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. 

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