Thursday, 30 November 2017

Copaxone: yet another mechanism

Previously on this blog I've written about Copaxone and its "mechanism of the week". For example, here and here. I haven't done it for a while, but can't resist bringing this one to your attention.

Now it's anti-bacterial. What next? It inhibits EBV :-)

But I guess it must be working by blocking the microbiome:-).




Christiansen SH, Murphy RA, Juul-Madsen K, Fredborg M, Hvam ML, Axelgaard E, Skovdal SM, Meyer RL, Sørensen UBS, Möller A, Nyengaard JR, Nørskov-Lauritsen N, Wang M, Gadjeva M, Howard KA, Davies JC, Petersen E, Vorup-Jensen T. The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria.
Sci Rep. 2017; 7(1):15653. doi: 10.1038/s41598-017-15969-3.

Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis. It contains a large diversity of essentially isomeric polypeptides with the cationic and amphiphilic character of many antimicrobial peptides (AMP). Here, we report that GA is antibacterial, targeting Gram-negative organisms with higher activity towards Pseudomonas aeruginosa than the naturally-occurring AMP LL-37 in human plasma. As judged from flow cytometric assays, bacterial killing by GA occurred within minutes. Laboratory strains of Escherichia coli and P. aeruginosa were killed by a process of condensing intracellular contents. Efficient killing by GA was also demonstrated in Acinetobacter baumannii clinical isolates and approximately 50% of clinical isolates of P. aeruginosa from chronic airway infection in CF patients. By contrast, the Gram-positive Staphylococcus aureus cells appeared to be protected from GA by an increased formation of nm-scale particulates. Our data identify GA as an attractive drug repurposing candidate to treat infections with Gram-negative bacteria.


And whilst on the subject:


Grossman I, Kolitz S, Komlosh A, Zeskind B, Weinstein V, Laifenfeld D, Gilbert A, Bar-Ilan O, Fowler KD, Hasson T, Konya A, Wells-Knecht K, Loupe P, Melamed-Gal S, Molotsky T, Krispin R, Papir G, Sahly Y, Hayden MR. Compositional differences between Copaxone and Glatopa are reflected in altered immunomodulation ex vivo in a mouse model. Ann N Y Acad Sci. 2017 1407(1):75-89.



Glatiramer acetate is big business as it is the number one selling drug. But there's one problem: (no, not its level of efficacy) Copaxone is now out of patent protection and generics are entering the market place. 

So what do you do to protect your product?


You aim to show that the competitor compound is different?


Copaxone is a random mix of 4 amino acids and so different batches of the drug are different. 


Glatopa (a generic Copaxone that induces some genes different to Copaxone) is one variant, but is it therapeutically different?




22 comments:

  1. Couldn't resist ;-)
    https://www.youtube.com/watch?v=2x8D4T--0v4
    Now if it could also sop Donald Trump tweeting..........

    ReplyDelete
    Replies
    1. https://www.youtube.com/watch?v=A2_snSkpULQ
      "It slices it dices, it picks the kids up from school, gets rid of age spots....step right up..." :-)

      Delete
    2. Oh yes, you can't beat a bit of Tom Waits ;-)

      Delete
    3. The only Trump Twitter feed I visit:
      https://twitter.com/trumpdraws?lang=de

      Delete
  2. Nice post Md

    Should we analize the others to,Alemtuzumab ,cladribine,dmf,etc

    To see if they kill bacteria?

    Obrigado

    ReplyDelete
    Replies
    1. Oh I think some of them make bacteria...on person said they were fungus mungus after talking drug x...as they go so many infections

      Delete
  3. Have there been any studies linking TB to MS? It's a bacteria that can invade the CNS. It would also explain why BCG has therapeutic effect on MS.

    ReplyDelete
    Replies
    1. We have a few cases of TB and MS in east London

      Delete
    2. So your saying it's coincidental?

      Delete
    3. BCG has a different mechanism of action (MD will not like that :))

      In their research,
      Dr. Faustman and team
      show that BCG may induce
      a permanent increase in
      the expression of genes
      that restore the beneficial
      regulatory T cells (Tregs) that
      prevent the immune system
      from attacking the body’s own
      tissues. BCG restores
      Tregs through epigenetics
      – a process that modulates
      whether or not genes are
      expressed.

      Pancreas must be involved in the process...

      Delete
    4. Also

      It has been proposed that BCG positive outcomes may act through the restoration of a normal NOTCH signaling [33], which can be perturbed by EBV infection via a RBPJ-mediated mechanism [34, 35]. These and other evidences implicate a role for EBNA2 and RBPJ in MS pathogenesis.

      http://www.academia.edu/13342106/EBNA2_Binds_to_Genomic_Intervals_Associated_with_Multiple_Sclerosis_and_Overlaps_with_Vitamin_D_Receptor_Occupancy

      Delete
  4. Ok, when it comes to studies with long words I have to look them up since I'm not a medical professional. This year I was diagnosed with 4 different digestive diagnoses. You are joking about blocking the microbiome, right? Thus the smiley face? Not my best year by a long shot, so please, please answer my question. Please. Thanks so much.

    ReplyDelete
    Replies
    1. Yes I am joking when I suggest the data suggests it is working by the microbiome

      Sorry to hear you are having problems

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  5. I wonder if this is why it's being tested for Crohn's...

    https://clinicaltrials.gov/ct2/show/NCT00731172


    There's also this of course: DOI: 10.1002/eji.201242758

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    Replies
    1. I guess this shows us how much weight the idea that copaxone is an MBP mimic has:-)

      Delete
  6. I will be unsubscribing. My many comments are never published or answered.

    ReplyDelete
  7. Any neurologist, with better therapies available today, still prescribing Copaxone in any form is either lazy, dense or getting kickbacks from Teva. If it does not stop disease progression compared to placebo, then it should not be prescribed.

    I don't care about its dosing schedule, generic forms, different mechanisms of action. If it does not prevent disease progression in any way, it is useless. The same goes with the interferons.

    The "CRAB" drugs are one massive economical and medical scam . How can they be cost effective to any healthcare system when they do not stop progression of MS, which is the only endpoint that matters?

    ReplyDelete
  8. You are not thinking at all about the patient.

    Sometimes Copaxone is the only thing people are able to get because of JC virus status, liver disease, previous cancer etc. Also, not everyone is thrilled about the potential risk of getting PML with some of the newer more effective agents.

    Just so you know, Copaxone is just as effective as some other "newer" MS drugs in reducing progression such as Aubagio (teriflunomide).

    ReplyDelete
    Replies
    1. Copaxone and interferons have the same level of efficacy as teriflunomide however that is worse than the others.

      Delete
    2. Anonymous 10:25 I am completely thinking about the patient and nothing else. Please show me one study that shows Copaxone stops progression of MS statistically significant above placebo. If it doesn't stop progression of MS, then you must ask yourself what place does it have in treatment of MS?

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    3. After 13 years of annual attacks, including a massive exacerbation in year 13 that knocked me out of the working world for 5 years I was finally diagnosed. The head of the local ms center told me he thought I was transitioning to SP and I needed to get on something. That was in January 2001. 13 plus years of Copaxone followed with no further attacks. I've now been off all drugs since 2014. What happened? Did Copaxone actually work?

      Delete

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