“This paper describes the effect of daclizumab on MSers with highly-active MS. It is reassuring to note that daclizumab is as effective in this subgroup as in MSers with less active disease.”
“Daclizumab is the dark horse of the current DMTs in late-stage development. It has a greater impact on decreasing disability progression that what you would expect from its impact on relapses. Therefore it may be having some impact on downstream events similar that what has been observed with laquinimod. This is interesting in that Daclizumab is a antibody therapy that appears to be working via expanding a population of immune cells called natural killer cells or NK cells. NK cells are part of our so called innate immune system and have a role in fighting viral infections. Could the NK cell link be more evidence that MS is due to a virus? Daclizumab also seriously questions the role of CD4 T cells and regulatory cells in MS. Daclizumab works by blocking a type of receptor on T regulatory cells and diverting the growth factor, IL2, that binds to this receptor to other cells types. What is all this immunological information tell us about MS? I think T cell immunologists should take their blinkers off and ask themselves some questions about the biology of daclizumab and what it is telling us about MS.”
Epub: Giovannoni et al. Effect of daclizumab high-yield process in patients with highly active relapsing-remitting multiple sclerosis. J Neurol. 2013 Dec.
Objectives: The current post-hoc analysis evaluated the effects of daclizumab high-yield process (DAC HYP) vs. placebo in MSers with highly active RRMS in the SELECT study.
Methods: Highly active RRMS was defined as patients with ≥2 relapses in the year before randomization and ≥1 gadolinium-enhancing (Gd+) lesion at baseline. Because results were similar in the DAC HYP dose groups, data from the DAC HYP arms were pooled for analysis.
Results: Treatment with DAC HYP resulted in similar effects in highly active (n = 88) and less active (n = 506) RRMS MSers. DAC HYP reduced the annualized relapse rate by 50 % and 51 % in the highly active (p = 0.0394) and less active (p < 0.0001) groups vs. placebo, respectively (interaction p = 0.82). DAC HYP reduced new/newly-enlarging T2 lesions (highly active RRMS 76 % reduction, p < 0.0001; less active RRMS 73 % reduction, p < 0.0001; interaction p = 0.18), the risk of having more Gd+ lesions (highly active RRMS 89 % reduction, p < 0.0001; less active RRMS 86 % reduction, p < 0.0001; interaction p = 0.46), and sustained disability progression (highly active RRMS 88 % reduction, p = 0.0574; less active RRMS 46 % reduction, p = 0.0383; interaction p = 0.22) vs. placebo.
Conclusions: DAC HYP efficacy was similar across the spectrum of MS disease activity as assessed prior to treatment initiation.
Is Prof G forgetting his immunology?. Interleukin 2 is a T cell growth factor and blocking interleukin 2 receptor (i.e. dacluzimab) could stop activated (CD4 and CD8) T cells from developing their function.However, it should block Treg function which should be disasterous according to immune dogma
Very interesting and useful knowledge, but I really feel sorry for those poor MSers with highly active disease injecting themselves every month with the placebo, and continuing to relapse and become more disabled. I think the ethics of using a placebo nowadays is very dodgy, whatever the FDA may say about trial protocols. I know you've talked before about placebos in trials, but I just think it's very sad
Hear hear no inert placrbo.
Until the regulatory authorities change their position on this, placebo-controlled trials are unfortunately the name of the game.
How does the T-cell debate/CD4 issue raised here and in other posts look in terms of Alemtuzumab's effectiveness? Isn't Alemtuzumab's primary action against T-cells?
Alemtuzumab depletes any cell expressing CD52 which includes B cells and monocytes. I think the B cells and monos come back quicker than the T cells.
"…sustained disability progression (highly active RRMS 88 % reduction, p = 0.0574; less active RRMS 46 % reduction, p = 0.0383; interaction p = 0.22) vs. placebo."How is sustained disability progression measured? It is not statistically significant in the highly active cohort and half as effective in the less active cohort.
The subgroup analysis is not powered to show a difference; i.e. there are two few MSers in the group to analyse the result. You need to look at the larger study. I have posted on this in the past. Disability progression is measured using the EDSS and you have to have an increase in the score that is sustained for at least 3 months. http://multiple-sclerosis-research.blogspot.co.uk/2013/04/daclizumab-phase-2-results.html
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ProfG will need to respond to this as you are using his own words against himself
Guess he wont be able to do this one of us has touched the delete buttonmay be me when thinking I am pressing the reply button. However the daculizimab programme is on going.
OK, sounds like you do not want any bad press against DAC thus the "inadvertent" deletion of the post.But I think the notion that DAC could reprogram defective Tregs is a valid question. It looks like others are finding this might be the case also:http://www.ncbi.nlm.nih.gov/m/pubmed/22593175/
no this is not the case please repost the question if you have it, I remember it states that you do not think dacluzimab will get approved and you supplied a link to where profG was talking about adverse events on dacluzimb and that this could affect licensing. I can't remember the weblink and think the section was from about two years ago, but as I say I cannot respond to this because it was not my words but profG you are agreeing with.
There is a rely and a delete button next to each other, if you touch the delete it is gone for good. sometimes if you are using a mobile phone to respond these are very close together an some itmes items get deleted innocently