Friday, 30 October 2015

Will Teva and Biogen Come together for the sake of DMF, laquinimod polypill

Hund AC, Lockmann A, Schön MP. Mutually enhancing anti-inflammatory activities of dimethyl fumarate and NF-κB inhibitors - Implications for dose-sparing combination therapies. Exp Dermatol. 2015 Oct 29. doi: 10.1111/exd.12892. [Epub ahead of print]

Fumaric acid esters, dimethyl fumarate (DMF) in particular, have been established for the therapy of psoriasis and, more recently, multiple sclerosis. In light of therapy-limiting dose-dependent side effects, such as gastrointestinal irritation, reducing the effective doses of FAE is a worthwhile goal. In search of strategies to maintain the anti-inflammatory activity of DMF at reduced concentrations, we found that NF-κB inhibition augmented key anti-inflammatory effects of DMF in two complementary experimental settings in vitro. At non-toxic concentrations, both proteasome inhibition with bortezomib as well as blocking NF-κB activation through KINK-1, a small-molecule inhibitor of IKKβ, profoundly enhanced DMF-dependent inhibition of nuclear NF-κB translocation in TNFα-stimulated human endothelial cells. This resulted in significant and selective co-operative down-regulation of endothelial adhesion molecules crucial for leukocyte extravasation, namely E-selectin (CD62E), VCAM-1 (CD106) and ICAM-1 (CD54), on both mRNA and protein levels. Functionally, these molecular changes led to synergistically decreased rolling and firm adhesion of human lymphocytes on TNF-activated endothelial cells, as demonstrated in a dynamic flow chamber system. If our in vitro findings can be translated into clinical settings, it is conceivable that anti-inflammatory effects of DMF can be achieved with lower doses than currently used, thus potentially reducing unwanted side effects
Tecfidera has poor pharmacokinetics meaning repeated administraion over the day and it has some problems associated with gut. This study indicaes that tecfidera has some affect on NF-kappa B, which is a factor that is involved in activating cells to produce cytokines and other pro-inflammatory things. In this study they inhibit the NF-kappa B  and this augumented the action of Tecfidera. So if you could do this could you reduce the dose and the side effects of tecfidera. So what drug inhibits tNF-kappa B and an answer is Laquinimod. This is a not very good DMT interms of blocking relapses but it may be neuroprotective. Do you think that they Biogen and Teva would form an alliance to see if a combination of the two would work...... Yep my thoughts too.

However this highlights the importance of understanding how drugs interact and whether the action of one interferes or augments another. It is important and it is also another reason why induction therapy has advantages as it allows you to add drugs on top of immunomodulation without the worry of drug interactions as the first drug.

7 comments:

  1. If blocking TNF responses "upstream" — at receptor or ligand site is detrimental in humans, how blocking them downstream (NF-kB) could be of help?

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  2. p.s. most of the tryptamines and phenylethylamines from your chart would "superpotently" block bf-kb/p65 translocation, you know. :3
    pps. including DMT (not DMT but dimethyltryptamine), coincidence? I don't think so

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  3. Here is the patent that claims higher efficacy in MS of dimethylfumarate combinations with teriflunomide, fingolimod, or laquinimod:
    http://www.google.com/patents/EP2692344A1?cl=en

    Here is an older publication of combination therapies (dimethylfumarate plus immunosuppressants) in psoriasis:
    http://www.ncbi.nlm.nih.gov/pubmed/15099371

    Is blocking nF-kB really important for combination therapies with tecfidera?

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    Replies
    1. And patents with data too
      WO2013148690
      TREATMENT OF MULTIPLE SCLEROSIS WITH COMBINATION OF LAQUINIMOD AND DIMETHYL FUMARATE

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  4. Would you consider Tecfidera as a good DMT compared to the others if, as myself, you don't get any side effects at all ?

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  5. "This resulted in significant and selective co-operative down-regulation of endothelial adhesion molecules crucial for leukocyte extravasation, namely E-selectin (CD62E), VCAM-1 (CD106) and ICAM-1 (CD54),"

    Isn't this the mechanism of action behind Natalizumab?

    And why would they need to use Laquinimod with the DMF? Why not just use what they used in this experiment?

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