Thursday, 18 May 2017

Beating the drum for drug C yet again...

Alvarez-Gonzalez CAdams A, Mathews J, Turner BP, Giovannoni G, Baker D, Schmierer K. 
Ann Clin Transl Neurol 17 May 2017

PLEASE READ IT IS OPEN ACCESS (CLICK ON THE TITLE)

Abstract
Rebound disease following cessation of disease modifying treatment (DMT) has been reported in people with both relapsing and progressive multiple sclerosis (pwRMS, pwPMS) questioning strict separation between these two phenotypes. While licensed DMT is available for pwRMS to counter rebound disease, no such option exists for pwPMS. We report on a pwPMS who developed rebound disease, with 45 Gadolinium-enhancing lesions on T1 weighted MRI brain, within 6 months after fingolimod 0.5 mg/day was stopped. Treatment with a short course of subcutaneous cladribine 60 mg led to effective suppression of inflammatory activity and partial recovery with no short-term safety issues or adverse events.

We have been accused of beating the drum for cladribine a little too often. However, please read this case of one of my patients, consider the alternatives, and you may agree there aren't many with a comparable risk:benefit profile. The arguments are detailed in the discussion.

There are a few lessons beyond the effect of the drug used such as:

(i) Even in somebody with the clinical phenotype "primary progressive" MS, the principal mode of disability accrual may be through inflammatory lesions that look no different on MRI from relapsing MS.

(ii) Based on this and previous reports one should be very careful stopping a DMT known to be effective in relapsing MS, even when efficacy in the trial (INFORMS) was not significant *on the cohort level*. In our case, my impression would certainly be that fingolimod did work.

Unfortunately, our acknowledgement appears to have been lost in the course of proof editing the paper: We would like to thank Novartis for letting us use the clinical data of this participant, and for providing the lymphocyte counts, acquired during INFORMS.

CoI: multiple


17 comments:

  1. Thanks DrK this is a really encouraging post on several counts, not least your patient was/is ok and recovered. Also good support for all MS being the same, lastly fantastic news that ever faithful cladribine came to the rescue :-)

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  2. I don't understand your constant banging the drum for this drug. I think it is one of the biggest contradictions on this blog.
    You constantly tell the HSCT'ers that looking at one offs on the success of that treatment is wrong, you have just done that here.
    Will you admit that cladribine as a treatment does not compare favourablely to Natalizumab to alemtuzumab (your safety profile argument stands,) but there is a lot less data available for clabridine so as with Natalizumab when it was first licenced there is a risk that IF it gets more widely used issues may arise?
    If it gets to licensed do you honestly believe it will be the same generic price it is now? Or do you think it will be similar to
    Alemtuzumab (Campath - generic, cheap cancer drug to lemtrada very expensive MS drug)
    Ocrelizumab (rituximab - generic, cheap (chimeric)) to Ocrelizumab (humanised) expensive MS drug
    Cladribine generic cheap cancer drug to TBD - expensive MS drug. Novartis will raise the price exponentially so then does it really have a place in the market?
    It's a shame that you this blog that is such a good site for information to market a drug that your egos refuse to let go of because it failed so many years ago. I agree 5ish years ago there was a market for this drug, now it's better than the CRABS but not the MAB's why bother? Do you have financial insentive and the end of the rainbow if it gets to market? Or is it your medical opinion that this drug should be prescribed in front of the MABS (putting aside patient preference just medical opinion)

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    1. This pwMS was treated with an off-label drug because there is no NHS England approved DMT for PPMS. Cladribine has a good safety profile, we know it works well in relapsing MS, and with active MRI, and it was available at short notice. She would not have fulfilled the treatment criteria of the London HSCT group, and I'm not aware of a trial looking at efficacy open for recruitment in the UK atm. Because pharma doesn't always take the right decisions we have undertaken our own research some of which already published, some due to come out soon. And look, pharma, has gone back to the regulators for a license. Our mission is the best choice of treatment for pwMS; sometimes this means venturing off the beaten track. Our conflicts of interest are available under "about" on the top left.

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    2. One of the benefits with drugs that have been around for some time is... that they have been around for some time. Regarding risk one obviously has limited data in pwMS, however there is plenty in people with hairy cell leukemia (the indication fro which cladribine is currently licensed), and the data is reassuring. Nothing replaces long term follow-up though, and that will no doubt happen on a broader scale if a license is given later this year.

      Regarding comparisons with other drugs the usual mantra applies - head 2 head studies are needed. We were hellbound doing a trial against alemtuzumab 3 years ago, however NIHR didn't award funding.

      I wonder a propensity analysis could bring us closer to an answer to your question though, and as you may know oral cladribine had been licensed for a few months in Australia, so may be a study would be worthwhile.

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    3. One of the purposes of the blog is to talk about work we have done. If we were sheffield we would be talking about HSCT, but we are not.

      ProfG was lead applicant on the oral variant and no doubt will be trying to help it on it's way back. When development of cladribine was dropped DrK picked up the baton to breed life into the project.

      You make some valid points but in terms of efficacy it appears to be in the same ball park, but lets do a head to head...Oh I forgot when this was proposed no-one wanted to fund it.by reducing lymphopenia to make the EMA happy, could make it lose its edge. We shall see.

      How does it compare to natalizumab...no PML cases.....yet. If and when it comes back the registries can look at real life and then one can see how they compare. Will their be a problem lurking. The only way to find out is to use it.

      Please remember there is already extensive use of cladribine in Hairy Cell Leukaemia, Clofarabine has same mechanism, but you are right as it is used more the side-effects will pop up. I am hoping/expecting that the EMA will licence oral cladribine so it will come back and it will be used. I found a clock counting down to the not too ditant future so we may not have to wait too long to find out.

      If oral cladribine gets licenced, Merck will set a price, when it was called Movectro it is was €20,000 I suspect the price will depend on the price set for ocrelizumab. lets see

      In this case generic cladribine was used £165/10mg and it was used off-label. It is never going to be licensed. The process is too expensive for a generic. Merck dont control the price of generic cladribine. That is unless they buy the company making it. There are more than one company producing it.

      Once oral cladribine comes back, then NICE may fund that but oral cladribine is not getting a licence for progressive/advanced MS until a trial is done.

      Its better than the CRABS but not the MABS. It has a ring...How about no secondary autoimmunities, no infusion reactions, no infusions, no monthly screenings, no Nabs, no PML, No, No, No I here you say.....

      Do I have finacial incentive me... not yet...Any offers:-), but if cladribine gets to market, ProFG gets an impact starement for REF2021, so our bosses will be happy.

      If it gets a licence from EMA will it be first or second line, line.

      Why not try generic CLAD first and see if it works:-)

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    4. Your contradictions are alive again. Wasn't alemtuzmab used as Campath for cancer with no auto immunity issues?
      So even though Cladribine was safe for cancer no guarantee it will be for MS?

      so if this drug isn't as effective as rituximab or Ocrelizumab. And the safety profile seems to be ok with that drug, why would you prescribe clabridine over rituximab if both are off label but what has more evidence And higher success rate? Apart from the fact that it isn't better for patients but provides you with hand picked examples of how CLAD might be successful. I notice that you very rarely if ever post any articles or examples of CLAD not working... it does seem very biased and misleading, in passing comment with neuros you barely if ever heard it mentioned - the white knight? Or Barts ego.... food for thought..

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    5. Merck has 7+ years data from their PREMIERE registry; had they detected a significant signal for cancer they wouldn't have gone back to the EMA.

      Head 2 head studies would be best, for now there's only imperfect comparisons from various populations, but if you re-baseline MRI, you'll find the curves look very similar. CNS penetration might be beneficial, which monoclonals don't, but that's hypothesis to be tested.

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    6. If you want to complain about the way I report..you ain't seen nothing yet:-)

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    7. P.S. Autoimmunity issues are a particular problem of pwMS. They occur with alemtuzumab with high incidence and also occur with HSCT. For MS there were hundreds of people treated and so if there is a risk of secondary autoimmunity it is small. Likewise alemtuzumab has a mechanism that creates autoimmunity, I do not believe the other MS drugs do to any major extent.

      We rarely pick posts of "it" not working.

      Since I started on the blog started, where are the negative papers to comment on and then we can report them. Perhaps you need to "put-up or" and show us what we are claimed to be misleading. Otherwise your comments lack substance

      Yes, we do post preferentially on our own research, particularly if it's going well. (Yes ProfG owes you a paper)

      I don't know which crowds of neurologists you
      walk through, I suppose at conferences, so you may be from one of the companies that don't enjoy people doing well on cladribine?

      Heard of Nivarna?..smells like ten spirit...rubbing shoulders with neuros "Smells like drug rep:-).

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    8. I'm not a drug rep. And I agree that posting research is a good thing, why this blog is so useful. But do make it unbiased. If you can't see the biased in the way you report CLAD that is ashame. It's just my opinion, maybe others disagree. But neutrality is key. Debunking CCSVI, and talking about the pros and cons of alemtuzumab is great. Do the same with Clabridine.

      Your mocking of me is interesting. I have MS, and have seen 7 neurologists and not one has mentioned clabridine. I'd be happy to give you a list of their names and hospitals I saw them at. Some were very conservative, some very forward thinking. I also partake in a disability working group at my place of work and we talk about MS so get to speak to many different sufferers from across the country. We talk about treatments and I know people who are taking interferon to HSCT... so I trust the people I talk to...

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    9. To Anonymous - I'm in US, have had non-relapsing MS for 3 decades. Took rituximab 2012 - 2013 in a trial, have progressed some since then. Currently taking cladribine - year 2. I was attracted by the combo of its target mechanism, safety, efficacy, brain permeation, tolerability and price. Considering these factors and my advanced stage of MS and comparing to the other drugs now available (and HSCT) guided me to try this - totally my decision. Is it working? Well, my lymphocytes have been reduced, but my progression is so slow that I can't say for sure. It's the best option for me.

      As far as neurologists go, many are not very curious, and very reluctant to consider prescribing off-label cancer drugs. I'm sure that I, and probably you too, keep up with the literature better, for me thanks to Google scholar alerts & this place. I trust myself as much as the neuros that I have seen, even the excellent ones at the NIH.

      As far as bias goes - there's a lot to like about C. You can find lots of folks who like other drugs. Once oral C is approved, I think it will be popular.

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    10. I apologize for the insinuation.

      Maybe the 5 years I have been banging my head against a brick wall has caused brain damage.

      Why have 7 neuros not mentioned cladribine?. They don't think about it? It never arrived and was dead and buried when it was withdrawn from the market in 2011. They believe it causes cancer because that is what the EMA/FDA inferred. They may also dislike off-label prescription? I don't know.

      I suspect they never mentioned clofarabine or fludarabine-both oral by the way (works the same way) either.

      Thanks for the tip maybe I will talk about pros and cons of alemtuzumab

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    11. The beasties are awake it's night time. Happy as chappies

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    12. Hi Tom in US
      Thanks for your comment, I've much enjoyed all the comments from Barts in this string and, like you, am learning so much from following this blog. I'm encouraged you can't sense / measure any worsening since C, early days perhaps but here's hoping :-) I definitely notice worsening year on year, even over six months. Hoping to start C as soon as I can....
      Very best wishes to you,
      Judy in UK :-)

      Ps think anon 7 neuros I'm not a drug rep has lost interest ;-)

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  3. Nice one DrK..the magnificant 7 reasons and cost not even mentioned in them. It also induces a dainty death of lymphocytes and rather than making them explode and releasing their comments like depletion that cause injection/infusion reactions.
    CoI : None relevant

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