Wednesday, 27 September 2017

Neutrophils lost after alemtuzumab

Marked neutropenia: significant but rare in people with multiple sclerosis after alemtuzumab treatment. David Baker, Gavin Giovannoni, Klaus Schmierer Mult Scler Rel Disord. 2017 .

HIGHLIGHTS

  • Neutropenia occurred in 20-25% of people in the 2 year phase III, pivotal trials of alemtuzumab.
  • However, grade 3-4 neutropenia (neutrophils occurred in only 5/811 people with MS (0.6%) in the year following the first infusion cycle and in 12/808 people (1.5%) in the year following the second infusion cycle.
  • Agranulocytosis was a rare occurrence but this responded to treatment.
Background: Alemtuzumab is a CD52-specific monoclonal antibody that markedly depletes T and B lymphocytes and inhibits relapsing multiple sclerosis (MS). However, polymorphonuclear neutrophils also express CD52 and can be depleted by alemtuzumab, thereby potentially contributing to the infections that develop post-alemtuzumab treatment. Surprisingly, however, the degree of neutrophil depletion in MS was not included in the pivotal trial reports.Methods: The regulatory submission of the Comparison of Alemtuzumab and Rebif® Efficacy in MS 1 and 2 trials was obtained from the European Medicines Agency through Freedom of Information. The data relating to neutrophils was extracted.
Results: Data extraction from the submission was straightforward. In year one 72/811 (8.9%) and in year two 116/808 (14.4%) people with MS (pwMS) developed neutropenia. The degree of neutropenia was generally mild, and only 5/811 (0.6%) in year 1 and 12/808 (1.5%) in year 2 developed grade 3-4 toxicity. Two pwMS developed severe neutropenia-related adverse events.
Conclusions: Treatment with alemtuzumab induces neutropenia, which is mild in the large majority of pwMS treated. Leucocyte levels following alemtuzumab should be monitored as a marker of efficacy and safety; persistent neutropenia may require treatment

Following on from a recent case report indicating that alemtuzumab, marketed by Sanofi Genzyme, can induce neutropenia (loss of neutrophils, which are your first line of defense against fighting infection), this paper was written and submitted within a few hours.

It is all well an dandy to know that something can occur, but surely it is important to know how common the problem is. 


We show that the occurrence of neutrophil loss is frequent but marked loss is not a common problem. This data was in the unpublished phase III trial data set, but as it is now 5 years since the trial report was published and add another few years since the work was done, the manufacturers had shown no interest in publishing the information.

We had it because we had the data set obtained from the European Medicines agency and so we could easily answer the question. Pharma could never write and submit a paper within a few hours.

Will they be miffed, as we have published the information?

Maybe/Probably  but t
he manufacturer has had 7 years to get the data published, as have their academic collaborators, so I should not feel too bad

Some of our colleagues are not too happy with this type of information source and have told us so in no uncertain order, but this is important, safety information.

I am sure the manufacturers are happy that we have put the case report in context.

But, it says to pharma, that the the world order has changed and now the machinery is at hand to get access to trial data. We have led the way.

So they now pharma can get up to 12-18 months to publish what they want, to publish in a way they want to publish the story, but after that it will be fair game. 

The race may be on to get hold of the ocrelizumab data...for example the phase II extension study...oh I forgot I've published the headline result already:-).

Anyway back to the alemtuzumab data set. 


It houses quite a lot of unpublished ideas and I had hoped that by publishing some details, such as the presence of neutralizing antibodies, it may have encouraged the academics & company to come clean.  It didn't, so I tell you here again.

Nearly 80% of people produce neutralizing antibodies and over 30% had pre-existing neutralizing antibodies and over 70% have binding antibodies by 12 months after the second cycle.  So if you need a third cycle there could be issues.

Will it be part of the CARE-MS extension data reporting?

It is important as the question is....How many people got anaphylactoid (allergic) responses during infusion? 


In the first two years it was very low and you take preventative medicine to prevent this


Importantly how often does the antibody stop working? 


These are theoretical problems based on immunological principals

and are a problem for all therapeutic proteins, but is alemtuzumab
extra special? 

One wonders whether the dosing schedule was developed because an issue of neutralizing antibodies was recognised (only 2 course as standard and only retreat at the year end and not when disease activity occurs, as you need to wait for the neutralizing antibodies to subside).


If you are paying $60,000-$80,000 for treatment, you would expect it to work, wouldn't you? 


But I know it doesn't always, however what is the scale of the issue?


I don't know, but I can assure you we will get an answer by hook or by crook, with or without company assistance. 


Maybe it is not an issue, but let's see the data!


As MD2 will testify, once the ferret's jaw locks...it locks..and with no costs and no resource to data crunch we can bide our time.


This is important because omissions by pharma are in the news at present so let's hope this is not a repeat case.


A report in the  Telegraph says


"Medical experts were “complicit” in allowing thousands of children to suffer deformity after resisting warnings on epilepsy drugs, campaigners have said.

"A hearing in London heard that regulators knew in 1973 that taking the anti-epilepsy drug in pregnancy could cause babies to be born with disabilities, but waited 40 years before alerting the public to the risks".  (The regulators have the data to see that there could be an issue of neutralization with alemtuzumab..if they had any immunological knowledge)

"Estimates suggest that around 20,000 babies in the UK suffered harm as a result of sodium valproate which can also cause brain damage and problems such as autism".

"Sanofi, which manufactures the drug, has said it has always been transparent with regulators about the risks of the medicine".

I think this apparent ignorance of the knowledge is rather odd, because when I have been teaching epilepsy since 2006 to our second year medical student's, one of the central topics in the course notes that is covered is the use of these types of agent during pregnancy and the risks of birth defects.

Why is this interesting to MS?

It shows the importance of disclosure and importantly.... dissemination of problems. 

In the telegraph article Medical Experts seem to have been suppressing the information flow.

In addition this interesting to me because our potential MS drug acts on the opposite side of neurological control (to promote relaxation/inhibition) to agents like valproic acid (blocks excitation). If blocking excitation causes autism. Will our drug inhibit autism and epilepsy?  

We will have to wait and see.

28 comments:

  1. "If you are paying $60,000-$80,000 for treatment, you would expect it to work, wouldn't you?"

    Not if it's a DMD. We've (you) already established ~50% efficacy in most.

    Honestly. I remember my neuro shoving tecfidera saying that pml was all but negligible. Then after two years, studies proving the opposite.

    The aim of hsct is to enter neutropenia and then bounce back within a few weeks post transplant. No long term side effects. I think the jury's out in many DMDs to be honest.

    It is very sad about autism in babies from mothers who took that drug. Also another reason to stay in EU. Standard unified warnings. Although I know in this case it doesn't apply.

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    Replies
    1. I thing the number of people who respond to alemtuzumab in terms of depletion is much higher than 50%. If the manufactureres produce the data we can say how many

      To counter the sipe you can equally pay $50,000 and it doesn't work and it will give you severe neutropenia that may help kill you.

      The aim of the stem cells is to produce cells that can fight infection following the immune ablation. It takes about 20-30 days for the neutrophils to a level where they can offer protection

      Yesterday was the first time you didn't mentioned HSCT in the same breathe as a comment...give it a rest please.

      If a person has disease and fails NEDA is does not say the drug has done nothing

      Delete
    2. "Yesterday was the first time you didn't mentioned HSCT in the same breathe as a comment...give it a rest please."

      Given that were discussing the side effects on neutrophils. It is relevant to mention hsct. It is a viable alternative that does not carry the risks outlined in this post.

      It's not my fault if hsct 'rights the wrongs' of many DMDs.

      If neurologists didn't outright lie, then perhaps I'd be less militant about the difference hsct can make and the lowering of the veil that neurologists and researchers hide behind

      Delete
    3. Last warning bearms, stop going off topic and steering everything to your hsct evangelism. We are not unsupportive, despite what you may think but we need more data before firm conclusions can be drawn.
      So, please stay on topic otherwise it's the spam bin ;-)

      Delete
    4. I wasn't even aware of any previous warnings?

      Delete
    5. You need to see animal house...double secret probation🍓🍏🐣

      Delete
    6. A viable alternative that does not carry the risks outlined in this post.

      Absolutely not, HSCT is a far higher risk with more likely 100% of people with severe neutropenia

      Delete
    7. "HSCT is a far higher risk with more likely 100% of people with severe neutropenia"

      That's a joke right? The above post is about long term / permanent nuetrophil dripping off. This doesn't happen in hsct. Because it's a one off hit and followed by recovery, rather than sustained suppression (which is presumably what does the damage).

      Delete
    8. actually this can happen with hsct too.

      but more importantly, i have stopped listening to neuros when it comes to bloods. consult a hameo, whether it relates to lemtrada, ocrelizumab, rituximab or hsct. they are the experts and understand the issues far better. they cannot give advice on efficacy in relation to ms, but side effects and dangers: half the neuros don't even understand how to read the bloods let alone the side effects. true story

      Delete
    9. You are speaking the truth.
      Even MS neuros don't get it right. My neuro is talking and I am literally recalling posts from here, trying not to offend him.
      And to be real. They are talking about MS Centers, but what is really needed is Autoimmune Centers that will have first of all Immunologists (not all neuros are), haematologists, neurologists, reumatologists, dermatologists etc. Many people have more than one autoimmune disease and they literally don't know which doctors the door to knock first. A part of the problem is that neuros are too arrogant to collaborate, even with each other.

      And they are proud that MS is the most "controlable" neurological condition, just to hit each others shoulders, only to hide that the Immunological part is somehow better now and the pure neurological part (neuroprotection, remyelianation etc) is still zero. Neuros...

      Delete
  2. From just a facebook statistics -which I know is not scientific at all- the failures of NEDA with Lemtrada are pretty pretty common. I am starting to wonder if FDA was right at first place when they said the benefits do not overweight the risks. Wonder if the updated version will be better.

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  3. You do not have to go to face book the 5 year data talk about NEDA but the look at the retreating rates and the effect looks much better.

    With cladribine and ocrelizumab doing the same thing with fewer side effects I suspect DMT natural selection will occur.

    Will the new variant fair better...I guess many of the problems are target mechanism generated...they have the same target.

    Simple question would be, does it cause a neutralizing antibody response with the first month of infusion. If the answer is no it will be better.

    ReplyDelete
    Replies
    1. "With cladribine and ocrelizumab doing the same thing with fewer side effects I suspect DMT natural selection will occur."

      until long term data becomes available or the potential for induction treatment becomes clearer, i do worry about the prospect of ongoing ocrelizumab treatment with no end of sight. i don't consider that a "lesser" side effect, particularly in the context of the breast cancer cluster for which there is currently no explanation.

      Delete
    2. I suspect that it will be shown that only a few cycles of alemtuzumab is needed for long-term benefit...this was shown from the unpublished data (that we published) from the phase II extension data. However it will need a trial......I like you worry about the permanent issues of total B cell depletion....because there will be infections. There are some signature infections that are controlled by CD20 B cells and they will crop up...Mark my word.

      Sadly maybe it will take a fatality for this to be investigated but the logic and data is in the literature.

      Also as you say we need to know what induction therapy means...I have some thoughts on this..watch this space.

      Delete
  4. At the risk of being off topic, but to aid cultural understanding: European and American Ferrets have very different temperaments. I only learnt this last weekend. A European ferret will lock jaws and is semi feral at best. American ferrets can make cuddly pets.

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    Replies
    1. Very intereesting, I'll remember to get an american one the next time I put em down me trousers..."Ee by gum"

      Delete
    2. Just be careful it doesn't fight with your whippet ;-)

      Delete
  5. I think these foi requests are brilliant! Pity they can't be used for unlicensed drugs too, well you could try I suppose ;-)

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    Replies
    1. cladribine was not licenced when we got the data, so it is possible

      Delete
    2. Its Q3 so time to go back to see what anti-BAFF did, or didn't do

      Delete
    3. Nothing there when this post reminded me to check yesterday :(

      Delete
  6. Congrats Dr: baker and team ,Excelent work

    Just some questions:

    "the manufacturers had shown no interest in publishing the information."

    So why you need EMA in the first place? Is this criminal?

    "Some of our colleagues are not too happy with this type of information" Why?
    First do no warm ...Should be the their first decisdion..Right

    Thanks again
    Obrigado

    ReplyDelete
    Replies
    1. Is this criminal... I don,t think so, but it should be about understanding risks.

      "First do no harm"....totally agree and this is why ProfG was happy to put his name to the papers, although it sour his relationship with the company, this because it is a safety issue and speaks to having integrity.

      What's coming next?

      Delete
  7. But the company had 7 years to get their own integrity and still nothing

    "What's coming next?" you tell me ,Are they gonna backfire on the team?
    Obrigado

    ReplyDelete

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