 comments:

  1. in hindsight it all makes sense.

    why was it not foreseeable?

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    Replies
    1. Perhaps not enough thought process by the people doing it.

      It is a shame that there were no reports of blood screening as whatever is getting into the blood and brain may have been spotted.

      Delete
    2. a cohort of powers to be doesn't want it to be spotted, we can prolly agree on that.

      but what about the cohort of those in charge of treatment decisions with ms whose information source is the charismatic cohort of those who don't want it spotted :(

      having to share your entry re gilenya and lemtrada to a friend who recently switched from gilenya to lemtrada and is experiencing new ms symptoms was a little bit heart breaking.

      knowing she only went on gilenya because at the time she couldn't find a neuro willing to prescribe lemtrada made the experience all the more gut wrenching. (she went on gilenya while she look for a brave neuro willing to give her lemtrada, something being better than nothing)

      she has 2 young children, one with a disability... it's not like she was only thinking of herself.

      no one knows yet what is happening in her case (and it may be that it is nothing but old damage representing itself in a new way). but i know she will lose a few hours of sleep over this. and she has enough on her plate without it.

      my partner has a therapist from her cancer days she still sees from time to time (psychologist). i asked her how i can be less angry and more understanding about all of this (aka how can i improve my attitude).

      she told me i need to take breaths from time to time. but my attitude is not the problem apparently :)

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    3. I am sorry, I appreciate that this is not good news and not good news if you have already gone down this path, but it seems that the second alemtuzumab treatment cycle puts one back on track.

      I wonder if we are guilty of this approach too as a switching strategy to get off natalizumab-fingolimod-alemtuzumab. The neuros will need to discuss what is their strategy moving forward. Maybe profG can comment.

      It is disturbing that some neuros won't prescribe approved drugs, however if does not surprise me. I know of plenty of Risk averse "Wait and See Neuros"

      If would be interesting to see which centres in the UK prescribe and which don't, I guess that could be done by freedom of information to see what MS drugs are prescribed in which centre. We now it can be done as we now a company (pharma) did this to find out what we were prescribing.

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    4. Thanks for the response.

      I have made FOI applications to public hospitals in Melbourne with MS clinics and am waiting for resutls... I have asked for documents which show the number of prescriptions by prescriber and consented to the prescriber's information being deidentified if there are privacy issues... $160 later (and still to pay for photocopying costs per request), I'm waiting for the information.

      Lucky I'm made of money, hey :)

      Delete
  2. every time we play the 'it's the t cells, it's the b cells, it's the t cells, it's the b cells' game, every time we play the rebound game and every time we realise 2 drugs' modes of action aren't really compatible and there is a lot in between that's been unanswered my partner sighs with relief that she used a sledgehammer to crack a nut and avoided all this.

    and i understand her point of view.

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  3. i can't emphasise how much this makes me feel people with ms are being repeatedly let down.

    is anyone critically thinking these days? or are we continually buying what the pharma markets to us?

    how can we continue to trust neuros?

    do i need to list the long litany of ms dmt travesties?

    at what point is this going to stop?

    am i naive to expect better of doctors? i know their excuse: it's been licensed, we weren't to know.

    but how many times until that excuse runs out? what's next?

    ReplyDelete
    Replies
    1. Are we continually buying what the pharma markets to us?

      I suspect for many the answer is yes.

      Whilst teaching last week, we asked the trainees how many papers they were reading a week and I was shocked, as it is not enough. So if people are not reading to get their info they are either getting it from conferences (where pharma impact to large parts what is presented) or they are getting it from pharma directly e.g. their reps.

      I would think the research active neuros are more likely to keep up with the literature.

      The best way to protect yourself is to be as knowledgeable as you can be. You will be able to determine if your neuro is trust worthy"

      Sorry to say I suspect there will be more litanies.

      Delete
  4. Great and very educative post MD! Thanks for all these details.

    However, it seems to me that people on fingolimod and natalizumab are trapped and they cannot stop their drug. Especially those on natalizumab and JCV positive have to stop after 2 years from on onset treatment to reduce the risk of PML. If they are going to switch to alemtuzumab, you've suggested fingolimod as the bridging agent during the wash-out period. But now it seems that alemtuzumab after fingolimod may not be effective. What should these patients do then?

    Do you expect that ocrelizumab will have similar issues?

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  5. I disagree.

    If you have fingolimod you can put on an immune depletor so cells are destroyed as they come out of lymph glands or you can clear the lymph glands with something else that has better activity. This could even be alemtuzumab mark II that depletes in lymph glands and bone marrow...this may help with the secondary autoimmunities. There are for options

    Now to natalizumab there are options too and one may find that natalizumab to alemtuzumab, you may do better because the cells are trapped in the blood in the firing line of alemtuzumab. However in year one as there are only about 4% relapse based on the Cardiff group. To show better than that the study will have to be very large numbers needed to see a difference or the effect would have to be great with 0% relapses.

    With regard to PML and natalizumab switch there are papers suggest that rituximab may have some utility. However one would need to do meta analysis to see what the whole evidence says.

    Re Alemtuzumab after fingo...the data suggests it is good for 75% of people, what you would bridge for is the time when fingolimod wears off... then it should be alemtuzumab as usual. This should be easy to monitor as fingolimod has a characteristic blood profiles so you can tell if it is working e.g reduced naive and central memory cells.

    However the question is will you try and bridge to alemtuzumab this way or use something else.

    It could be possible that ocrelizumab could have similar issues as I think they probably work in the same way as alem. However with ocrelizumab the cells targets are constantly depressed by the 6 monthly infusion. Alemtuzumab is hoovered out of the blood pretty quickly, ocrelizumab has terminal half-life of a month.

    Also it depends on how the 600mg of ocrelizumab is administered in some trials you get first infusion and then the next infusion a month later so you get a fresh dose as cells would be escaping.

    This is how cladribine is administered it will get into the spaces where antibodies don't go.

    so you are on drug effects when the fingolimod wears off

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  6. Be warned about the natalizumab switch to alemtuzumab because as depletes B cells and CD8 T cells there is no way back if there is sub-clinical PML. The cells that would destroy the virus are gone. This has happened resulting in a PML death

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    1. "Be warned about the natalizumab switch to alemtuzumab"

      Can you re-explain this please..I just can't quite follow it.

      Delete
    2. "Whilst some people view progressive MS, as a different disease, this I think is a dumb view and importantly a dangerous view."

      So is "secondary progressive" just a stage where someone has
      accumulated damage where the plasticity of their brain ca no longer cope with ongoing brain shrinkage taking place.

      Delete
    3. I was talking about switching treatment in this case from natalizumab to alemtuzumab. Natalizumab carries a risk of PML and that is why people want to switch treatment. You can wash out the drug but if you wait too long the cells can get into the brain and trigger a relapse.

      So how long do you wait before starting the switch drug.

      You could start it before you with draw natalizumab to avoid disease returning. However the other risk is PML.

      PML is caused by a virus. Your CD8 T cells and B cells that give you some immunity against the virus but if you switch to alemtuzumab then the protection potential is lost.

      Therefore is there is subclinical PML that you havn't detected when you start alemtuzumab, then you kill the T can B cells that could kill the virus. Therefore the virus grows killing oligodendrocytes and making PML worse. The end result can be death. This I believe has happened.

      Delete
    4. Therefore if you plan to switch from natalizumab to alemtuzumab you have to de-risk the chance that there is subclinical PML due to the natalizumab. One approach is to use a bridging drug such that you keep MS in check to give time for subclinical PML to show itself.

      Delete
    5. Dear Adam 10:10
      Yes you are correct but it may be more nuanced because the cpacity to have plasticity in one nerve tract may have been exhaused where the plasticity in another may not. hence the hope that profG has in which whilst it the reserve in the legs may get exhaused first you can still save the nerve capacity in the hands

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  7. The problem with fingolimod is that a small proportion of patients coming off the drug have persistent longterm lymphopaenia (years). By following fingolimod with a depleting DMT you may render these patients long-term lymphopenic and put them at high risk of opportunistic infections and delayed cancers. Therefore there is a delicate balancing act to sequencing DMTs post-fingolimod; i.e. to stop fingolimod and wait to see if the lymphocyte counts are returning before giving an irreversible depleting DMT. Our current protocol is to wait for counts to get back to ~800, which typically takes about 3 weeks after stopping fingolimod. This is hopefully insufficient time for rebound to occur in. With fingolimod we typically see rebound at 6-8 weeks after stopping the drug. Unfortunately, the 800 threshold is pragmatic based on scientific principles and is not evidence-based.

    When using alemtuzumab post-fingolimod there is another reason for waiting for peripheral counts to return; we need to allow lymphocytes to recirculate to deplete them. There is a theoretical reason for doing this; alemtuzumab is meant to deplete circulating cells better than cells trapped in lymph nodes. Despite me saying this I am not sure this is correct; I have seen secondary lymph organs shrink post-alemtuzumab. We are in the process of formally looking at this in more detail.

    Another interpretation of the active cases, or rebound, on alemtuzumab, post-fingolimod, could be ascertainment bias. In other words selective reporting. We have seen several patients who have had major relapses in the first year after their first course of alemtuzumab that have not been on fingolimod. What do these cases represent? In other words the cases post-fingolimod are simply patients that have yet to respond to alemtuzumab. Please note that the reason why NEDA rates are not that good on alemtuzumab is that the current data includes the baseline scan in the NEDA analysis. If we had to re baseline alemtuzumab patients at year 1 the NEDA rates in year 2 will be close to 80% on alemtuzumab. Alemtuzumab takes time to work and counting activity on the drug in year one disadvantages its efficacy.

    I personally remain to be convinced that rebound post-fingolimod is due to a failure of alemtuzumab to work. What will it take to convince me? Data. The MouseDoctor and I have already discussed a series of animal experiments to test the hypothesis.

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    Replies
    1. "I personally remain to be convinced that rebound post-fingolimod is due to a failure of alemtuzumab to work. What will it take to convince me? Data."

      What if you don't have the data and have to make decisions? What if there is a chance half your life depends on those decision (I think you mentioned rowing and running recently). Do you ignore it until it goes away or try to extrapolate?

      Delete

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