Thursday, 9 November 2017

#MS News. NICE being Nice for a change. Oral Cladribine now available on NHS in England


Although I have been accused of being a Merck Stooge, this is not the case. 

I believe TeamG can be proud of their involvement in the development of Cladribine. 

ProfG was at the forefront in being the lead investigator on the Phase III CLARITY trial in 2010. 

After Merck Serono dropped the reigns in 2010, they were picked up by DrK and ProfB and they kept the drug in the public eye, until Merck reawakened their interest in Cladribine in 2015/2016. 

ProfG was at hand to assist Merck in navigating the EMA and as you know oral cladribine was recently approved within Europe.

We had a presentation at ECTRIMS2017 showing how cladribine works.

We discuss it, because it is our research.

Anyway So now you expect that it will take NICE a year or two to give the approval. However you would be wrong. NHS England has entered into a commercial agreement that allows NHS patients in England immediate access to the drug. Yesterday doctors within England have been given the greenlight to prescribe oral cladribine. 

The other Home nations will hopefully follow soon.

This is the first MS disease-modifying therapy that has gone straight to a positive final recommendation in the NICE appraisal process, involving just one committee meeting. NICE seemed to conclude that cladribine tablets are less costly than other treatments and require less frequent dosing and monitoring requirements. Therefore, they appear to believe that it is cost-effective

So this is good news for People with MS and also for TeamG because their work will have clear Impact.


It will now be interesting in what happens with ocrelizumab and how NICE will handle its appraisal.

CoI: None...yet...ProfG and DrK multiple

34 comments:

  1. Wow, great news and thanks Team G for your hard work!

    What is the oral cladribine protocol? Do pwMS take the tablets at home or at hospital with MS nurse?

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    1. Home delivery + patient support (phone calls, video, app, the works)

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    2. Gosh so many drugs to choose from and all the top five have simliar efficacy. Is Alemtuzimab still the most effective? Does this also mean Ocrelizumab has missed the boat in UK?

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    3. Top five have similar efficacy......you forgot HSCT?

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    4. Nope. I haven't. I Don't think the technology is mature enough YET. Sorry, 0.6 death rate is too high for me and besides. It's taking a sledge hammer to crack a nut.

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    5. Where are you getting 0.6 from? Hsct death and secondary AI disorders, liver damage all still lower than HSCT.

      Sledgehammer? There was an article on this site explaining exactly why reversing the pyramid is vital to best ms.

      When will you understand that it is precisely HSCT's protocol that beats ms.

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    6. Hi beams. Get most info from neurologist. Wasn't NHS suppose to finish phase 3 trial soon? Hey if NHS says i should have HSCT instead. I will definently sign up for it!

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  2. good news indeed. Well done, to all involved.

    As a tysabri patient, while grateful would really like life without the monthly infusions.

    2 questions

    1) how does Cladribine compare to Tysabri (and the other DMTs for other readers benfit) in terms of effectiveness, % of reduced relapse rate and progression rate ?
    2) what would be the method of going from Tysabri to Cladribine? would a washout period be needed?

    I am JC-, but want to improve QOL by reducing visits to hospital.. and also, consider longer term, could become JC+

    Therefore, does it make sense to avoid a rebound effect, and switch over quicker?

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    1. All we can say is, there is data in MSbase comparing real life data but this is based on 30-40 people there is no real head to head.

      In terms of transition mabe ProfG or DrK will comment but they prefer to bridge people to reversible treatments to be safe

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    2. Thinking about the effect of ALL the current DMTs on brain atrophy and hoping you may have recent data to be able to compare which have the most impact on decreasing the loss of brain volume. If possible, an up-to-date list giving percentages would be so helpful - especially interested to find out how Cladribine and Ocrelizumab compare with Alemtuzumab and Natalizumab. Thank you.

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    3. If you are on remission while on Tysabri, then you are not allowed to get Mavenclad. Is this somehow going to change?

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    4. I second the question above regarding brain.

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    5. One problem of exploring te available data is that often the populations are not directly comparable eg in alemtuzumab mean disease duration was about 2 years verses 4 years in the CLARItY study. So in one you have lost an extra 2 years of brain reserve. t would be good to have head to heads

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    6. Hi MD, But your making the following assumptions:-

      1) All patients get diagnosed at the same time. Not true.
      2) All MS progression is at the same rate. Not true.
      3) All patients repair damage at the same rate. Not true.

      So by stating populations were different is generally not true. Also there is therapeutic lag with Alemtuzimab since white cells repopulate at different rates. And yet it still out performs caldribine, Ocrelizumab. I don't want to sound like a nut pushing for therapy but just pointing out to use this as reason for difference in efficacy is like grabbing the lowest hung fruit.

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  3. Will it be classed as category 1.2 or 2.0 ? I read on the NICE committee papers
    ' It is not currently known into which category Cladribine Tablets may fit or whether a separate category may be required. ' Does this still stand?

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    Replies
    1. It can be first line in highly active people or in treatment failures, I think

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    2. What about ABN category (Association of British Neurologists), either 2.0 for Highly effective (as with Tysabri or Alemtuzumab) or 1.2 Moderately effective (as with Fingolimod/Gilenya)? As on the MS Trust MS Decisions Aid website.

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  4. As a new patient, why should I take tysabri at all? I now have 3 other treatment options that don't seem to have a significant PML risk.

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    Replies
    1. Perhaps because you may not one your immune system to be suppressed (long term cancer risk).

      Rituximab is a real threat to Tysabri mind you.

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  5. Woah! Another DMD. Man, that's made my day. I'm sure everything's going to be much better for pwMS now. Phew.i was worried that we were just going round in circles with low efficacy poisons.

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  6. In terms of emerging treatments, how to cladribine and rituximab (or ocrelizumab) compare?

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    Replies
    1. I believe they have essentially the same mechanism of action,

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    2. I found it helpful reading Dr Giovannoni's post from 2nd Feb this year titled 'Cladribine and end-organ damage'; clearly states that Cladribine is safer than Ocrelizumab but not as effective.

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    3. Two more useful posts about Cladribine written by Dr K dated 13th and 15th January 2016 - interesting comments make Cladribine sound very promising, perhaps more so than Ocrelizumab? I suppose time will tell.

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  7. So still nothing for people with advanced MS, disgraceful

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  8. Would it be a wrong pattern to start with cladribine that penetrates the brain and continue with Ocrevus or similar when there will be no danger of lymphopenia? Wouldn't that be a more whole process?

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  9. 'In the summary of product characteristics the recommended cumulative dose is 3.5 mg/kg body weight over 2 years, taken as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, 1 at the beginning of the first month and 1 at the beginning of the second month of
    the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient takes 10 mg or 20 mg (1 or 2 tablets) as a single daily
    dose, depending on body weight. Following completion of the 2 treatment courses, no further cladribine treatment is required in years 3 and 4'(NICE).

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  10. But if people follow the advice (on here) and use fingolimod as a bridging treatment, they can end up with B cells in their lymph glands. Cladribine doesn't get into the lymph glands and is gone by the time the B cells emerge. Result: horrible rebound relapses a few months after taking Clad.

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    Replies
    1. Pretty sure cladribine would enter lymph nodes if it is also able to cross the blood:brain barrier.

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    2. Why then do some people not see their B cell count reduced (much) after treatment with Cladribine? Does anyone know? And are the people who still have a near-normal B cell count after Cladribine the same ones for whom the drug doesn't work?

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    3. Most people on cladribine get a normal B cell count....however that is a CD19 B cell count. However, this is a composite of 4 or more different cell types. Once you get B cell depletion you have space filling of the blood by immature B cells exiting the bone marrow, giving you the impression that all is back to normal.

      However, we are finding that there is a subtype of B cells that are dramatically depleted for a long time. We think that this subset of B cells is key to the action of cladribine and other DMT.

      The next question is does depletion of the subset correlate with disease activity. The answer is we don't know yet.

      We have recieved supoort from the MS Society to look at this issue and I am sure Merck will address this too.

      Next question is, are their people who do not respond to cladribine, clearly the drug does not work for everyone, and it may be that this B cell subset comes back quickly. This is seen in some other conditions after B cell depletion, dictating the requirement for a new dose.

      Next question is are their people who do not respond to cladribine, I am told there are some such people and investigating this is on the to-do list. We need to identify such people. We have found alemtuzumab non-responders.

      The protein that determines the activity of cladribine is called deoxycytosine kinase and there are loss of function versions of this gene I can see about 6 ways this occurs but these variants are very rare e.g. 0.00001735 this is about 2 people in 100,000 have one copy so that would be one in 10 billion people would be loss of function mutation. There are some (missense) variants that could effect function and occur at a frequency of 15/60,000 and 44/60,000 so that is 3 in 2,000 people,


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    4. But if people follow the advice (on here) and use fingolimod as a bridging treatment, they can end up with B cells in their lymph glands. Cladribine doesn't get into the lymph glands and is gone by the time the B cells emerge. Result: horrible rebound relapses a few months after taking Clad.

      Cladribine takes time to kill every thing, but as it is a small molecule it will get into lymph glands and there is no evidence of a rebound a few months after cladribine in people bridged with fingolimod. I don't think I know enough to say there that it is not possible.

      In the oRACLE trial is was evident that most relapses occured within the first three months of treatment but our data indicates that it takes 2-3 months to have a full depleting effect.

      Next I am not convinced the action of fingolimod is in the lymph nodes, I think bone marrow may be a better explanation.
      I also thin

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    5. I was a cladribine non-responder. I had a bad relapse six or eight weeks after having two sets of injections of clad (a month apart). Please get in touch if you do get round to analysing non-responders. Dr K knows who I am - I never had the next set of clad, because I went back on fingolimod.

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    6. Also wanted to put in this quote "The therapeutic efficacy of cladribine was associated with a sustained reduction in lymphocyte count." That came from "Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study" and I didn't have a sustained reduction.

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