Saturday, 8 April 2017

The Memory B cell and MS Evidence Destroyed.

Free Grant Idea of the Month

We have been making a suggestion that B memory cells may be important for the control of MS. 

In non-MS diseases, memory B cells have also been implicated and in these cases it appears that these B cells increase in the blood upto to 4 months before the subsequent attack.

If you look for B cell increases in a B cell depleted background the important ones may be easier to spot.

Therefore, there are some obvious studies to try and address the question. You could spend thousands/millions trying to do the experiment or you can ask pharma for their data.  

Question
Is there an increase in memory B cell activity with disease activity?

You can ask this in cases of 
(a) disease breakthrough, where the drug is working
(Two companies have such data)

(b) Where disease occurs because of treatment-induced worsening (Two companies have data).

We have been very public about Ely Lilly and their failure to disclose the results of the clinical trial with blocking BAFF.
   Did it simply fail or did it make MS worse?

However we have also been in touch with other companies, so the next one apparently not disclosing data (yet) is...........



Actually to be fair they have published the clinical trial data, and were not to know of the importance of the memory B cell. However, there were other trials interfering with the BAFF pathway and acaticept was used and blocked BAFF/APRIL, which reduce mature B cells and plamsa cells but cause an increase in Memory B cells (Based on information in other conditions).

What happened in MS?

The trials in MS were terminated when it was realised that MS was being made worse and Merck Serono stopped their other two trials one was the Atacicept Extension study in MS, which was extending the orignal trial and the other was an optic Neurits trial, which also showed worsening.

Tissue samples were collected. What were the result of their analysis? 

We now have the answer (Thanks for having a look but...).
According to EMD Serono, USA the information was thrown in a bin and destroyed.



Although samples were collected they were not analysed, presumably waiting until the trial finished.
When the trial was terminated, presumably so was interest in using the samples. 

Therefore rather than seeing if this could provide clues for the cause of the worsening, perhaps important evidence was destroyed.

This happened because there is a maximum limit on the time the samples can be stored, due to the informed consent provided, and they were not used before that time. 

I wonder if it is really ethical to take samples and then do nothing with them? 

So Merck have destroyed evidence that may have told them how oral cladribine works, so an oppertunity missed. 

So one down...three to go!...

We know it was not all thrown away. 

6 comments:

  1. Re Merck cladribine, great shame. What tissue thrown away? Do they have to repeat trials? How lo-o-ong to wait?

    Have been thinking (a lot) about cladribine, as an anti-metabolite must target rapidly dividing cells yes? Has confused me somewhat as memory B must be long-lived?
    D'oh,have just twigged these are the very cells primed for rapid, like really rapid, proliferation should cognate antigen be encountered again. And then at some point these cells decide to either stay as they are (refreshed store of memory B) or become plasma cells producing IG.
    Little point targeting formation of new B cells via BAFF/APRIL when memory B sitting there ready to go! No wonder didn't work....

    So anti-metabolite like cladribine should be pretty good at selectively targeting rapidly dividing memory B cells in MS. Especially as crosses BBB?


    It's a great shame about the failure of the repurposing bill and reluctance of MS charities to support, think about the good that could be achieved today with generic cladribine....

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    Replies
    1. Merck acacicept great shame, Merck cladribine, they either have the data from extension study or will have to wait to manusfacture...I think we know what's happening.

      Cladribine has an active metabolite that is a product of chemistry that is cytotoxic irrespective of whether cell divides or not but accumulates in lymphocytes because of the balance of enzymne they have. So it will kill B cells (proliferating cells will be easier to kill) and can kill plasma cells and can get into the CNS, but does enough get in? We are looking it at the moment.

      The repurposing bill was not necessary to prescribe off-label, we got a letter from a UK minister saying just that. Your neurologist could prescribe it. We had a number of people with progressive MS who have taken this agent and have had people refered in.

      We have proposed a new trial for people in wheelchairs, lets hope the MS Societies get behind this initiative

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    2. Sorry muddled up Merck trials, yeah, atacicept shame but at least published.

      Thanks for further explanation re cladribine. Yep, understand off-label :-) no problem with that at all. If neuros hadn't embraced idea for Campath would we have Lemtrada? Maybe it'll take time for off-label cladribine to percolate through the system. .... I don't have time :-(

      Look forward to hearing more about pw wheelchair trial, wheels aren't so bad these days at least everyone has to be nice to you ;-) but loss of hand function? Must be so tough, really feel for people living with that :-(

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    3. Maybe DrK will publish our current protocol

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  2. In non-MS diseases, memory B cells have also been implicated and in these cases it appears that these B cells increase in the blood upto to 4 months before the subsequent attack

    My neuro thinks that way too, he and is colleagues treat about 600 ms patient in the hospital he said to me that when they monitor the b cells and they are increasing for sure the patient is going to have a relapse

    That makes for some proactive treatment decisions

    Obrigado

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    Replies
    1. Yes thanks we know about this and have just recieved support so we can see it it happens in MS, like it does in SLE, arthritis NMO, and many more.

      Genzyme have the data, which we have yet to see.

      But you are correct it allows you to be proactive these will be in the review

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