Understanding cladribine. ChariotMS

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As you know ProfK is a CLAD lad and we are gearing up to start ChariotMS with us going to use oral cladribine.

Today I give you a link (See below) to a review on cladribine and as a COI The content has nothing to do with me.

If you are considering the trial, make a cup of tea and you can read it for the next few minutes. Hope it doesn’t act as a sleeping tablet, as it is quite long. But it gives you background data on the drug.

The Development of Cladribine Tablets for the Treatment of Multiple Sclerosis: A Comprehensive Review. Rammohan K, Coyle PK, Sylvester E, Galazka A, Dangond F, Grosso M, Leist TP.Drugs. 2020. doi: 10.1007/s40265-020-01422-9

Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule’s ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing-remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS. The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review 

So as you know there was writing support from the manufacturer…which to me says it was written by a professional writer paid by the manufacturer and then given the OK by the authors. As it has pharma support there is no integration of the knowledge and no speculation, just a sea of facts.

As such they can’t explain how cladribine works, in my opinion, as they don’t mention immune cell subsets, despite our speculation reported in 2018, shown to be consitently true in an increasing number of published real-life studies.

I think the explanation is rather simple based on the expression of the molecule required for the action of the drug (mainly deoxycytidine kinase) and the function and repopulation characteritics of the immune cells affected.

ProfK and I have been involved in the generation of some vidoes that will explain all of this, which we will show soon.

However, there are some pretty pictures showing how cladribine affects immune cell subsets. Although not speculated, this could explain why cladribine may not be expected to have expose people to risks of infections like SARS-CoV2, despite it being considered as a lymphocyte depleting drug. It is a T and B cell depleting drug and this is why it inhibits MS. However, to put in perspective alemtuzumab depletes lymphocytes by 80-90% and for CD4 T cells they stay below the Lower Limit of Normal (LLN) for over 12 months after infusion.

So what happens with Cladribine

Monocytes: These fight infection and stimulate other white blood cells (Lymphocytes) in the immune system to help fight infection. Not really affected. They stay above the lower level of Normal (LLN), , so will fight infections

Neutrophils: These are first line of attack to fight infection. They are can be involved in anti-mediated killing of the infection. Not really affected. They stay above the lower level of Normal (LLN), so will fight infections

CD4 T cells. These help the innate (monocytes, neutrophils) cells, antibody production (B cells) called plasma cells and killing cells (CD8) to fight infection. Depleted so some inhibition but stays in the normal range for most of the time. So infection can be fought and T cells can help the B cells to make a vaccine response

CD8 T cells. Kill infections inside the cells, notably virus infections. They are depleted but stay within nomral limits, , so will fight infections

NK cells. Kill cancer cells and are good at killing infections that have been marked for destruction by antibodies. Depleted by stays within the normal levels

CD19 B cells. A B cell (excluding antibody producing cells and B cells stem cells). Activate T helper cells and can produce antibody producing plasma cells. Markedly but transiently depleted. The only cell type to go markedly below normal levels, that recover before the next infusion.

How does cladribine inhibit MS?

You have no real clue? It doesnt deplete T cells very well and the effect on B cells doesn’t last very long. This is the problem for the review

However, if I can tell you that the CD19 subset is not a single subset but a composite of effects on many different cell types, if becomes clearer. Memory B cells are depleted by over 80% for the whole year of therapy below the lower limit of normal. This is also the case for all the high efficacy depleting treatments that work in MS. There as important cells appear to be within this population…MS is controlled. Some may say this is spectulation.

The recovering CD19 B cells represent the immature/naive B cells that are able to respond to new vaccinations/infections and are back to normal levels before the next cycle is needed. Therefore time for a vaccination if needed. Antibody secreting cells have low levels of the enzyme that causes cladribine induced killing. I could speculate what happens to them after cladribine, but the “proof is in the pudding“.

COI: Multiple, I have consulted for the manufacturer of cladribine

About the author

MouseDoctor

7 comments

  • …”Antibody secreting cells have low levels of the enzyme that causes cladribine induced killing. I could speculate what happens to them after cladribine, but the “proof is in the pudding“. ”

    So…? More in the next episode? Can you tell your hypothesis, please?

      • But… time is brain! 🙂 it has been a while since I started thinking something is bubbling in the pot, but let’s wait and see.

          • They get clad but not all of them are killed… people relapse after first and second cycle, but Rejdak paper shows some people lose OCBs so indeed there is a depletion. This year I saw a Merck set of slides probably ean or aan digital which show decrease in PB and PC. My Neuro said they have people fine on clad after 10 years. So I think they can be depleted by death by aging and by the lack of replenishment by memory b cells or by direct action of the drug. If the first case is true then all anti cd20 soon or later will get to the point… In the end people start losing IgG in the blood. If it’s the second point then the dose is not high enough or two cycles are not sufficient to remove them all. That is: we lack the use of a biomarker that says “now it’s enough the job is done and maintained”. I would think that young PC take clad and die off older PC don’t.

            I imagine the process that turn a plasma blast to a long lived plasma cells as a slow process that involves the downregulation of enzymes, receptors and so on and this could leave a treatment window open. I will ask a question about the topic soon 🙂

            Thank you for taking the time to answer

  • Very informative post MD. Detailed information about a DMTs mode of action and expected impact on lymphocytes is the exact type of transparency pwms need, in order to make well informed treatment decisions. Looking forward to future posts/videos related to clad, which you have so coyly teased 😉

    I do find it humorous when the the drug companies say “the exact mode of action of drug x is unknown”….. if they do not know how it works, then wtf should I feel safe putting it into my body.

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