Saturday, 13 September 2014

The regulators got it wrong and throw drug away

#MSResearch. Regulators help throw away a useful MS drug

J Pakpoor et al. Is there an increased cancer risk in people with relapsing multiple sclerosis taking cladribine? MS J Suppl




The FDA/EMA saw a few cancers in the Movecro (oral cladribine) trial called CLARITY led by ProfG and wanted further trials to document whether the drug was safe.  

Merck Serono was in a race with Novartis to be the first Pill for MS and had gambled that one trial would be enough. This came back to bite them.

The company did not want to do further trials and pulled the plug.

Movectro supply to Russia and Australia, where it had been licenced, was stopped. They also pulled the plug on further ongoing trials that would actually show the increased perceived cancer risk was nonsense. 


Down the toilet went the millions of dollars, they had spent repurposing the generic form of cladribine into a pro-drug that was a pill that released cladribine when eaten. Why did the do this?....seems that they didn't think they could make enough money to wait because the patent life was running out. This could have been done and dusted by now, gilenya faltered and got a second line licence. Did  the producers get it wrong. 


There were  a few cancers in the drug treated arms in CLARITY and none in the placebo arms. 

This new work reported at ECTRIMS did an analysis of cancer risk of all other trials used in the licencing of MS drugs

There was no more risk of developing cancer in MS than with any other MS drug currently on the market. Further in the CLARITY trial there was no more risk of developing cancer than in the placebo group of other trials. 

So the European and American regulators helped to pull the handle to ensure the flush was complete. People get cancers it is a risk of life but by fluke there were no cancers in the CLARITY placebo group.

So you had a drug that is as effective as Lemtrada, Gilenya and Tysabri (and tecfidera) and twice as effective as Aubagio, Rebif, Avonex, Betaseron and glatiramer acetate, but without the side-effects of Lemtrada, Tysabri, Ocreluzimab etc. 

Based on the CLARITY extension data, an induction therapy as good as Alemtuzumab for getting rid of peripheral immune responses without causing masses of unwanted secondary autoimmunities, and unlike Alemtuzumab and other antibodies can readily get in the brain and gets rid of oligoclonal bands. Furthermore it is rapidly eliminated from the body despite its long term effects, so maybe good for pregnancy or adding on other repair and protection drugs.

Will Movectro get resurrected? It is years on....so the patents have even less life in them than when the accountants pulled the plug

Nice one FDA/EMA..You served us well....Not!

47 comments:

  1. Are we living in a madhouse?

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    1. Possibly, the regulatory system is not helping deliver drugs in a timely way and is helping the cost inflation spending millions on trials is not helping you get cheap drugs

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  2. This is unbelievable, makes me sad and angry

    Question: why do you call it an induction therapy? I thought it was tablets

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    1. !induction means that you dont have to take it all the time but it resets the immune system.
      alemtuzumab is an induction therapy, ocreluzimab could be and induction therapy based on the data but probably wont be sold that way. This means once the drug has gone for alemtuzumab with is a few weeks for cladribine itcwould be a few hours and you are drug free so great for add ons say a neuroprotectant as this eliminates drug drug interaction.

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    2. Datapresented at ectrims2014 that after 2 courses of alemtuzumab 50% dont need a third course. They are NEDA. Are they cured....i dont know it will take afew years to tell but they could be. This comparablewith the clabribine extension study. Merck Serono has to follow up people given cladribine.

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    3. Going by my rituximab experience, ocrelizumab will not be an induction therapy.
      A dose is needed every 6 or 7 months. That is when permanent symptoms start worsening and old symptoms start reappearing

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    4. Rituimab was given at repeated doses as you say. In the Cambridge protocols retretment occuured after failure

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  3. That's what you get if you want social healthcare: commissions, councils and ppl. who are not familiar with the disease and the ppl. who suffer from ist.

    And o.c. hysteria and hype. This is more true these days as it was 20-80 yrs ago.

    Was the risk of getting cancer higher than with Mitoxantrone? I guess not...

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    1. Definitely not, the mechanism of action of mitoxantrone may lead to certain cancer risks,

      http://multiple-sclerosis-research.blogspot.com/2014/07/leukaemia-risk-from-mitoxantrone-higher.html

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  4. "..can readily get in the brain and gets rid of oligoclonal bands."

    Quite a claim, but where is the proof? I hardly think you can make this statement from results of an extension study.

    You need to hold yourself to your own standards.

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    1. A claim from published biology nothing to do with extension study orCLARITY.
      There are many papers on cladrine few as movectro and alot as generic cladribine. Of that injected 100% is bioavailable with movectro 40% is bioavailable there is no difference bewtween the two except cost and you need to eat twice as much. The PK data is out there as are effects on OCB.

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  5. One wonders to what extent are the regulators flexing their power too much. These days. There existence is often funded by pharma e.g. MHRA, EMA, but their desire to show safety and efficacy is driving up drug costs, making it impossible for anyone but pharma developing drugs..ensuring they will continue to be expensive and slowing the process of drug availability.

    For Movectro, post-marketing analysis (phase IV) would have found if there was any cancer signature as 2 years clinical trials are never going to give the real picture so have to do extra trials would have not really shown the cancer risk. Therefore they serve to halt access to an active drug.

    We heard at ACTRIMS/ECTRIMS of a number of trials the numbers being recruited in some studies were staggering and it is not surprising that companies are spending millions doing them.

    The European regulators wanted a placebo arm in the trials comparing generic glaterimer acetate verses Copaxone/ Hundreds of MSers got nothing when surely all that is needed is a a non--inferiority trial to show that the two compounds are no better or worse than each other. These trials were undertaken in Eastern Europe, where maybe people were not getting access to drugs. But is this ethical. Surely not! Is it time that Neuros stood up to the regulators and pharma who want placebo arms.

    Some trials are getting so big with thousands of peoples in each arm....this is adding so much cost to pharma to do the trials...all will be passed on to the consumer

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  6. Is there any research into increased risk of Cancer for MS sufferers?

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    1. Yes there are alot of studies. Search the blog or pubmed. In many cases there is no increased risk for most cancers. Some types may be higher others lower.

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    2. Thank you. I know about the breast cancer study, but I don't want to waste the researcher's time studying my multiple primary cancers if the science is already available. I've never been on any treatments.

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    3. So if MS patients have an increased risk of cancer, treatments and drugs trials will be dumped. Unless they know what caused the cancer, I can't see how anything will ever get approved.

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  7. Are you saying it is better for some of us to get cancer and then pull the drug?

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    1. I think he is saying that if you develop cancer it would have happened anyway. The drug is not the cause of the cancers; there appears to be no increase in risk of cancer due to the drug.

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    2. how does he know that for sure?

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    3. He doesn't. All he appears to be doing is quoting the data. It is not him speaking, but the data speaking. It is all about statistics.

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    4. My question was, is there increased risk of Cancer for MS sufferers? I would like to know, regardless of whether or not a person is having treatment.

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    5. I'm sure there were many who proposed that Tysabri was a cure also after short term trial results. But as we have seen trial results don't necessarily translate to real world safety. The same goes for Mitoxantrone.

      From a logical point of view, Cladbradine is used to treat leukemia which does create a higher risk for developing secondary malignancies. I applaud the FDA for rejecting this drug as well as Lemtrada.

      Cancer agents are not a cure, they are shortcuts. Fortunately, people are looking for a real solution such as those from Bristol.

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    6. Thanks anon 1.22. The point i am making is that the risks of developing a cancer if you are taking cladribine appear to be similar to that of other medications and this is similar to the cancer risk of life. In the claridbine study there were no cancers in the placebo arm in the ORACLE study there were more cancrs than in the clabribine arms.

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    7. Anon 10.27 If cladribine and lemtrada are approved for cancers then why not for MS too?
      The doses are higher for cancer and side-effects are worse but they are allowed because they save lives.
      Saving brains is as important as saving lives and many of us want something that will do that.

      We don't have time to wait for the 'real solution' from Bristol or somewhere else


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    8. "I'm sure there were many who proposed that Tysabri was a cure..."

      It is clear that if you stop tysabri that disease returns within a few week, so this is not a cure in my world view however if you are JC virus negative, you can do very well.

      With cladribine and alemtuzumab about 50% people at year 3 don't need more treatment
      is this a cure only time will tell. We know that if used later on then the both failed and progression occurs. We simply don't have the data.

      As to applauding the FDA (it does protect US companies from more competition after all)......I am sure many drug reps zagree (excluding Merck KGA and Sanofi) do applaud. However MSers however lose choice.

      There are many MS drugs that have a history in oncology rituximab anti-CD20, beta intereferon, mitoxantrone, cyclophosphomide, alemtuzumab infact only copaxone and tysabri have their history in MS all othe MS drugs are repurposed.

      Until we get specific treatments for MS there will be risks.All we can do is search for better treatments an help mitigate the risks. However they are some way away

      Likewise the

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    9. "If cladribine and lemtrada are approved for cancers then why not for MS too? "

      The difference is that MS is a chronic disease where many cancers are terminal. If you are waiting for a toxic drug to treat your chronic MS condition that is a shame since there are at least 10 treatments that you have a choice from.

      No doubt there are those with aggressive disease for which the approved therapies are inadequate, and I would agree they may benefit from oncology therapies such as HSCT, But for the majority of MSers these drugs are unnecessary.

      If you think these drugs are needed to restore disability, this also is a false assumption.

      What is needed urgently is a simple, foolproof test to identify those with MS so that they can be treated before progression sets in. Repurposing cancer agents gets us no closer to making MS a thing of the past. I guess this line of thought is a threat to the "MSologist" profession.

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    10. Where is the proof that any of the ten choices have different cancer risks. The point is that there is no difference between any of them based on the pivotal phase III trials. They all have risks some worse than others but in contrast there are marked differences in efficacy.

      "If you think these drugs are needed to restore disability, this also is a false assumption."
      The best treatment to restore lost function is not to let it happen in the first place.

      "Repurposing cancer agents gets us no closer to making MS a thing of the past"
      I am afraid I disagree repurposing is what pharma do for MS drugs........EBV can cause cancer.... so do we stop Charcot project before we start?

      "This line of thought is a threat to MSologists profession"

      They can only use the tools they have available to them so it makes largely no difference to them, however is does to the MSer.

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    11. Those who want to wait for a safe miracle cure that will halt the disease and restore disability are free to do so!
      The rest should have as much choice as possible and effective treatments should certainly not be denied

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    12. No one said you should wait for a safe miracle cure, the point is if you are looking at the results of a two year trial with the relapse rate as a measure of effectiveness this does not directly translate to longterm effectivness.

      This is looking at developing MS drugs from a statisticians point of view rather than trying to find the true cause and a cure that treats it. But as much money as there is in MS drugs, even the insignificant scientists need a piece of the pie and I guess repurposing cancer agents is a good racket.

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    13. If you think us insignificant research scientists are only in it for the money, then you are not only insulting but gravely mistaken. Our priority is and always has been to improve the lot of MSers and hopefully cure MS by whatever means that might be and if that means putting ourselves out of a job in the process, then so be it.
      The cost of Cladribine would be minimal, thus the pie would be small, which cynic as I am, may have a lot to do with the resistance encountered.

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    14. Some people feel the European regulators got it wrong when they licensed alemtuzumab, a re-purposed oncology drug. I wonder what Prof. Compston and the Reverend Dr Coles would say to being called insignificant scientists?

      Anonymous (11:04:00 am) clearly has little insight into the biology of MS and how drug discovery works in real life.

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    15. "This is looking at developing MS drugs from a statisticians point of view rather than trying to find the true cause and a cure that treats it".

      The genetics linked to susceptibility nearly all of the 159 genes point at an immune problem/ The solution treatments are targeting the immune component.

      Please tell us you world view. You are clearly very opinionated..what is the cause..This insight could save us twiddling our thumbs until their is proof of the cause.

      You missed a chance to ask this to neurologists and pharma talking about the subject in a live debate or were they too insignificant too?...

      Many of the drug reps were however too busy courting business to be there

      As for repurposing being a good racket....I think that pharma would agree because nearly all of their drugs are repurposed. This allows them to charge $40,000-$80,000 for a $1-2,000 drug. I guess you are happy with innovartion to continue to pay $50,000 plus forever.

      I'll ask Doctor Klaus for his repurposing slide. MS pharma are now even repurposing their own drugs.

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    16. I can understand why Team G has no clue as to the cause of MS, hence the initiation of the Charcot project. Fortunately the majority of MS scientists are on the right track. I imagine this is why redundant, dangerous drugs have been rejected by the FDA. Team G is an outlier in the MS field.

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    17. Your valuable input is most appreciated.

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    18. Your welcome. I doubt any open discussion will help you since Giovanni seems to have you on a tight chain.

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    19. Anon 3:54. I see little discussion from your end but merely insults.

      You are tarring the character of many people in Cambridge and many people involved in CARE I and CARE 2 and CLARITY throughout the world. Why do this?
      Sorry to say you sound like a CCSVI evangelist with your anti-pharma tack...

      I was speaking to Rev C about their repair trial, I suppose they should forget about repair as it must be on the wrong track. However luckily we do not all have a monoculture world view. Some people would rather try and fail rather than sit in their armchair and do nothing.

      P.S. Happy to be an outlier if that is what I am. There are too many lemmings in science

      PPPS. Thanks to Dr Klaus for adding the pharma way of drug development...yep repurpose, repurpose

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    20. "I'll ask Doctor Klaus for his repurposing slide. MS pharma are now even repurposing their own drugs."

      Done! (see above)

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    21. Well we are merely insignificant scientists. As your posts seem to be fact free, ad hominem attacks, an open discussion would be fruitless.

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    22. I don't see how repurposing an immunosuppresive drug is a cure. Of course this is going to have an effect on MS, since it is well acknowledged that MS is an autoimune disease (except for the yes men on the blog).

      So, lets just keep selecting immunosupprsive drugs and putting them through trials and eventually we will have a therapy that can be used when an MSer are diagnosed that won't have a detrimental impact on their health in the long run.

      Oh, and this drug can only be used on those who are not too far along as it has been proven over and over that immunosuppresion does not prevent prgogression once it has started.

      This is one way of looking at MS research, but is it the best? As stating, other "lemmings" are looking at a cure for the disease and our hope lies with them.

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    23. If the FDA get it wrong, Merck should have done the work to show them they are right.

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    24. Re: "I don't see how repurposing an immunosuppresive drug is a cure."

      Cladribine and alemtuzumab are not immunosuppressives; they are induction therapies that reboot the immune system with the aim of getting rid of autoimmunity. The fact they put a large proportion of MSers into stable long-term remission suggests they may cure the disease. Immunosuppressive drugs are taken continuously. Immune system rebooters are only immunosuppressive whilst the immune systems are repopulating.

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    25. For what it is worth I was treated with Campath 8-years ago and my MS is stable; no relapses, improved disability and no MRI activity. I may be cured; only time will tell.. I have developed thyroid disease and have to take thyroxine every day of my life; a small price to pay for the possibility of being cured and 8 years of very good quality of life. Dr Coles, my neurologist, is one of my heroes and to suggest he is an insignificant scientist is simply ridiculous.

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    26. Wrong, these considered immunosuppressive therapies that deplete the immune system enough to where a new system is rebiult. The same is true for HSCT.

      Watch the video by the lemming Dr. Bowen:

      http://youtu.be/1EMKoaBysOk

      As you'll note this treatment is not recommended for the average MSer. I think all of the lemmings will agree that restoration of self tolerance is the way to cure ms. Those on the fringe think it is directly caused by a virus.

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    27. "Dr Coles, my neurologist, is one of my heroes and to suggest he is an insignificant scientist is simply ridiculous."

      Once a cure that re-establishes self tolerance is introduced, he will be a footnote.

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    28. Campather - my experience is identical to yours. Dr Coles is my hero. I have an MRI every couple of years and hearing "there is no sign of any disease activity" is the the best possible news.

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    29. Re-establishment of immune tolerance is a holy grail for immunologists aiming to control autoimmune responses....we can do it very effectively in EAE. We don't all think about viruses.

      You presume to know what we think.. Please don't.

      Maybe you presume to think that you know what is the target for self tolerance. Maybe you think about shares in the immune tolerance approach you are so keen on or the company you work for or are so desperate to defend the science project you are working on. Hiding behind anonymous we'll never know

      However re-establishment of immune tolerance is to be applauded it has utility...this is not necessarily lemming like...you miss the point.

      However, until you can show effective self-tolerance to your target and it has a meaningful impact, then you either kill the field because of some misguided studies or you do the business and show it works...and we shut up and take notice.

      Immune tolerance has been around for some time, yet it has yet to deliver..why is that?
      It has had a number of false starts. Maybe what is round the corner are other false starts, maybe they will not be.

      People with MS must make choices that influence their future now. They can chose not to have an oncology drug, if it is an option, they can use a myelin mimic if it is an option. People can choose to wait until the grass is greener and hope that a better treatment comes along....however they may pay the price if they wait too long. Maybe they can't pay the price because existing MS drugs are too expensive and have to hope that something cheaper comes along. Will this happen?

      However ProfG is back from ECTRIMS and will slap my wrist for bothering to respond.

      Maybe the anonymous people posting above are just Sanofi/Genzyme reps advertising...or maybe, just maybe they are people with real life experiences of science in action. Maybe they a people who took a risk and are living with the consequence of that risk. Maybe they were glad to be given an opportunity to do something about their, not your, MS.

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  8. Jeez this is a crazy discussion. It's very interesting to hear about the personal experiences of people with MS on Campath, but the rest is a bit much for me.

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