Sunday, 7 July 2013

Restoring self-tolerance is the way to go

#MSresearch #MSblog restoring self-tolerance for a cure

You said "The name of the game is restoring self tolerance not immunosuppression" I could not agree more. 

This is the approach we developed a while back a quick depletion and then onto an immune tolerance strategy. 

No one has paid attention....which is sad.

In a mouse two injections in a lifetime and no more destructive autoimmunity if done quick enough.  Works virtually every time. Relapse rate dropped >99%.  Compare this to the chaff, we read week-in, week-out

Both elements have now been used safely in MS, both elements individually not great. 

However, not very useful for a pharma who are into selling units. It took a certain company or two, years to do studies to show you do not have to inject drug so often to get the same benefit could you drop it down to once a month etc.

Maybe we should see if this works with GA in the beasties

Mike Boggild from Liverpool, now banished to Australia:-), 
developed an treatment regime that applied this approach


Mitoxantrone has been approved by the FDA for worsening relapsing-remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased. 

No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone. A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans. Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.
Disability was stable or improved in all patients a mean of 36 (16-66) months, which is better than some current first treatments.


The sustained drop in relapses is as good as anything on the table, I remember seeing the data and thinking it was pretty impressive, but I do not think the Teva were particularly supportive at the time as they had their own agenda, could be wrong. An opportunity missed.
I never understood why this was not developed further. Probably cause they (Teva) could not patent the combination as Mike had the idea and spoke about it. Who knows? 

I think we will see this approach being developed in the future my guess would be lemtrada then aubagio both Sanofi/Genzymne drugs or a mix with laquinimod.
We will see if this approach works in the hands of ProfG as we have some brave pioneering MSers see his trials.

4 comments:

  1. Better yet use the combo : nanoparticle with myelin ags developed at northwestern and switzerland after mitoxantrone as immunosuppressant to restore tolerance. Phase one is under way.

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    1. Great idea

      OK you have now had that thought in the public domain so Northwestern cannot patent it so how will they protect the approach?

      However I wish Northwestern would put this into the mix when they do the next stage it will make their drug work better.

      We are testing this approach in human autoimmunity, recruitment has been slow.

      Delete
  2. That looks like a good approach. Its too bad if the combination or sequence has to be put through a trial before the physician can use it. It seems many patients on Tsybari have nothing to transition to and have the possibility of rebound after stopping. If they were able to start Copaxone six months prior to stopping Tsybari they might not have a rebound and have a solution that they might be able to live with permanantly.

    I think the patch peptide drug would be ideal if it works. I don't know why Teva hasn't looked into this but I suspect it is harder than it seems. Here is an article about peptide drugs:

    http://www.esciencecentral.org/journals/MCA/MCA-1-e103.pdf

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    Replies
    1. There are a few peptide approaches in development, maybe that is the next encarnation of glaterimer "cop in a patch" when the next patent runs out.

      In the age of litigation it is hard for the neuros to take the plunge.

      Maybe in the future someone will bring it onto the agenda however can neuros develop an MS drug or drug combination without the backing of a pharma. Does anyone have some good examples, that are not in the field of cancer? Has anybody every developed a drug in modern history without pharma involvement, especially when there is a pharma alternative.

      The Wellcome trust and the Government is asking for studies to repurpose drugs, which say means taking a drug for one disease and then use it in say MS.

      An example would be simvastatin= a sniff of activity in phase II trial next stage is do a phase III trial taking x years, but then what?

      Do you apply for licence for simvastatin from MS..but who pays for the regulatory aspects, which is not insignificant. Who holds the licence. What will NICE think.

      If you do not know the answer to this should you start the process.Now pharma then get a drug that works and then where are you, surely there can't be double standards and academics will have to jump through the hurdles that pharma jump through

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