Monday, 12 June 2017

NEWSFLASH. How Alemtuzumab works and why secondary autoimmunity develops

#MSResearch #ClinicSpeak 

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How does alemtuzumab work and why does it cause B cell autoimmunities? 

The answer we thought could lie in what alemtuzumab does to the immune cells and it was not all about T cells.   

To our surprise when the pivotal trial data were published, there was no real data presented to say what it actually did to the different cell types, even in supplementary data. The suggestion was that everything for the B cell is back to normal at 6 months (Cohen et al. 2012, Coles et al. 2012). 

Why if the data was generated, why was it not published? 

This is especially as research papers following analysis of a few people and abstracts on trial results (if you know where to look) told us what could  and would happen.

Although some people may be shocked by the revelations today.
The major ideas contained within the paper where presented to people within Genzyme some time ago as a method to de-risk alemtzumab. Some aspects were dismissed, which made us do more searching and this supported our view further. 

So we though best get them out in the open, to be discussed.  

See if you think it is rubbish too?

Therefore, we decided to do some investigating so from 221b Baker Street, MD got on his Sherlock outfit and his trusty assistant.....DrK...I mean Watson...started Investigating. 



Therefore, under a Freedom of Information requested public documents and we obtained the full regulatory submissions of the CARE-MS I, and CARE-MS II trial data set from the European Medicine Agency, which we could assess without any company involvement. 

This contained data that had never been properly published and data that is generally under appreciated. 

When we asked neuros some questions. They were not aware of the data to answer the questions, perhaps because they hadn't searched for it.

We had found some of the information in the ECTRIMS/ANN abstract vault, presumably never to be published, as at least 3-5 years had passed since presented. 

We believe there was important data which speaks to efficacy and perhaps safety issues, so we have decided to publish the findings and get them more in the open, accepting that this would not make us popular. However, all we have done is put the information that you can find, but we have put it in one place and tried to explain it.

If you are taking or are prescribing alemtuzumab, what does this mean? 

Perhaps not a lot, but it may explain how alemtuzumab may work and why it causes side effects, so you can discuss and prepare for these issues.  However, there may be implications for some people failing treatment. 

The study indicates a potential reason for failure of the drug in some people needing repeat infusions and the risk of failure increases with more infusions. Had we had access to the full data set we may have been able to say how little the risk is, but our requests for data have fallen on deaf ears so far.

Moving forward, it suggests ways to reduce side effects and maybe how not to go about this, so avoiding risk.

So what does this manuscript show?

1. The data suggest that there is long-term depletion of memory T cells, but we suggest that MS is controlled because of a long-term depleting effect on memory B cells. We have reported this view, but seeing the unpublished data within the dataset awakened us to information already published that was forgotten/ignored and drove use to focus on the memory B cell.

http://multiple-sclerosis-research.blogspot.com/2017/02/ms-is-b-cell-disease-and-memory-b-cells.html

2. Secondary Autoimmunity is probably due to incomplete depletion of  B cells from bone marrow and lymph glands, whilst removing a number of populations of regulatory T cells that allows autoimmune immature B cells to develop in the bone marrow. This creates a B cell "overshoot" in the blood and a mechanism to explain secondary autoimmunity.

This concept had however been dismissed based on the assertion that T regulatory cells increase, whilst they are in fact dramatically decreased, as evident from the trial data. 

So by squeezing the data into the dogma box to explain how alemtuzumab works, we have perhaps been looking into the wrong place to get explanations. Perhaps doing trials that were unlikely to work and importantly little has been done to de-risk the use of alemtuzumab.

3. It is evident that depletion of regulatory immune subset occurs that allows B cell autoimmunity to occur but these issues allow the escape of anti-drug antibodies, including those that neutralise the drug from working. Again this was not disclosed in the pivotal trial reports in an adequate way. (It is present in the FDA/EMA labels), when it was known that this occurred, and based on immunological principles, could be a problem for at least some people, if not during the trial but importantly after it finished. 

Just before the second infusion cycle there were few people with neutralizing antibodies, but in thse needing 3 cycles then about a third had neutralizing antibodies, which would be ready to block the drug working and about 80% of people had bindnig antibodies that could make infusion reactions more problematic. This information should be clearly known. It may not be a big risk but until the occurance of neutralizing antibodies is acknowledged, it is not surprising that the frequency of their occurance is not known. Now you know that neutralising antibodies occur with high frequency (about 80% pwMS) maybe the company will tell us how infrequent these issues occur with each cycle of treatment and the level of neuralizing antibody that can stops the drug working. 

Using this knowledge there is a suggestion of how secondary autoimmunity after alemtuzumab could be stopped.

If when you read this the post, the paper is not still open access, if you sign up to the JAMA Neurology App you can read it for Free.  If they ask for a subscription at the end of the free period just say No. 

They didn't when I used it.

You can get views of someone else, as this has an Editorial (CLICK)

Furthermore, I will explain these aspects in depth over the next few days, so you don't need to read it now.

However, I am not sure the EMA product description is really correct

The increases are relative to something else and there 
are absolute decreases in memory T and B memory cells and a decrease in the absolute number of T regulatory cells.

Should the Label information be amended? It says:


CoI: ProfG, DrK multiple. 

P.S. It was not ProfGs idea to obtain and interrogate the data, so don't blame him. 

25 comments:

  1. Well done, a great piece of dogged detective work that may reveal a lot about how autoimmunity can develop.

    ReplyDelete
  2. Nice post...You say:The data suggest that there is long-term depletion of memory T cells, but we suggest that MS is controlled because of a long-term depleting effect on memory B cells.
    So where does the black swan fit in this?
    Thanks
    For posting

    ReplyDelete
    Replies
    1. Dogma is that the action of alemtuzumab is via effect on T cells. We make the argument that the effect mayb be via memory B cells...ProfG will say that means you are depleting EBV so there is his swan.

      Delete
    2. Since you have access to raw data, why don't you plot disability progression as function of B-memory-cell population. If a single B-memory-cell-depleted patient progressed, your idea is disproved.

      Delete
    3. Unfortunately we did not get the raw data. We can only see the tabulated data. We have been requesting access to the raw data since November 2016 and no joy so far.

      The company may do this analysis but without being able to interrogate this we are at the mercy of the people doing the analysis. The effect of antibodies on outcomes is presented in different ways.

      I have requested that the B memory levels and disease activity be examined, but I think we will find a B cell depleted person will have activity as this happens in arthritis (empty blood but relapse in the joint. This may be because B cells in Brain or tissues are important.
      The odd cell in the blood may be all that is needed. but until we get data i cant't comment further

      Delete
    4. Thanks MD, i owe you a trial proposition... on mice.

      Delete
  3. What does the team in Cambridge think about this paper / findings?

    ReplyDelete
    Replies
    1. Not sure.

      We proposed the B-cell autoimmune hypothesis to Genzyme in 2013 and made Cambridge, UK, aware of it as well. It is now 2017 we would almost certainly have had results from our proposed rituximab-alemtuzumab trial by now.

      http://multiple-sclerosis-research.blogspot.com/2016/12/genzymespeak-derisking-alemetuzumab-is.html

      May be we aren't good enough at communicating, or selling, our ideas. It is a real pity, the trial could have provided a lot of immunological insights into the mechanisms driving B-cell autoimmunity. There is no way we could this trial now because there are now too many other treatment options on the table.

      Delete
    2. No sure they have seen it yet. They won't be happy as it does not fit with their reported ideas.

      They have seen the basic ideas.

      As ProfG said we wanted to do a study to try stop the autoimmunities, but there was no appetite at the time

      Delete
    3. P.S. Mr Angry/Impatient unrelated blogger comment 1 June was enquiring if I could go there, suspect I may not be welcome:-(

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    4. PPS. Anon 8.17 come back at the end of the week to ask the same question...or maybe give your views:-)

      Delete
  4. Read the paper and

    1º is the almost exact b cell pattern(correct if i am wrong )

    Between this hsct study

    http://multiple-sclerosis-research.blogspot.com/2017/05/blast-from-pastmemory-b-cells-depleted.html

    And the b cell recovering of the Alemtuzumab paper


    " alemtuzumab can
    induce T-cell immunity,30 and during the trials, 327 of 376
    peoplewithMS(87%) inCARE-MSI and 364of435 people with
    MS (83.7%) ... This is not good
    3º The amount of Treg dramaticaly reduce will cretaly cause proinflamatory activity?
    4º Those cd19 and mature b cells over shoot could be treat with anti cd20 theraphy(rituxan)?
    Thanks
    Luis

    ReplyDelete
    Replies
    1. 1. Yes this is why I posted it so well spotted. You may be interested to know that HSCT can cause secondary B cell autoimmunity too. Ocrelizumab and cladribine does not do this and dont cause secondary autoimunity.
      2. Yep not good the race is one to show this is important
      3. It doesn't because when there is no T reg there is no pro-inflammatory cells to make worse by the reg cells reporver quicker tahn pathogenic cells
      4. An idea.

      Delete
    2. After autologous HSCT for primary AD, the cumulative incidence of secondary AD was 9.8% ± 2% at 5 years.
      Lupus erythematosus as primary AD, and antithymocyte globulin use plus CD34(+) graft selection were important risk factors for secondary AD by multivariate analysis
      https://www.ncbi.nlm.nih.gov/pubmed/21596847

      Delete
    3. In conclusion, patients with SLE, younger age at HSCT, or receiving severe T cell-depleting conditioning (ATG, alemtuzumab, CD34+ selection) need close monitoring for secondary AD after autologous HSCT.

      Delete
    4. so 10% HSCT verses 50% alemtuzumab for secondary autoimmunities, so what is the difference?

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    5. 40%?
      Loll
      If you look at the paper they sle patients have more at risk
      thanks

      Delete
    6. No. There are about 40% thyroid problems based on the Tuohy et al. 2015 data and the unpublished MS-CARE-Extension data published over a year ago at ECTRIMS (Senior et al.). After I pointed this out last month about the data dump in meeting abstracts, I was told by ProfG that an "irate" spokesperson from a certain company had said that a paper on the adverse events over the MS-CARE Extension was on the way.

      Then there is the extra 8-10% of people getting ITP, Goodpastueur's and other weird B cell autoimmunities.

      I haven't checked out the SLE literature so obrigado for the information

      Delete
  5. Is there any indication from the data of what these autoimmunities mean for the effectiveness of alemtuzumab in controlling MS?

    I have been unlucky enough to end up with ITP 8 months after my second round (although it responded very well to steroids). My MS has completely silent for 3.5 years now, and I'm hoping this doesn't mean signal that my immune system is looking to run wild again.

    ReplyDelete
    Replies
    1. I think mechanistically they are irrelevant to how alemtzumab controls MS,

      However is their a link between developing autoimmunities and anti-drug antibodies..which could impact on efficacy if you need more infusions. I don't know Genzyme or Cambridge could answer this.

      Delete
  6. Congratulations MD & Dr K, and thank you for this work.

    That's a good editorial and great praise from Prof Steinman-
    "Gratitude is extended to Baker and coauthors1 for those careful measurements of immune cell repopulation after a successful therapy for MS and for their astute interpretation of the data, all emanating from an unwanted SAE. Their observations may kindle further advances in understanding how autoimmunity arises."
    http://jamanetwork.com/journals/jamaneurology/fullarticle/2630677

    ReplyDelete
    Replies
    1. Thank you, we were pleased, there were also some nice comments by the unknown reviewers too

      Delete

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