Friday, 6 October 2017

The new ideas of alemtuzumab

Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord. 2017;10:343-359

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including real-world experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, pre-existing disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

This is a review and we don't report of reviews but it is perhaps good that you can get an alternative view.  If you can get access to this.

However I have been spending the day getting my poster ready for ECTRIMS 2017 and so was happy to see the state of play, 

but....reading through this makes me feel that I am am living in an alternative universe:-(. 

Apparently there are "no new safety signals" emerging so best not give a plug for the ECTRIMS poster that shows alemtuzumab can stop working

P1231. C. Eggers, K. Akgün, T. Hofer, M. Egger, T. Ziemssen
Abrogation of the lymphocyte depleting action of Alemtuzumab by neutralizing antibodies - a case report. 

Apparently there is "recent evidence on the mechanism of action of alemtuzumab" so I thought great...our ideas are gaining some traction....but then the depression sets in. 

So in addition to the mechanism of inducing depletion and repopulation of T and B lymphocytes ,we get a result in a relative increase of cells with memory and regulatory phenotypes...yeah that's T cells. 

I guess memory B are not on the radar yet.

So  the 30,000 cells per millilitre going down to 2 is still an increase in the minds of my peers?. Maybe that the 2 Treg cells are now controlling the 1 surviving CD4 T cell is the relative cell increase we need.

The new mechanism is a expansion of NKCD56 high, so it works like daclizumab too?

Have a read of this and tell me what you think.

http://multiple-sclerosis-research.blogspot.com/2017/06/looking-in-wrong-place-to-find-efficacy.html

So if we do reviews, should we regurgitate a string of facts or try and tease mechanisms from the literature...I prefer the latter but maybe I am in a minority....too much speculation. 

What do you think?

Come back tomorrow. I'll have a go.

7 comments:

  1. Why the obsession with Alemtuzumab? To you it's like an ex-wfe you can't get over. You dig and dig trying to find some dirt. In reality it's a highly effective treatment which puts many in long term NEDA. I assume Prof G is still presribing it to some of his patients. Time you got over your obsession. A nice philosophy is 'create don't destroy'. You seem determined to undermine Alemtuzumab. Would be better to focus your efforts on indentifying new and better ways of treating this disease.

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    1. The "obsession" with Alemtuzumab has in fact been extremely rewarding giving us new insights on not only autoimmunity can develop but also revealing the memory B cell as a key player in MS. All our focus is on identifying better ways of treating disease as I'm sure you're aware with the cladribine story.

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    2. Re: "I assume Prof G is still presribing it to some of his patients.."

      Yes we are one of the biggest prescribers of the drug in the UK. We offer it first line along side other platform DMTs and large number of pwMS want to to be treated with alemtuzumab and choose this option. Please note it is about choice.

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    3. Thanks Prof G. I have had excellent results from Lemtrada and the monitoring by the neurology team has been first class. Before opting for the drug I was made aware of the risks. I'm sure Prof Mouse means well, but I was left quite alarmed by some of his claims in earlier posts (claims that data has not been disclosed and that risks have not been reported). I live in the real world, not the academic / theoretical world. I had to make a real decision about my treatment choice and I can't thank my neuro enough for her support and advice.

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    4. Science is obsession I'm afraid and I don't do things half heartedly.
      As for digging for dirt...I found dirt along time ago.

      With more transparency we would know how big or small the mud pile is and there would be nothing to find.

      However, recognising the dirt will make alemtuzumab a safer treatment for some people.

      Anyway mud pie on the way-(.

      However MD2 is correct without trying to understand alemtuzumab we would not have understood how the others work too. All you need to do is read.

      If changing clinical practise requires digging. I have a big shovel;-)

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    5. Re: "I have had excellent results from Lemtrada ...."

      Thanks.

      The alemtuzumab brain atrophy data is quite extraordinary and better than any other DMT, apart, maybe, from the Canadian myeloablative HSCT trial data. The latter however did cause a lot more early brain atrophy before it stabilised.

      In short alemtuzumab has the best end-organ damage data and hence I am sure pwMS who are really in the know will continue to want to be treated with alemtuzumab despite the risks and monitoring burden. It is all about choice.

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  2. My understanding as an MS Caregiver (my spouse has MS, diagnosed 2 years ago - Canada) is that Alemtuzumab has the best end-organ damage prevention of any of the existing DMTs on the market, as you say Dr. Giovannoni. Is there any reason to believe that Ocrelizumab may match or beat this record?

    My spouse has been on DMF for two years, but has failed it and is going to be escalating to Alemtuzumab soon (unfortunately in most of Canada we have to go through the escalation process...), but I want to gather as much info as possible before we confirm the decision, as Ocrelizumab was also just approved here.

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