Cladribine for MS – Merck back on the road to licensing


So now it’s official: Merck’s submission to the EMA for marketing authorisation of their oral Cladribine preparation (Cladribine tablets) for treatment of people with relapsing MS has been accepted. The EMA may now take approximately 15 months until a decision is out.

Many of you are aware we have been working hard during the ‘gap years’ Merck took from Cladribine after their first applications to the EMA and FDA were rejected in 2011 to keep the drug on the menu as an option for pwMS given its unique combination in terms of (i) efficacy, (ii) convenience, (iii) safety, and (iv) cost. Whilst there’s little controversy about – but since publication of ORACLE MS a rather significant boost of – (i) + (ii), rest assured there will be much discussion about (iii) + (iv). 

The EMA will naturally focus on safety & (confirmation of) efficacy, and yes we take some credit (and hopefully a couple of impact statements in our REF return) should the rapporteur this time around take into account our independent meta-analysis when reviewing the cancer figures. Six years ago the panel included some uncontrolled data to support their claim of an increased cancer risk, which I doubt everybody was and remains happy at the EMA.

We can also expect some further papers finally seeing the light of day that weren’t completed earlier as Cladribine operations at Merck ground to a halt after the rejection in 2011. See ProfG‘s and MouseDoctor’s recent comments for a little preview.

Provided the EMA gives the green light, cost of the drug in the UK will obviously be down to health technology assessment (HTA) by NICE.  No doubt teams at Merck are already beavering away at how to price Cladribine “Tablets” such that it will be acceptable for the NHS. Remember NICE HTA will have to ignore the fact that a subcutaneously injectable version of Cladribine – on which the dosing of Cladribine tablets was designed – is readily available on the shelf, in the UK for £165 per 10mg vial…

Will approval of Cladribine tablets change anything for people with deteriorating (“progressive”) MS?  I’m afraid absolutely nothing, certainly not in the short and intermediate term, other than in a small number of centres that are prepared to use subcutaneous Cladribine off-label. For large scale use, certainly in high cost health care environments, we need more trial evidence than what has been produced in the 90s (for references check here).

Will there be funding for a trial of Cladribine in people with deteriorating MS, the forgotten thousands for whom there is nothing?  Where even Ocrelizumab or the MS-SMART drugs (if successful) may not be used as the trials conducted have not focussed on upper limb function, swallowing, cognition and included people with an EDSS >6.5?

I don’t know, but we have decided to give it go by designing a trial doing exactly that: Including people with an EDSS of 6.5-8.5. Why Cladribine? Because inflammation continues throughout the disease. Cladribine is CNS penetrant, may therefore be able to stop ongoing inflammation and thereby preserve function.

Merck will only invest (will they?) in such a project if Cladribine “tablets” are approved, but are public funders and donors out there prepared to invest now thereby enabling us to take a shortcut instead of twiddling thumbs for 15 months and with uncertain outome?

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  • "Merck will only invest in such a project if Cladribine "tablets" are approved, but are public funders … out there prepared to invest?"

    So you want me (Mr. Anonymous) to take all the risk and invest in a proof-of-concept for Merck to reap the benefits with no profit sharing agreement whatsoever?

    • Volunteering for clinical trials offers no profit sharing but is so vital to the drug development pipeline.
      I have spent the day asking about recruitment to trials. Without people volunteering there would be no progress.

  • Am glad that this is heading in the right direction, but 15 months is a long time. Why was Ocrelizumab fast tracked by the FDA and this is in the slow lane. Is it due to the progressive indication?

    I look forward to the day when the newly diagnosed RR people get a prescription for a course of tablets and they are unaware of how things used to be.

    • Yes you are right ocrelizumab gets the fast lane because there are no treatments for progressive disease, this may help carry a decision of ocrelizumab in the middle lane as one thinks they have to see the RRMS data to offset the cancers in the single trial 9 verses 0. For cladribine it was 3 verses 0 and it was sunk for these 5 years. CLAD gets the slow lane as it is a re-assessment not a new one but how long does it take you to read a hundred thousand pages, that's what the last one was.

    • "there are no treatments for progressive disease"

      Because of the obsession with B and T cells…? And Ocrelizumab only helps _some_ people with progressive disease to _some_ extent.

      #Sigh# We need more MD2s with ideas about treating microglia.

    • Insects survive without lymphocytes, but they have macrophages. Is there anything that is really specific for microglial that wont mess up other macrophages otherwise expect side effects.

    • Well, I'm no expert, but MD2's ideas about NSAIDs are really interesting I think.

      All current B & T cell busters, i.e. current DMTs have side effects, some of them potentially lethal. To take them for progressive MS such as mine doesn't seem such a good idea. If something is going to have side effects, it should at least work.

    • FDA Breakthrough Therapy

      2) What are the benefits of a breakthrough therapy designation?
      Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

  • Would you try crowd funding this trial? I believe there are many people who read the Blogspot who would want to help fund such a trial – I definitely would.
    There are many people who read the Blogspot who believe that the doctors at Barts are helping people with MS in a way that no other doctors are. I think you got a flavour of this when you tried to close the Blogspot. We (your readers) want a chance to help you help us (and to help people who will get MS in the future).

    • This would be great i don't know the costs per person and the number required but we would need to be innovative. However it would be good to give people a voice. Given the right people it can't fail to be of some benefit. I know of one case where post-stopping a progressibe trial and drug supply withdrawnthe, brain lit up like a Christmas tree with new lesions. Was treatment regression to mean or NEDA who knows but giving people access to something rather than nothing has got to be worth a shot.

      However todays news on the return of oral CLAD makes it much harder now as it creates a split. ProfG in the red (pharma) corner and DrK in the blue corner although they have batted in both corners over the years. However the conflicted element increases and will get worse once CLAD gets licensed.

    • Cordelia, crowd sourcing, charity, public funders, donors – all options are on the table, perhaps in combination. If you read the funding section of MS-STAT, the phase II Simvasatin study, this is exactly what happened. We really appreciate some readers are in the position & willing to support this, and our plans for a "BartsMS Charity" are at an advanced stage.

  • For a trial we maybe able to get the costs of CLAD down. We simply can't get the study done to get a licence as the costs are simply too great we have to create a weight of evidence and hope that common sense prevails and you get adoption but as we have seen even pharma struggle to achieve this for some of their products.

  • Excellent news about CLAD being back in contention.
    Am I correct in thinking the previous trial application was with the injectable kind? Surely trying to 'tabletise' this would mean back to the drawing board for any trial as taken orally rather than injectable would introduce a huge number of variables into efficacy / potential side effects previously not encountered / does stomach acid eat it ?

    • Tracy, the largest trials (CLARITY, ORACLE MS) were undertaken with the oral (tablet) version of CLAD. Previous trials were done with injectable CLAD. Given injectable versions came off-patent, Merck-Serono were searching for a way to make CLAD patentable (= profitable) again. This was achieved by manufacturing the pro-drug of CLAD as a tablet, which provides 42% bioavailable CLAD, i.e. 42% or ingested drug appears in the blood; injected CLAD is 100% bioavailable. We've met with the MHRA three years ago to confirm *bio-equivalence* between oral and injectable CLAD, i.e. there is no difference in the drug as such whether used as a tablet or injection. The difference in dose required (due to different bioavailability) can be solved by applying a simple rule of three.

    • Dear Dr Schmierer
      1. What are your thoughts about purchasing Cladribine on line from the USA ?
      2. If there is no active disease in a PPMS patient, would you still advocate Cladribine therapy ?
      Thank you.
      Sent 2/7/2017

  • Dear Dr

    My wife has PPMS and has been on a trial of Alemtuzamab ( 4 annual doses ). She is experiencing a slow but progressive debilitation and I fear will be in a wheelchair within the year. Her neurologist who is unquestionably the most excellent physician and at the cutting edge ( I don't say this lightly ) of MS research has told us that as she has no current inflammatory lesions, another type of medication, e.g. Cladribine will be of little value. I am desperate for her to try anything and having read the articles published, am mindful to buy the drug on line in the USA. Please give me your thoughts on Cladribine in her situation as well as what your thoughts are about purchasing the drug on line.
    Thank you. Yours sincerely Dr C. MBChB

    • If you can travel Atara is starting a clinical trial now
      for progressive ms this would be your best option if you
      could get in.

  • That there has been 4 doses the first question I would ask, was alemtuzumab working?

    We have identified that some people do not deplete after the first injection, then there are people who protralizing antibody responses and the drug can stop depleting or depleting only partially.

    However as was originally shown alemtuzumab does not stop progressive deterioration and so some elements do not stop in response to immunosuppression.

By ProfK



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