Sunday, 15 January 2017

No Evidence of Disease activity with daclizumab

#Clinical Speak. Where to position daclizumab

#AchillesHealSpeak.Is MS a Tcell issue

Kappos L, Havrdova E, Giovannoni G, Khatri BO, Gauthier SA, Greenberg SJ, You X, Wang P, Giannattasio G. No evidence of disease activity in patients receiving daclizumab versus intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis in the DECIDE study. Mult Scler. 2016 Dec 1:1352458516683266.


BACKGROUND:

No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS).

OBJECTIVE:

Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150 mg subcutaneous versus intramuscular interferon beta-1a 30 µg for 96-144 weeks.

METHODS:

NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd+) lesions. Logistic regression models adjusted for baseline covariates compared treatment groups for baseline to week 96, weeks 0-24, and weeks 24-96.

RESULTS:

From baseline to week 96, more daclizumab versus intramuscular interferon beta-1a patients achieved NEDA (24.6% vs 14.2%; odds ratio (OR; 95% confidence interval): 2.059 (1.592-2.661); p < 0.0001). ORs for clinical NEDA (no relapses, no CDP) and magnetic resonance imaging (MRI) NEDA (no NET2, no Gd+ lesions) were 1.651 (1.357-2.007; p < 0.0001) and 2.051 (1.628-2.582; p < 0.0001), respectively. ORs in favor of daclizumab for weeks 24-96 were consistently higher than for weeks 0-24.

CONCLUSION:

More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time.

Here is one for ProfG to do as he is a coauthor of the paper, he may have an answer and maybe this is going to be something that he will have to wrestle with, that is if NICE approve the treatment. I suspect they will after abit of haggling over price.  

But the big question is going to be where is this drug going to be positioned?

Based on its effect on relapses it is in the moderately effective treatments and is injected every month. Looking at the rate of NEDA, it is better than beta interferon but a long way behind the highly effective agents.  

There is a risk of skin reactions with this agents and in a few percent of cases it can be quite severe. Maybe this is because it depletes T reg cells because they express CD25 and daclizumab blocks CD25. 

This is the high affinity interleukin-2 (T cell growth factor). 
Does this work because it blocks activated T cells which express the IL-2 receptor? This was surely the logic for trying it because if they knew about Tregs then surely T cell immunologists would not have attempted to use it.

Block Tregs and MS should get worse if we follow the dogma, because T regs block autoimmunnity. This the dogma and something that must make the T cell brigade wiggle
Surely MrT will agree with this. 

Maybe MrT will give the answer...it doesn't deplete Tregs enough for it to be important. Maybe the job of the Treg is to stop autoimmunity occuring in the first place, but once immunity has been intitiated they don't do much?

However, it doesn,t make MS worse so again what does this say about T cells causing MS? 

However when you block the CD25 the circulating levels of IL-2 increase this binds to the intermediate affintiy interleukin 2 receptor and this is expressed on natural killer cells and so they expand. Natural killer cells are a type of immune cells involved in killing cancers and infections. So is this how daclizumab works, by being more anti-viral?  So is this saying that there is a virus linked to MS?

Is it working some other way than T cells, this agent has to tell us something about MS because after all it is doing something.

The big dilema is how to position this drug? 
It has efficacy of some first line drugs, but side effect that may lead to second line (being too expensive normally guarentees this with NICE). 
How do the companies marketing the drug, position the drug? As they have 
loads in their stable.

Not being a clinician I don't have to conudrm

CoI Prof G is author

4 comments:

  1. When BG12 approved for MS (Tecifdera) I heard about a presentation in which the performer noticed "It might will cannibalize Natalizumab (Tysabri) because BG12 is highly effective agent with very low PML risk. In the last 4 yrs we have seen that BG12 (Tec.) is only a moderately effective treatment below Fingo. (Gilenya) and above CRAB drugs.
    I think Daclizumab will have the same place...
    Whats your opinion? MouseDoctors, ProfG?

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    Replies
    1. I think they can be ranked by their mechanism of action activity

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  2. Have you heard that there has been a 5 case of PML on Tecfidera. The patient had a low lymphocyte count as well.

    ReplyDelete
    Replies
    1. I have no not maybe ProfG may get the low down

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