Tuesday, 8 November 2016

All things Alemtuzumab, raison d'etre?

Drug Des Devel Ther. 2016 Oct 18;10:3379-3386. eCollection 2016.

Alemtuzumab in the treatment of multiple sclerosis: patient selection and special considerations.

Dörr J, Baum K.


Abstract


Multiple sclerosis (MS) is among the most common chronic inflammatory diseases of the central nervous system. Although not curable, the constantly increasing armamentarium of disease-modifying drugs now allows control of disease activity in many patients. The humanized monoclonal antibody alemtuzumab is a powerful drug licensed for the treatment of MS. Upon binding to the CD52 surface protein on CD4+ and CD8+ T cells, B cells, and monocytes, circulating CD52+ cells are eliminated via antibody- and complement-mediated lysis, and a less autoreactive adaptive immune system is reconstituted. The efficacy of alemtuzumab in terms of both clinical and magnetic resonance imaging outcomes has been demonstrated in several phase II/III trials including long-term extensions and follow-up studies. Treatment response to alemtuzumab is strongest as long as active inflammation is the predominant pathophysiological feature, and it is becoming less efficacious in neurodegeneration-dominated later stages of the disease. Thus, the optimal placement of alemtuzumab within treatment algorithms of MS is crucial. The impressive efficacy of alemtuzumab is counteracted by a less favorable safety profile. Besides usually manageable infusion-associated side effects, development of secondary autoimmunity in almost half of treated patients is the most disconcerting risk of alemtuzumab. The high frequency, the delayed occurrence, and the potentially severe course of secondary autoimmune diseases require awareness and a close long-term monitoring of patients treated with alemtuzumab. Biomarkers that would allow prediction of treatment response to alemtuzumab on the one hand and identification of patients at risk for the development of secondary autoimmune diseases on the other are not yet available. Thus, the overall success of alemtuzumab treatment critically depends on the patient selection. The aim of this article is therefore, to characterize the significance of alemtuzumab in the treatment of MS with a focus on the selection of the optimal patient.

If you ever wanted to find out everything about Alemtuzumab, this review is for you. Door and Baum summarize everything from the mode of action, to clinical trials, efficacy and risk considerations. As with all monoclonal antibody treatments, the secret to Alemtuzumab's efficacy and adverse profile are one and the same.

Alemtuzumab binds to CD52 on the surface of T cells, B cells and monocytes. This then effectively removes these cells form circulation, but the popular belief is that the cells in the lymphoid organs (e.g. lymph nodes) are spared. Subsequently, their is reconstitution of the immune population from the cells that have escaped eradication. The dynamics of the re-population differs from cell to cell, with B cells and monocytes reappearing well before the T cells, which may take on average 5 years to return to pre-treatment levels. The latter may explain the durability of treatment effect, with low sustained relapse rates and stability in MS over this period.

The Achilles heel of Alemtuzumab is the predilection for autoimmunity. It was originally published that baseline IL-21 (a cytokine) may predict the development of autoimmune disorders following Alemtuzumab treatment, however this has not panned out on repeat testing. There are therefore ongoing studies to look for changes in the immune system profile after Alemtuzumab to see if certain changes are predictive of the development of autoimmunity (e.g. NCT02419378).

Markers of treatment response beyond the standard clinical scores and MRI markers are also scarce. Importantly, biomarkers that can predict those most likely to benefit from the treatment are also scarce. Again there are ongoing clinical studies in this area: 1) Diffusion and myelin fraction water changes on MRI and changes in normal appearing white matter (studying disease activity and repair) NCT01395316, and 2) Motor evoked potentials to determine who will require a third cycle of Alemtuzumab.

In all, as we understand more about how these treatments work at a biological level, the more likely we would be able to select the most appropriate treatments and of course monitor them!

14 comments:

  1. A few weeks ago I was slagged off for not doing any research and you said go and do some work and make Alemtuzumab safer and more effective. If we understand how it works and how it causes problems then you have solutions...Paper 1 on the way.
    Hope it is not savaged too much.

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  2. Regarding the often overshooting of B-cell reconstitution around the 6 month mark post infusion; would a relapse at this time point be suggestive of anything, such as the disease in this patient being driven by B-cells?

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    1. Good spot this has been the elephant in the room. We will explain this very soon but on the whole this is not the reason for a relapse but if one occurs then you are spot on..

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    2. So would a patient in this predicament perhaps respond better to Rituxumab / Ocrelizamub?

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    3. I doubt there is much difference between the two except a few Bob.
      The anti cd20 appear as efficacious as alemtuzumab but without the side effects

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  3. ...understand more about how these treatments work at a biological level...

    That would be good. But I am sceptical about achieving that any time soon. (Particularly when it comes to progressive MS, but that's another story.) Is it even known for sure how paracetamol works yet?

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    1. We are taking relapsing MS and active progressive MS. Do I have all the answers...no do I know where to look for them yes. MD2 has a plausible explanation of progressive MS too

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    2. Can't wait to read the whole story on progressive MS. Literally cannot wait.

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  4. I have read now a couple times the statement that anti cd20 and alemtuzumab have the same efficacy, that keep being a reality in lets say a person 6-7 years after last infusion and someone doing active 6 monthly treatment with ocrelizumab? If you stop taking ocrelizumab the effect disappears?

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  5. Where is the evidence that you need to keep treating?

    Where is the evidence that you don't....Hauser et al. 2013. Neuro AAN.

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    1. The cells return in an induction treatment

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    2. The cells also return on alemtuzumab, right now my last control I was all on normal level, lower lymphocyte count that baseline but right on normal levels, still there's no need to retreat me (alemtuzumab), only if I relapse of course... then why ocrelizumab needs to be 6 monthly? It doesn't add up in my understanding

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  6. A few considerations go into this, one of which is a dose response curve which is done (called pharmacokinetics). This is done early on and determines final dose. Through to cost-utility analysis (business model) and potential side effects. An agreement is then reached between these and other factors.

    If you take rituximab for example, this varies on whether a neurologist or a rheumatologist uses it. For another autoimmune condition (an orphan disorder) I've used more than one rituximab cycle back to back to achieve the desired response.

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