Sunday, 10 January 2016

Ernest Beutler (1928-2008)

Beutler was one of the key clinician scientists involved in the development of Cladribine. Read his oral history here, and watch his acceptance speech of the Wallace H. Coulter Award for Lifetime Achievement in Hematology here.





Ernest was also the father of Bruce A Beutler (*1957), who happened to become the 2011 Nobel Prize Laureate, together with Jules A Hoffmann, for "their discoveries concerning the activation of innate immunity".

 Nobel Prize 2011-Press Conference KI-DSC 7512.jpg

Here's an interview with Bruce, revealing among other things, that he started working in Dad's lab from the age of 14...

19 comments:

  1. One with well insane ideas: If a partnership with another country does not work for the launch of generic Cladribine as a treatment approved for MS (and I would love it to be a first line option without waiting for the person with MS have a second bout / event so that they could opt) why not try to launch a campaign along the lines of ice bucket challenge for research and development of treatments for ALS, so the money raised would serve for the purchase of patent Cladribine for she could be released with such a proposal? I remembered a publication in which the MD had said Cladribine of patent value was around £ 4 million ...

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    1. There's no need for a patent. Cladribine in the tablet formulation is 42% bio-available whilst parenteral (subcutaneous, intravenous) Cladribine has a bio-availability of 100%; the effective drug (Cladribine) is identical. All you need to do to arrive at the dose equivalent of Cladribine tablets in terms of subcutaneous Cladribine is a simple calculation.
      Just under £5 Mill was the amount of funding we asked the NIHR for to support a trial comparing subcutaneous Cladribine with i.v. Alemtuzumab, however they felt this is too expensive despite excess savings during the proposed trial due to the price difference (<£1000 for s.c. Cladribine vs £35,000 for Alemtuzumab per year). Any big donors reading this please…?
      The lack of a marketing authorisation 'for MS' (it does have such authorisation in many countries for people with hairy cell leukaemia) means Cladribine can only be given to pwMS today, including in the UK, under specific circumstances.

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    2. Oh I understand Dr. Klaus Schmierer. But my idea remains the same: if not get by partnerships, if not arise a donor, could a worldwide campaign to try to raise this money to support the clinical trial Cladribine vs. Alemtuzumab ... Maybe think of it as a plan B or C ...

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    3. This would need the MSIF to lead perhaps

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    4. Exactly MD, put it in outline as alternatives and lead to them. Why is something real, not like the idea of ​​commendable campaign ice bucket for ALS where the money raised would be used to make things happen on the stage of the disease. What we see with Cladribine is concrete, no data was already proven its effectiveness, it can be a weapon against MS with the approved and recognized treatment for the disease, etc. only need a trial then showing that she can be as effective, less expensive, with far fewer side effects than the alemtuzumab. ... I just have no idea how to contact MSIF, but it's something to think about. Anyone reading this blog ever thought what Cladribine could do in the course of MS in the world? People have access to a powerful drug and can have some peace in their lives, they become with so much fear of when the next outbreak? And how it can help science itself concentrating on the repair in neuroprotection, in the pathophysiology progressive forms and causes of the disease? I raise this flag, as well as Charcot II ...

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    5. A nod from the EMA should convince most doubters of Cladribine's beneficial risk-benefit profile; this would send a message for generic uses too and could give the drug truly global potential. In that situation a trial against another induction treatment would potentially be redundant in terms of safety and efficacy, however testing generic Cladribine versus Ocrelizumab in people with relapsing MS with a health economics outcome could be of interest.

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    6. Oh sure it's in my best interest. I think it is in the interest of all MSers in the world: a very effective treatment, well tolerated side effects compared to currently available treatments and still possible is much cheaper. Just stop to think in the case of Interferons: Drug very low efficacy but with so many side effects and expensive. Anyway ... I just don't know if Roche/Biogen assume a clinical trial of Cladribine vs. Ocrelizumab, since he not even hit the market...

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    7. I'll pay you 5 million to work on a cure rather than peddling a rejected drug

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    8. OK let's see them greenbacks you know our email and we can give you a bank account. Maybe time to put up or...

      However, unless you are pharma it seems a rather strange comment. If you have the cash please contact us and surely more choice is better than less choice.

      What are you afraid of? The development of a drug that wipes the spots off other MS drugs?

      Are you afraid of something that can get in the CNS and work in the brain to switch off the immune system, unlike any other current MS drug

      Are you frightened that the regulators support the use of Movectro?

      Are you frightened about access to a cost-effective treatment that can make Movectro irrelevant?

      Maybe give us your thoughts? Part of the process has been PPI (public patient involvement) so please give us your thoughts. Is it the mud has stuck and you believe the cancer risk issue. However the only way to address this issue head on is to use the drug and monitor the situation carefully as the cancer risk is not really going to show itself in a 2 year trial. Importantly it did not show itself in another trial. Look at the data for cancer risk of mitoxantrone, but have the FDA banned this. What will happen to other agents?

      Part of the immunological cure is having an immune-depleting agent before switching off the established immune response, as I have said many, many times before. Ideally this would be anti-CD4 but neuros threw that one away years ago.

      However until the community start to treat early and effectively them the opportunities to develop a cure is more limited. I may get taken to task by some of the neuros out there but some of them need a good shake and ask what are they protecting their brain or their patients.

      Read the brain health leaflet on the upper left of the blog.

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    9. Doing a head to head with agasinst cladribine would be commercial suicide for a company. As the moment they take on low hanging fruit like the CRAB drugs that they know they will beat. Cladribine will beat beta interferon hands down. However if you do work it is a marketing nightmare...look at laquinimod. It looked worse than beta interferon in its trials and now the heart effect risk, which they knew of the parent molecule. Trying to appease the regulators and they have maybe shot themselves in the foot.

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    10. As far as I'm aware the EMA hasn't completed its current assessment (have Merck even submitted?).

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    11. I have money but I would not give it to cladribine. Does it stop MS? No. Are you 100% certain that it does not increase the risk of cancer? No.

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    12. I am happy you have money and maybe you want to donate a pound/euro/ dollar of your hard earned cash to the crowdacure appeal.(P.s. This is nothing to do with me)

      Does it stop MS? I don't know but based on published data about 50% of people were NEDA after one years course of treatment This means that 50% of people did not need another course of treatment...is this for the rest of their lives? I don't know but if it was 10 years of disease and drug free, before needing another course would you take it. Based on this figure of NEDA rate it is better than other published phase III data for current MS drugs.

      What is a cure and what does it mean?

      So you are happy to donate money to search for a cure, where the only outcome is hope and a 10-15year development plan before it reaches someone with MS. This is because you and I know this is how long it takes to develop any new treatment, even with millions and pharma behind it, yet you are not willing to support something that can offer immediate benefit to every body with MS (as all people have active lesions even pwSPMS/pwPPMS). Maybe Merck will tell us how many people went on to develop MS in the ORACLE study but it was 70% less than the placebo group and had they re-baselined after 3 months (Most failured occurred within 3 months probably because it was to late for the drug to be active for those indivdiauals) it would have been much higher

      As to cancer risk and being 100% sure, only a fool would say I am 100% sure, but the only way to find out is to try it an see. Life has a cancer risk and cancers occur with every MS treatment. It is a fact of life.

      Only today ProfG puts out the word on cancer risk and alcohol. Will we stop taking alcohol tomorrow because of this? I haven't read the report to know what is the real risk. 1 in 100,000 compared to 2 in 100,000 which is double the risk but only 1 more case in 100,000 people.

      Will someone like you donate their money...I would not be so presumptious to say no....because many people do and I am not so blinkered. You put our money where you like and so millions have gone on supporting stem cell research that have yet to have impact. Yes maybe it will in the future but some of it won't. That is the nature of research no everything works.

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    13. MD clearly you are passionate about cladribine but you are basing this on data from 1 or 2 trials, which were no where in the same league as lemtrada for rigour (interferon comparator etc). You guys continue to ignore the EMA submission reporting 20+ malignancies in cladribine treated populations. The data on effectiveness is not real-world. But regardless, whatever your stats on the data you have, it is still not NEDA for all patients is it? So that's why I would not support it.

      I'd support something that has some balls (which I thought team g had) but the current crowdacure campaign is such a wet blanket I won't bother. The study as is will not help any MS patient- it doesn't even give any idea as to whether famv reduces ebv.

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    14. There was one completed trial which was done to the same rigour as the lemtrada trials as that is standard trials. There were other trials that we terminated and there are a host of academic trials, but you are not reading properly. The view by the MHRA was that more data was needed and we accepted that and aimed to obtain more data.

      To state we ignore the EMA submission is a diservice and we have examined the number of malignancies and some were not malignancies however you sound like the raconture for the EMA/MHRA because 20+ without looking at the demoninator is daft. 20 in 100 is different from 20 in 1000 is difference from 20 in 10,000.

      We do not have data in the real world yet because Merck has not published such data. However I am sure this part of the submission as there is a follow-up programme and the fact that Merck are going back to the EMA suggests that they are satisfied that it is not a waste of time.

      However, you mention real life can I draw your attention to the real world on Alemtuzumab in the paper recently published in 2015

      http://www.ncbi.nlm.nih.gov/pubmed/26514979
      In 100 people there were 10 with malignant or pre malignant conditions i.e. 10% in the clarity trial there were many hundreds of people involved.

      It is not 100% NEDA so I will not support it...So you can be safe in the knowledge that you will never support anything. You need a reality check because no treatment will be used optimally and there will be failures. This is a cop-out statement that sound like, without wanting to be rude more mouth than money.

      I would support something that has balls...like what for example?...Something that was taking on the establishment is not balls?, fool hardy maybe but lacking balls I think not.

      Some people put their money wehre their mouth is , hopefully you will to and I am sure the people you pick will be very grateful

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    15. Hello Money Man (or Woman), don't leave us - you're just teasing aren't you? Rigour of trials? Remember Alemtuzumab was initially rejected by the FDA given trials were not double-blinded. There are limitations in testing drugs that almost invariably have acute side effects (infusion related reactions, flu-like syndrome, etc). Let's see what happens with Movectro at the EMA - if it happens. The evidence is so convincingly in favour of bringing Cladribine to the table that some manufactures must be scratching their heads whether stopping Merck from doing what they are saying they would might be in the better interest of the industry(?). But then - as MD pointed out - will they do it at all?

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  2. As the EMA aplication been submitted...Probably not and maybe it never will.

    A good way to stall everyone

    Merck seem to have been re-submitting for years and we are months on from the announcement that they were were. Every second wasted and they are losing money if they wanted to go back to the market they could be doing so in Russia and Australia but are they I think ot. Are they going to commit to re-manufacturing the drug before they get approval. If they wait until they have approaval how many more years of patent life have they wasted..Already it has been 4-5years

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  3. I don't have the money, I do have MS - but I just want to go back to the topic of this post and thank you for the links to both the Ernest Beutler biography and the Bruce Beutler interview. Truly enjoyable! Those who question motifs of scientists doing research should read/watch these pieces.

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