How Does Cladribine Work?

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Here is a new offering from the CLAD lads :-), and follows on from the information that we got from the European Medicines Agency and from stuff in the public domain. This is not a pharma supported piece of work and they may have different views of how cladribine works or how they want to portray how they think this works, but as usual for us, it contains ideas of the unknown. Things we and importantly they can and should test.

This is our take on how cladribine may be working…it may be wrong, but it incorporates available data and does not follow the Treg-control of every thing dogma. It puts the T cell dogma into the perspective of the B cell reality….Ha Ha:-).

Some people may not be happy, as we have mentioned the content of published abstracts that they were on, but have not published, and interpreted their conclusions in a different way. Yep, there is now no need for them to waste paper as the essential information is out in a way that makes more sense:-).

I can see the moaning email winging its way to DrK.

You will notice this does not include ProfG, who will see this manuscript here for the first time too. He is a lead on the pharma view and we were sneaky and got and published the stuff that he could have published. So this way ProfG does not get his hands dirty. He may have additional takes on this story, as he has the inside information and insight that we don’t.

As to the people who may be upset…… “You snooze, you lose” they have have had ample time to publish the findings. Too much time going to meetings on pharma coat tails and not enough time writing I guess:-(.

Importantly this manuscript contains stuff that it appears academics seem to fear the most….Yep Opinion and Speculation. No wonder we get so many reviews that are a ramble of unrelated, supposed, facts that lack any insight:-(. This of course means that we get alot of scientific headless chickens running around

We have met this fear and need to accept and pacify dogma time and time again during the review process.

It suggests to me that many of these scientists would make terrible police officiers.

Why? They can see a dead Dr Black (UK)/Mr Body-John Doe (US) with a big knife in their back and a blood trail from the study. However, they are too frighened to say that the knife killed Dr Black, unless they see the video of it happening. Unfortunately nobody was there with a smart phone to do this, so they would you have to look at the evidence. God forbid that they could suggest that it was Colonel mustard, who did it in the study (Cluedo). Yet they are happy to accept and suggest that Dr Black dies from food poisoning, because of an altered microbiome, because that is what everyone else thinks should happen. They are happy to ignore the machete. in search of the antibiotic, whilst ignoring the problem with knife-crime. Sad thing is…they would have to stick a machete into someone to show that it can be a lethal weapon, before they can believe it.

Why is science a slow process?

DO NOT PAY FOR THIS ARTICLE!. IN A FEW DAYS I WILL POST A LINK THAT WILL GIVE YOU FREE ACCESS

Potential mechanisms of action related to the efficacy and safety of cladribine David Baker, Gareth Pryce, Samuel S. Herrod, Klaus Schmierer

Multiple sclerosis & Related Disorder

https://www.msard-journal.com/article/S2211-0348(19)30090-2/fulltext

Oral cladribine is a novel treatment for relapsing multiple sclerosis (MS). This appears to be a semi-selective immune-reconstitution therapy that induces long-term therapy from short treatment cycles. It has a relatively good safety profile that currently does not require extensive monitoring associated with some continuous immunosuppressive and relatively non-selective immune reconstitution therapies. The efficacy and safety of cladribine relates to its particular physicochemical properties, the function of the lymphocyte subsets that are selectively targeted by the drug and the repopulation kinetics of these subsets. As such, there is marked and long-term depletion of memory B cell subsets, which probably relates to the therapeutic efficacy. This is also coupled with a more limited, but likewise long-term, depletion of CD4 T subsets. There is limited depletion of cells of the innate immune system and modest effects on CD8 and probably plasma cells, which provide immediate and durable protection from infection. Targeting of CD4 T regulatory cells, CD8 T suppressor cells and regulatory B cell subsets appears more limited as these populations recover rapidly and so repopulating pathogenic cells re-emerge into a regulatory environment.  This appears to lead to re-establishment of immune-tolerance that produces long-term control of MS. Although this hypothesis contains a number of unknown details, it is based on knowledge about the biology of cladribine, basic immunology and the effects of other high-efficacy B and T cell depleting agents that exhibit stereotyped repopulation behaviours. These concepts are relatively simple to interrogate, and can be modified as new knowledge about the durability of disease control and safety with cladribine emerges.


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MouseDoctor

19 comments

  • So I still haven’t worked out what this is all about. On shift ms people seem to be on cladribine .
    Is it available on the nhs ?
    Is it for people with all forms of ms ? Some people with SPMS seem to be taking it ? It’s the randomness of all this that really annoys me ,

    • What would you really like to know?

      Oral cladribine tablets are available on the NHS. Stupidly the regulators restrict it to highly active MS. It is no more risky than alemtuzumab which has a liberal licence and is available to anyone that is active.
      This is for relapsing MS.

      Will it be useful for SPMS probably yes. Is it going to stop SPMS..in the short term no, as you need more than a treatment like cladribine.
      However it could be an excellent base on which to layer other things.

      Could i say the same for other treatments..yes

      Is it for all forms of MS… yes if there is evidence of disease activity. However the licenced version is currently for relapsings only. Maybe with more patent life they will now look into PPMS.

      The alternative is off label generic cladribine. Access to this may depend on your neurologist. We have a number of people with SPMS and PPMS on this variant administered via the NHS.

      DrK is hoping to get trial in people with advanced MS going. Its only taken six years so far to do something that os a no brainer

      • Thanks for the clarification. Really useful. Looks like not for me ! On a brighter note this new site is fab. Huge improvement and much more interactive and easy to use .

      • great post MD.
        Can you explain why some patients get cladribine as tablets and others as cub-cutaneous injections of off label? Is there a difference in efficiency or comvenience of follow on tests? In an earlier post I recall the sub-cutaneous injections were quite infrequent.
        Thanks

        • If you fit with the NICE/NHS England criteria for high;y-active relapsing MS you can have the cladribine tablet. If yu live the US these are not yet approved. If you slip through the cracks and are not eligible for treatment, we (DrK) has been offering off-label cladribine as an option to get something rather than nothing. He and this team have treated over 200 people

          DrK started doing this in 2014 and remember cladridine tablets were not available until the end of 2017. DrK has been cautious to limit the degree of white blood cell loss with the off-label variant and has got severe lymphocyte losss down to about 1-2% compared to 20-25% in the early studies and it is still about 10-12% with the de-risked approach in the current licened tablet. Whether this reduces efficacy is unknown as we have nothing to compare it two, however we are can see benefit such as by seeing reductions i, but this is done as a service and not as a trial. In terms of dose the subcutaneous variant about twice as much drug enters the system. So you use half as much. The subcutaneous route is a 15 second injection verses swallowing a for a pill. Monitoring requirements are minimal and is simply measuring white cell levels before the next dose. The number of swallows are about 3-5 a a mouth twice a year apart.

  • Can you explain how this mechanism of action differs from Ocrevus in terms of the cells targeted? Am I correct in saying Ocrevus targets the same cells, but is more effective than cladribine? If this the case why would I want cladribine when I can be treated with Ocrevus?

    • The simple answer is that they do the same thing but it leaves more of the T cell population intact. It does the same thing to the B cells. However with cladribine they can recover to fight infection with ocrelizumab they maintained in a wiped out state

      Is ocrelizumab better than cladribine. There is no good evidence to suggest this.

      Cladribine is a pulsed treatment leaving you drug free for 3 years
      Ocrelizumab is continuous. This may have some advantage but is offset by disadvantages.

      They are both give and forget drugs with limited monitoring. Cladridine is easy to administer and lacks infusion reactions

      I predict that you would not need to dose every six months,which is the time.bomb that ocrelizumab is probably creating. There are B cell controlled infections and these issues will arise sooner or later in some.people. The experiment is now ongoing as there has been massive take-up of the drug.

      The question is do you need T cell depletion for the durability of response. we need a trial to test this.

  • Thank you for this article. Looking forward to the full text.
    Could you elaborate on why Clad. but not Ocrevus restores this immune tolerance that you are referring, since the effect on other immune component is limited according to the abstract?
    Thank you

    • We dont know that ocrelizumab doesn,t. If you stop ocrelizumab how long does benefit last, we have data showing at least 18 months, with rituximab benefit appears to last for two years and longer in others.

      It could be that the T cells wonto become property tolerant unless they are depleted.

      Should i publish this data being hidden by pharma?

      • “Should i publish this data being hidden by pharma?”

        Yes, absolutely. Open access and open data is going to be mandatory in few years anyway 🙂

    • Also how about alemtuzumab. The data has been published in a.way.that you cant say howmany people are disease.free after 5 years nased on the phase iii trial

      • Hi,

        Thanks for posting!!

        Forgive me, I might be slow, but I didn’t quite understand why Cladribine is stated to be an immune reconstitution drug, while Ocrevus is not 🙂 Has cladribine been tested in ways Ocrevus has not, which had resulted in evidence for this? I read
        in a PPT slide package from a presentation Prof G held, that Lemtrada and Mavenclad was immune reconstitution drugs. Ocrevus was categorized with a question mark. So what does Mavenclad and Lemtrada has in common which makes them this?

        One last question; could it be a theory, that if one received multiple rounds of Mavenclad, more or less the entire immunesystem would be rebuild eventually?

        • Clad is given a a few pulses and the effect.lasts four years at least. Alem dosing.idea is similar one year of treatment and for 40-50percent of people thats it for years. For.clad we.will not.get the data soon nevause of the messed up development of clad. ocrelizumab is given continously every six months. According the company they would have us believe it lasts 6 months. I do not buy this and suspect it is an IRT as much as cladribine is. So the effect lasts longer than 6 months. I know this but the data has not been published but the concept has been replicated replicated. I promise you this information gap will change.

          So there maybe no difference between alem clad and ocre. However alem and clad get rid of T cells too. Is this important. It maybe.
          We need to do a study.

          Multiple rounds will probably lead to infectious complications. CLAD preferrentially hits lymphocytes but we know from other studies that with frequent dosing other cell types get.it. indeed a cladribine like variant is used in HSCT.

  • Thanks for the update MD look forward to reading latest paper. Maybe one day someone will agree to risk Rx me off-label C. Clock is ticking….

  • I’ve just read the whole paper (one of the perks of academic access, I guess). Really interesting stuff! Although, a lot of info in it was kinda already there if you read “between the lines” in comments and several other papers/posts on this blog (not the toleration effect on memory B cells though, that theory is novel to me.) Now it’s all clearly written and referenced.

    I do have some followup questions:
    – “The effect of cladribine tablets on the oligoclonal bands remain to be established.” Why do you think that tablet version of Cladribine won’t have the same effect on OCBs as other routes of administration? It all boils down to concentration in plasma and subsequent penetration in CNS. Why would it be different?

    – ProfG was suggesting in some other comment that Cladribine’s effect of getting rid of OCBs needs to be confirmed as it was suggested berore

    Btw, a big big thank you to you and everyone at Barts. If it wasn’t for this blog, I know it

    • Clad and subcuataneou clad wont be different as the dosing is essentially the same, but the referee wanted use to highlight what we think we knew and what we were speculating.

      In the polish study the oligoclonal bands disappeared in over half the people treated but this was looked at 10 years after treatment. Based on the level of the enzyme that leads to the depleting , it is low in antibody cells so we predict it will not kill plasma cells directly so removal of oligoclonal bands may be slow, we are on this case and we have CSF from people treated months earlier.

      The B cell regulatory effect is a hypothectical. The repopulating B cells make IL-10 and so the T cell biologists call these regulatory B cells because IL-10 control T cells. However I personally thing the IL-10 is there not to suppress T cells but to make B cells grow

      • “The B cell regulatory effect is a hypothectical.”

        ” alemtuzumab, rituximab that does not target plasma cells directly and even haematopoietic stem cell therapy (HSCT) do not readily target the oligoclonal bands of immunoglobulin, which typically persist following treatment”

        Sure. But if it turns out to be true, this could mean that Cladribine is better than other high efficacy DMTs, especially if you take into account its good safety profile. Am I reading between the lines correctly? Is this why you hinted that Pharma won’t be happy with this explanation/theory?

        Will ProfG’s comment on this paper? I’m really curious about his take on this.

        • Cladribine is a high efficacy, but not a very high efficacy DMT. Its impact on brain volume loss in after 6 months in the CLARITY trial was moderate.

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