Cladribine is not Alemtuzumab-Discuss

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During the COVID-19 your neuros have taken the cautious lazy approach> intitially in the UK neuros were told to: Stop, Stop, Stop the high efficacy treatments and cladridine as an immune reconstitution therapy has been lumped together with alemtuzumab due to laziness and a lack of appreciation of the different biologies. Alemtuzumab is not cladribine.

Cladribine is in my view one of the better treatment options in the pandemic and the biology is reassuringly simple.

May be the advice panels might want to read this paper

Potential mechanisms of action related to the efficacy and safety of cladribine.Baker D, Pryce G, Herrod SS, Schmierer K.Mult Scler Relat Disord. 2019 May;30:176-186.

It is here for free

https://qmro.qmul.ac.uk/xmlui/handle/123456789/55609

If you can’t read :-), then maybe watch these videos (part 5 explains how cladribine works (Part 1-3) are useful background

https://multiple-sclerosis-research.org/2021/01/bartsms-filmweek-part-4/

https://multiple-sclerosis-research.org/2021/01/bartsms-filmweek-part-5/.

P.S. Although made by the manufacturer of oral cladribine the content ideas were provided by ProkK & B.

This is a graph I made and showed the manufacturers of cladribine.

This graph in part explains the biology. The green means the cells have the cladribine killing mechanism and the red and yellow is an inhibitor of it. It is more simplistic than their version that had about five NT5 molecules I excluded the surface and the mitochondrial variants and then asked a chemist of the other cytoplamsic 5 prime nucleotiases whichh one would work on deoxy adenosine, that way I could focus down on a couple

So what does it predict (There may of course be people on the extremes of this view).

(a) Neutrophils and monocytes are spared…Innate immune system intact first line defence against infections including SARS-COV2 intact.

(b) NK and CD4 cells modestly effected so T cells intact and can help other cells to fight infection

(c) CD8 cells relatively unaffected, so anti-viral immunity is intact.

(d) B cells are mainly targeted but the drug is gone in a day and then the immatutre cells come back so you can make new antibody responses if infection of vaccination comes around

(e) Antibody forming plasma cells are laregly not affected, so established vaccine responses and protection from childhood diseases are intact. This element is speculation based on the expression of deoxycytidine kinase (target for cladribine) expression this drops as a B cell mature. Hope to get some evidence on this one, as soon COVID-19 allows.

(f) MS is controlled because the memory B cells are targeted and they repopulate slowly and arrive back into an environment where there is CD4 and CD8 T cell regulation, so MS is controlled. (Second half of the sentence is speculation)

A-D have been shown to be true, E is my spectulation First part of F has been shown to be true

Alemtuzumab is much more depleting. It is on CD4, CD8, B cells and monocytes

http://www.biogps.org

Monocytes can be depleted CD8 T cells are depleted for a Year, CD4 T cells are depleted for 18 months to 2 years. There is an infection risk shortly after infusions. This is largely not an issue with cladribine. Memory B cells are depleted (MS controlled) but the immature cells come back quickly and like cladribine the memory B cells are depleted long term and when they come back they return into a regulated environment. Plasma cells show remain intact once depleted. Cladribine is much more subtle in the depleting effect. I predict once formed antibody responses are spared as CD52 is weakly expressed on antibody making plasma cells

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Yellow is alemtuzumab and red is the approved cladribine dose, Green is dummy drug. You can see how much more the T cells are inhibited. B cells are more inhibited with cladribine as they recover faster with alemtuzumab, is this a reason why the No-evidence of disease activity after cladribine was beeter than that reported with alemtuzumab

Alemtuzumab is a good drug but it is not the same as cladribine. No wonder people are frightened of cladribine, because they will fear all the side-effects of alemtuzumab, which simply do not happen.

Part of the fear is because the key opinon leaders lack focus. I sat through a lecture the other night and there was an hour slide show of the clinical trial results and not one single piece of intepretation. People are making a career of saying it is this interacting with that and blah, blah, blah, blah, blah. They may have a large lab to feed.So people are and stay confused and don’t know what to do:-(

Once you say this is the important target for MS and this and that are important to prevent infection you know where to look and you can start to predict what happens and it is all very simple and avoids soiling your pants when something new appears. You can try and show the orignal idea is wrong and move on or you get more support that you are on the right track,

COI: Multiple. We have recieved honoraia from the makers of cladribine within the last 3 years.

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MouseDoctor

3 comments

Leave a Reply to Tommyboy Cancel reply

  • “Potential mechanisms of action related to the efficacy and safety of cladribine” is an exceptional manuscript. Spent the afternoon reading the paper, highlighting important sections, and taking notes. Several areas were well beyond my comprehension, whilst the graphs and figures significantly helped in understanding the discussion around DCK and 5’NT. This paper does an excellent job describing CLAD. Anyone considering CLAD should read this paper!……well, after watching Prf. K/B videos.

    I am now 100% convinced, CLAD provides a similar therapeutic effect to ALEM/HSCT, without some of the additional risks. By no means in CLAD risk-free; however, on the risk/reward scale, I choose CLAD over ALEM/HSCT. CLAD also seems to address a lot of the topics and concerns discussed on this blog, regarding EVB, deep tissue/CNS penetrant, secondary auto-immunity, risk of long-term suppression, memory b cells controlling MS disease activity, smoldering MS, brain atrophy, PML risk, COVID, and the list goes on.

    (1) “Following disease breakthrough, it would be feasible to re-dose”……..what type of re-does? A single course followed with a pulsed treatment four weeks later? or repeat the entire two course cycle?

    (2) “Therefore, it is important to be vigilant CLAD is adequately depleting, because without this action it is unlikely to be active”……..are basic lymphocyte subset tests sufficient or would more sensitive tests be required it ensure adequate depletion?

    Summary Outline:
    – Semi selective IRT
    – Long term benefit from short treatment cycle
    – Hits all the right marks, as in reduction of lesions, less brain atrophy, and fewer relapses
    – Small molecule, better deep tissue penetration (EVB?)
    – CNS penetrant, reduction/elimination of oligoclonal bands (only DMT that does this)
    – Pulsed 5 day treatment reduces the risk of secondary autoimmunity
    – Maintain protection from bacterial/viral infections, including childhood immunity
    – Low probability of developing PML
    – Short treatment cycle limits cancer risk and long-term immunosuppression
    – Impact on memory b-cells is significant and consistent with that observed with ALEM and HSCT
    – Block central T cell mechanism to control MS, without needing aggressive T cell depletion
    – Penetrates and acts in bone marrow, unlike the antibody DMTs
    – B cells repopulate in a regulatory environment
    – Avoids cytokine storms caused by cell lysis

    THANK YOU! THANK YOU! THANK YOU!!!!

    • Thank you…we asked for a donation for it to go open access but as Merck did not instigate or contribute to it they declined.
      I would think only one cycle but you have to ask ProfK what he has done with the subcutaneous cohort. This was presented at ACTRIMS n=250 number with a second cycle is about 200 NEPAD was 62% (95%CI 32-86%).

      Lymphocyte depletion look at least CD19 and best to do memory B cells, there is a massive range of depletion with cladribine if you just look at lymphocytes and many people dont appear to depelete lymphocytes but them look at B cell

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