Friday, 24 June 2016

#Cladribine4MS - effective disease modification for all, even (or particularly?) after Brexit

After oral Cladribine was dropped by Merck Serono in 2011, we identified other sources of Cladribine and developed a UK network of over 30 MS neurologists willing to try and do a head to head study with Alemtuzumb, with a view of licensing generic Cladribine.

This was not funded in 2014/15 partly on the basis of considered lack of need and the cost of the trial: Though £32,000,000 would have been saved for the NHS by doing the study our request was £2,000,000 above the ring-fenced budget that British Science (NIHR) would fund.

Since that time, with the failure of the repurposing bill, UK Government ministers have asserted that generic Cladribine can be prescribed off-label.

video

Based on published data, Cladribine is as effective or more effective than current MS DMTs.

It is just as safe (or safer) than current highly effective agents and not known for the development of PML or autoimmunities characteristic of other MS drugs.

It is as convenient (or more convenient) than any agent, requiring only a few cycles of administration a year, and after just over one year you monitor and wait & see whether you remain NEDA or re-dose, compared to monthly monitoring for drugs such as teriflunomide or alemtuzumab.

Cladribine is the only MS DMT that is CNS penetrant and has a mechanism of action that can work inside the CNS. It targets dividing (like beta interferon, teriflunomide, DMF) and non-dividing lymphocytes and may kill plasma cells (antibody producing cells). We know that targeting lymphocytes is beneficial in MS, because HSCT can be very effective.

This sounds like good news for Merck (Serono no more), who claim they are going back to the regulators to get their oral version licensed for relapsing MS, yet we have heard that for about 18 months now with submission still being "imminent", confirmed as recently as yesterday...

I am also told Merck might try hard to keep the price at a reasonable level should a license come their way, but is this likely I wonder?  More likely this will be priced in the region of current MS DMT, i.e. 20-30 times the cost of generic subcutaneous Cladribine, of which all gets into the body (100% bioavailability) compared to only 42% of what is ingested with the Cladribine pro-drug pill, which is converted to Cladribine after digestion.

Cladribine could be cost effective alternative for resource strapped healthcare settings, such as the UK.  Current MS drugs cost about $50,000, multiplied by 5 years thats $250,000 for most MS drugs, for some it is more. If you are NEDA after only 1 course of Cladribine that could be $350 - $1000 depending on the source. In the UK one course costs about £1600.

How about creating access to an effective DMT for the 300,000 or so pwMS on the planet whose annual income is lower than the annual cost for a DMT (and that is for the least efficacious brands)?  ECTRIMS, ACTRIMS, PACTRIMS, MSIF, MS Societies of the World - anybody interested?

That aside, Cladribine may still be a useful approach for people with progressive MS, who have slipped through the current DMT net, and this is where we can focus our energy in the UK to give people with nothing an alternative to nothing.

Please tweet the Video: https://youtu.be/Yk7_JpK33i4

I’ve tweeted the link earlier today, so you could just retweet that if you prefer (https://twitter.com/KlausSchmierer).

+++ Latest Brexit News +++ Withdrawal of video considered as according to LEAVE campaign leaders now £350 Million/week extra for NHS available +++ Apparently, The Palace considers overuling referendum due to concerns over new Scottish exit vote +++ As a result video remains available on Youtube until further notice +++

19 comments:

  1. Professor Schmierer I think you are over-hyping Cladribine; we simply don't have the long-term data to support widespread prescribing. Creating unrealistic expectations is something you should try and avoid. Please be careful.

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    1. Long term data by their nature will only emerge with use. Those with no access at all will certainly appreciate having an option to decide for/against if the alternative is just a void.

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    2. Merck how have 8-year safety data from their register that is being submitted to the EMA. If there was a safety signal they wouldn't be resubmitting an application to get cladribine licensed. It is a pity that there is no long-term efficacy data from this cohort.

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  2. I had Cladribine six weeks ago and I'm already seeing improvements. They will sound small to other people but they are huge to me - bladder control returned, being able to walk upstairs without having to use my hands to lift my legs. Everyone with MS needs to know about Cladribine. Everyone with MS needs to know which neurologists can prescribe this drug - I thought it was only the doctors at Barts. Please let people know where else they can go to get this drug.

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    1. The information sheet we're using as part of the discussion about use of the drug can be found here: http://multiple-sclerosis-research.blogspot.com/2016/01/bartsms-off-label-cladribine-use.html
      We'll release an updated version in the near future.

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  3. An enjoyable and informative post - thank you. This is exactly why this blog is so important - this is not standard or easily accessible information but may provide another treatment avenue for some people to explore. Without this blog I would not have been aware of cladribine. Feeling more informed once again thanks to you.

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  4. Excellent post thanks. If Cladribine, a form of chemotherapy, is a very good CNS penetrant and works on all lymphocytes, including plasma cells, in the brain then it should work extremely well on all forms of MS, including any progressive MS patients? That is if, in fact, there is an autoimmune force of B and T-cells are driving the progression of MS. I think the working hypothesis as to why RItuxan did not work in progressive MS by Dr. G. was because of its poor bioavailability in the brain that it did not fully inhibit B-cell activity, including plasma cells.

    Are there any trials that have been done so far in Cladribine on MS progression or SPMS/PPMS? If it does not work on stopping progressive MS, is this not a major "dagger" to the hypothesis that progression of MS is autoimmune or at least B or T-cell related?

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    1. Re: "If Cladribine, a form of chemotherapy, is a very good CNS penetrant and works on all lymphocytes, including plasma cells, in the brain..."

      Cladribine has reasonable penetration into the CNS, CSF levels are about 40% of blood levels. We don't really know at this stage what effect it is having on intrathecal B cells and/or plasma cells. We hypothesise that it is having effect and want to study this in detail in the future. The trial of cladribine in multiple myeloma (malignant plasma cells) was in combination with another chemotherapy drug.

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    2. Re: "Are there any trials that have been done so far in Cladribine on MS progression or SPMS/PPMS?"

      Yes, one trial in SPMS, but it was too short to give a definitive answer. The trial was also done in an era when we didn't know how to design and run progressive trials. We are planning a trial of cladribine in SPMS. We will need to get the community behind this trial so that we can get it funded.

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    3. I, for one, am very keen to donate for a good trial on Cladribine and SPMS. The sooner, the better. Tell us if there is any more information about this that we can share on MS chat fora. I've posted links to this Blogpost on a couple already.

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  5. DRK I sent, there are 2 months, an email to the largest Association in Brazil, called ABEM, and I was disappointed with the answer given by the Neurologist part support team of the ABEM.
    She said that "admired the efforts of Barts-MS team in try an alternative therapy more efficient and cheap for the disease, but that there are no studies sufficient supporting your use for treatment of in!".
    I explained the email saying "as well there are no studies enough about the Cladribine as alternative therapy out of market for EM?! Since the Merck Serono announced in AAN 2016 the end of the phase 3b of studies with Cladribine in the oral form form(so that Merck may have the patent on it, since the substance itself is generic), and will have the release of marketing to the end of the year (the request has been made to EMA)..."
    Or the Neuro wanted "out by the tangent" or she is outdated about what is happening in scenario of EM, even giving support an Association facing individuals with the disease...

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    1. The question is when is enough enough - How many trials for how long with which outcomes will satisfy neurologists to prescribe a drug, and is this identical with the level of evidence required to convince regulators to give the drug a license for the indication MS? It is increasingly becoming clear the answer to this question is often yes, but sometimes - such as in the vase of Cladribine - it is no. And posing the question itself assumes a company bothers taking a drug to the regulators, which usually implies a patent and the expectation of a large price tag as otherwise companies (and their shareholders) don't have an incentive to invest. Until recently this applied to Cladribine - why is the commercial project resurrected now? No new trials have been undertaken, and to establish risk the follow up achieved now better judgement by the EMA in 2009/10 would have helped. 3 years later a different drug with significantly higher risk was licensed. Why? Because a different assessment panel perhaps combined with a more convincing team supporting the application were involved, and MS seen for what it is: a bad disease for which those affected are prepared to take a risky drug.

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    2. Oral cladrine was licensed in Russia and Australia but without a generalised licence neuros are cautious and some are cautious about prescribing off label. It gives risk-adverse neuros an option to do nothing

      Some people (cant say who) think that only pharma drugs should be used in resource poor countries and off-label drugs should not be used as they may be considered unproven and substandard.

      If oral CLAD gets approved would generic clab be considered substandard? If you drink the generic clad version you get half the amount of clab from intravenous and subcutaneous the same as if you take movectro but you cant drink generic cladribine as this route is patented

      There are numerous studies but only the one published trial for oral CLAD. The oracle trial which was positive in optic neuritis was apparently done in a way that it could not be the second phase iii. There is another trial of CLAD vs interferon not completed or published exceptin abstract form.

      If movectro is approved by EMA/FDA, if it ever gets submitted, then neuros will probably stay clear of generic CLAD too.

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  6. I read someone's comment here that is already dealing with the Cladribine and it was very realistic. Realistic as well as part of someone with the disease and is already benefiting from the beneficial effects of the drug and having a bit of their autonomy returned. This is one of the things we want with the disease. DRK isn't crowing, it's just reality.
    I know that scares a little know of a cheap drug that was there in front of everyone, and that can implode an entire market created around a disease. Side effects? All medicines on this planet Earth have? Does anyone here know of cases of cancer in fingolimod, or the first case of stomach cancer in a patient who was a 07 years with Tysabre? Or cases of Lupus in Interferons? All these data came as these drugs were being used by patients. More data on Cladribine will be provided as it is being used, prescribed, I think this is clear.

    It is all drugs have a side effect, but all I have researched so far the costs and benefits of Cladribine are much higher than those of other DMTs. What is depressing is to have MS and have not yet realistically effective alternatives to treat the disease and live with quality...

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489670/

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  7. Very keen to see this trial happen. Do you have any details yet - hypothesis, outcomes, control, in/exclusion criteria etc?

    How do we show support and to whom?

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    1. We have the draft design including sample size & outcomes. It will be key to discuss a few aspects of this to make a strong case for potential funders given their limited number and resources. I will post on this shortly.

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    2. Thanks for this, I look forward to hearingmore about the trial - good luck with the design, funding etc. Good to hear you speak about it at the UCL research day best wishes Bouncy

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  8. can you please provide a copy/link to trial involving this drug? Not an open label trial either? I've seen very few Neuros mention this drug yet the way you talk about it you seems to think it's the best MS drug out there?

    If it does get an MS licence it will go the same way as Campath did, the 'MS' price will be 10's of thousands of pounds.

    Is the drug as efficient as HSCT? If not then why not push HSCT as hard (as the most effective MS treatment) as you do Clab which is inferior? (Is that not better for patients - the best/most effective treatment, not one that is not quite as good but cheaper?!?

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    1. I doubt cladribine is in the same league as myoablative HSCT based on published results but nor does it have a 0.5-4% risk of death due to treatment.

      A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ; CLARITY Study Group.N Engl J Med. 2010 Feb 4;362(5):416-26.

      Why not push...we push what we can do we do not HSCT

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