Saturday, 25 November 2017

Are we Overdosing Ocrelizumab

The eagles (ocrelizumab for RRMS and PPMS)  may have landed in Europe, but how often should the birds be used to kill cells in MS?

A view-point argues it's too often and that it can be personalised and smart.  I agree but for different reasons.....

Avasarala J. Anti-CD20 Cell Therapies in Multiple Sclerosis-A Fixed Dosing Schedule for Ocrelizumab is Overkill. Drug Target Insights. 2017 Oct 25;11:1177392817737515.
Anti-CD 20 therapies have found significant uses in multiple sclerosis (MS). Based singularly on the accumulated evidence with the use of rituximab (RTX; Rituxan, Genentech, and Biogen) in neuroimmunological diseases, ocrelizumab (OCR; Ocrevus, Genentech) was developed as a treatment option for MS and selectively targets CD20 B cells, a cell surface antigen found on pre-B cells, mature, and memory B cells, but not on lymphoid stem cells and plasma cells. On the basis of indirect evidence, elimination of the antigen-presenting capabilities and antigen nonspecific immune functions of B cells appear to be central to the therapeutic efficacy of anti-CD20 B-cell therapies. An important question is this-Why does the drug need to be dosed at fixed intervals and not based on a measurable endpoint, such as tracking peripheral CD20 cell counts? There is minimal scientific validity in infusing the drug every 6 months particularly if CD20 cell counts are negligible in the peripheral blood. In this analysis, a case is made for following CD19 cell populations as a surrogate for CD20 cells on a monthly basis to guide OCR redosing parameters and does not follow a scheduled dosing parameter.



Ocrelizumab is used every 6 months, but this study argues that this is too often and that it should be personalised based on monitoring CD19 positive B cells so if CD19 positive cells in an individual have not returned you should wait until your next dosing. This is personalised medicine.

Unfortunately there is often no insight provided to the action of ocrelizumab and this is because of the T cell MS world view and all too often the B cell is seen and shown as a single population.
But once you realize this is not true...the pennies can drop (realise the true situation).

We have made the point that cells within the memory B cell populations are the important subtype(s) to target

Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis.  https://www.ncbi.nlm.nih.gov/ pubmed/28161400

If you monitor this subset to determine retreatment it may become even more personalised and as these cells take a long long time to re-appear (months-years). Retreatment may be even less frequent.

Looking at the graph shown below where doses would be at week 0 and week 24 you can see total B cells are well down for months

So should you dose every 6 months?

I suspect Pharma and Neuros will have their fingers in their ears going La, La, La, La, La in the response to the idea of personalised medicine...I could be wrong

They will give the drug every 6 months and they will follow the label.

This is what the data from the trials indicates them to do and that is the label.

However, if  we have a death (based on events in Lupus and Arthritis where termination of drug development occurred) because of severe infection due to cell depletion, I suspect that people will "pull their fingers out" and take notice of the views above and below. 

There will of course be deaths in people taking drug, because this happens as part of life and not all deaths are drug related. Adverse events could occur early or late  (We are aware of some rumors) this will be due to chance of when the infections strike and there will be infections associated with B cell depletion. But if you take the treatment forever the risks must accumulate due to chance

However, I have hypothesised that ocrelizumab is an induction therapy just like alemtuzumab and cladribine.....Why?

Because, in my current view (this could change) they work the same way and all deplete memory B cells

Based on the unpublished, (why was it not published...Is it ethical to put people through these trials and not properly document the data but in the public domain see the Stephen Hauser ECTRIMS talk or [Click here]), ocrelizumab phase II extension data set show activity in most people 18 months after the last dose.

Does it need a tragedy, before people think about this? 
Maybe the manufacturers should plan and do a trial now...Maybe I am wrong and they can shut me up! 

They can do this by showing us the data.

Personalising Treatment is surely a positive move.

COI: Non-relevant yet.
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EDUCATION:


Ocreliziumab is a CD20-killer and it does this by complement fixation to blow holes in the target and uses antibody dependent cellular cytotoxicity to blow holes in the target. 

"Complement fixation" is where the complement binding site on the antibody molecule stimulates the complement cascade starting with C1 and ending with C9.















The complement system consists of a number of small proteins found in the blood, in general synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). When stimulated by one of several triggers, proteases in the system cleave specific proteins to initiate and amplifying cascade of further cleavages. 



The third complement component binds to the cell/pathogen surface and stimulates C5 to split in to CD5a and C5b.



This stimulates the production of the membrane attack complex.(C5b, C6, C7, C8, C9) to form a pore in the surface of the target so that the cell contents explode from the cell.

                      It is just like a pin popping a balloon.

Antibody dependent cellular cytotoxicity.  Antibody binds to the target cell and then a natural killer cell binds to the tail of the antibody (Fragment crystallisable = Fc) via Fc receptors. The natural killer cells release porforins that punch holes in the targets.

We know alot about rituximab and how it depletes, Ocrelizumab is more active than rituximab at complement fixation and ADCC and so it is going to be a more effective killer. 


11 comments:

  1. "I suspect Pharma and Neuros will have their fingers in their ears going La, La, La, La, La"

    Gordon Gekko: The point is ladies and gentlemen that greed, for lack of a better word, is good.

    Very nice post Md

    Obrigado

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  2. Given autoimmunity is driven by b cells. Can one take ocrelizumab after 2 or 3 doses of Alemtuzumab? To stop any secondary autoimmunity? Also will surly increase the efficacy of Alemtuzumab.

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    1. ProfG proposed doing this study many years ago, but there was no appetite. Now the question is can the study be done. Is it too late. However, this may occur now that ocrelizumab is licenced and if the NHS does not pay for more that two-three courses of alemtuzumab.

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    2. Thanks MD. It makes sense. I think the future is combination therapies. For instance posinimod and tecfidera phase trials shows complete suppression of ms. Surely alemtuzumab and ocrelizumab combined will be functional cure for MS?

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    3. There is this interesting case of administrating RTX after alemtuzumab in MS:

      Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy
      http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30382-9/fulltext

      I wonder how those combination therapies that are on trial will be paid when the cost will exceed the 100.000$ a year. They will prefer to give us rat poison to get this over with (or maybe re-consider HSCT ;) )

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    4. Yes I agree completely. In the end we're breaking/weakening what protects us. However given the henious nature of ms. It's still a risk worth taking. If ms people can live normal lives.

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  3. Ocrevus is a potency bomb and the bomb will blow at patients faces (with upper respiratory fatal infections probably). The side effects of the drug are way more intense than the RTX according to patients descriptions. Is there a reason for this intensity (and patient suffering), that is the question. I doubt there is.

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    Replies
    1. It is clear that ocrelizumab creates patent advantage and the pharma way is to make more and more potent variants. There will be more potent variants than orecelizumab.

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  4. On the matter of dosage: why are the doses of DMT's the same for every person? This is true for all DMTs used in MS.

    It looks like nothting has any effect on the mode of action.
    It doesn't matter if you are female or male, if you weigh 40kg or 400kg, if you have low or high blood pressure etc.pp.

    Could someone shed some light on this?

    Thanks. :D

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    Replies
    1. You may notice that oral cladribime is dosed on weight.

      Is it sexist that males will pay more than females for a course of treatment (The average male weighs more than a female).

      As for being fatists let's not do there, but you are right if you use the same amount of drugs small people get more.

      We mentioned this could be a problem for laquinimod where the double dose was dropped due to suspected heart problems. A 50kg would get twice as much as a100kg person. Animal experiments 101 show that weight to dose impacts on biological activity

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    2. MD: from a patient’s perspective it has little to do with pricing per kg and everything to to with balancing side-effects and efficacy. You weigh less you might increase the efficacy but at the expense of acquiring the side effects. Tipped to far either way and you either miss the benefits and the side-effects, or reap the benefits but suffer the (sometimes fatal) side effects. Or just get lucky. Can anyone explain why DMTs and PIRTs (apart from cladribine and cyclophosphamide I HSCT) are not adjusted for weight?

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