Questions for today’s Symposium

ProfG is at the European Neurology Meeting in Amsterdam.
Today, there is a SANOFI GENZYME Satellite Symposium: From clinical data to real world experience – similar results, similar benefits for multiple sclerosis patients?

I guess MS CARE extension data will be presented. The message will be alemtuzumab is a very good drug.

The bad news will be that the proportion of people with secondary autoimmunities from the trials, about 20% will have dramatically increased to about 50%.

Here is the programme

Rogier Q. Hintzen, Rotterdam,
The Netherlands

Welcome and Introduction. Rogier Q. Hintzen, Rotterdam, The Netherlands

Mechanism of Action:New Insights into Immunomodulation
Luisa Klotz, , Germany

From Phase 3 controlled trials to extension trials: What do the data
tell us? Celia Oreja-Guevara, Madrid, Spain

Daily practice: How does real world evidence reflect clinical data? Tjalf
Ziemssen, Dresden, Germany (lead author of ECTRIMS abstract-2013 on binding and neutralizing antibody responses).

Q & A:Rogier Q. Hintzen, Rotterdam, The Netherlands

We can see there is a Q & A session which is great. 

If you are there scratching you head seeking a question, maybe you can ask a few questions.

I wonder what are the new insights? Weren’t they publish last week:-)?

What is the mechanism?

Wonder if memory B cells will get a mention? Give us a tweet.

If they don’t here’s a few questions for the Q&A.

Q. Why do you think MS is a CD4 Th17 T cell mediated disease given that treatments targeting CD4 T cells have typically failed in MS?

Q. Why do you think there is an increase in Treg T cells when their absolute numbers are decreased by over 80%?

Q. Why are you not associating Tregs influences as a major influence on B cell autoimmunities?

Q. Do you think memory B cells are involved in the action of alemtuzumab?

I will guess. Most people don’t get a third course, few got 3 or fewer get 4 courses of drug. This indeed impressive.

I guess this is not mentioned that most people develop binding and neutralizing antibodies, which they must do given the levels at cycles one and two (about 80%).

Q. How many people develop binding and neutralizing antibodies on cycle 3 and cycle 4? 

Q. At 12 months after last infusion how many people have persistent anti-drug antibodies and do they affect depletion.

Q. What is the proportion of people who stop depleting or what is the proportion of people who only partially deplete? We already known at the population level there is depletion (Kousin-Ezewu et al. 2014) but at the individual level, are there people who neutralise the alemtuzumab response.Q. If there are, what is the titre of neutralizing antibodies associated with lack of efficacy.

Q. Are their any non-depleters.
Q. Is there any difference in anaphylaxis/anaphylactoid reactions after third or forth infusion given that most people make binding antibodies and over 70% of people have persistent anti-drug antibodies. Does this relate to pre-existing titres of alemtuzumab binding antibodies?
I suspect if you ask these questions there may be some blank looks .
COI None relevant

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  • Mouse said: "The bad news will be that the proportion of people with secondary autoimmunities from the trials, about 20% will have dramatically increased to about 50%."

    I don't like the way you play with the numbers. Here is a paper from the Cambridge team published in May 2014 i.e. over three years ago:

    Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy – May 2014
    [page 7] "Secondary autoimmunity rates in this study (48%) are higher than previously reported, probably reflecting the longer follow-up."

    You always make a comment that appears to suggest that Cambridge are hiding data or not being honest with the data. The paper above makes clear that secondary autoimmunity (long term follow up) is approaching 50%. I don't know what you have against the Cambridge, but you need to get your facts straight. There is no cover up or dramatically worsening situation. The Cambridge team have already made public that nearly in nearly 50% of Alemtuzumab treated patients, half go on to develop secondary auto-immunity.

    • To say about 50% is pretty close to the 48% in the Tuohy et al. paper.
      Yes we are talking about the 5 year extension data so it is inherent in my response that we are talking a longer time frame. This contrasts with the trial a 2 year study. My facts are spot on. So I don't understand your gripe.

      The group of Robinson have likewise published a 50% rate (Willis et al) so I am not saying anything that is unknown.

      I am sure Barts could do the same.

      I am simply stating the reality, I could add more the extension data for thyroid problems are 39% in the the Tuohy et al. it was I think 41%.

      I can say these things because the data has been published somewhere, but it is often hard to find.

      This has got nothing to do with Cambridge it is about the Genzyme symposium and their data, Genzyme data. It is you who are saying/infering Cambridge were hiding data.

      Were they complicit in not disclosing the neutralizing and binding anti-alemetuzumab response, it depends what they knew. Genzyme knew this because, we know they measured it

      I would say in the trial reports this issue was indeed minimised, presumably according to the wishes of the companies who presumably wrote the paper.

      Eg in phase II the percentage of people making anti-globulin was 0.5% (Coles et al 2008) and got cursory mention in phase III reports. The actual level was over 80% in the phase III (Baker et al 2017). This agrees with the Cambridge data (Somerfield et al 2010) at over 70%.
      Cambridge obviously knows or believed there are issues otherwise they would not have done a trial to reduce the impact of antibodies (Somerfield et al. 2010).

      So again I think my facts are straight.

    • Before you say it the 0.5% was above a predefined limit in Coles et al. Next question was below this limit unimportant and above important, if so important for what?

    • Or the mysterious non-mention of the rapid over-shooting (from baseline) B cell repopulation.

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