Tuesday, 2 October 2012

Will BG-12 be neuroprotective and useful for Progressive MS?

The question of BLOGGERS is what interesting is going to appear act ECTRIMS 2012 next week. 

There is an expectation that the new drug BG-12 is going to be good news and we know about the results of the phase III trials. This will feature heavily at ECTRIMS next week as the results of the CONFIRM and DEFINE trials are reported. 


Whilst new MS reports are thin on the ground maybe some food for thought.

The question we are all interested to know is what would BG-12 do in progressive MS? Is there a trial planned?

There is clear data from the trials in RR MSers that BG-12 can inhibit the development of relapse, but there is real interest in whether this drug has additional neuroprotective effects. There is a clear inference that it does and is neuroprotective by an action on Nrf2 , which gives anti-oxidant activity. 

What happens in animal models? Well at doses of 100mg/kg/day in rodents it does have neuroprotective effects as was presented at ECTRIMS 2011. [p958] Arnold H et al Neuroprotective effects of BG-12 on malonate-induced striatal lesion volume in Sprague Dawley rat brain

This dose is more than used in human trials, at up to 250mg three times a day (750mg/day = 10mg/kg). At oral 15mg/kg these was a marginal inhibitory effect of the immune response in rodents suggesting more drug is needed.

Now is we use the 12.5 times rule, which is used to estimate human dose based on a dose in mice (12.5 times less) which has a more rapid metabolism of drugs than humans then we may be in the right dose range. But the poster at ECTRIMS was interesting because if indicated that BG-12 was over 90% excluded from the brain compared to the blood. Maybe accounting for the need to use whopping doses. 

If this is correct the drug does not reach the nerves much, so it would not be as good as it could as a neuroprotectant. The question that needs to known is what are the brain levels of the drug in MSers (This may be known?). This may give us an idea of whether it can be neuroprotective. If it is great, there may be ways to engineer the drug to get more into the brain for more effect. Food for thought.

CoI: Team G has recieved funds from Biogen the makers of BG-12 and Prof G is involved in clinical trials.

6 comments:

  1. The EU commission banned Dimethylfumarate from products in 2009

    http://www.bis.gov.uk/assets/biscore/consumer-issues/docs/d/12-664-dimethylfumarate-direction-2012-dmf-guidance.pdf

    So this raises 3 questions for me

    1. If Dimethylfumarate is as toxic as the EU commission says, why can it be used in drugs?

    2. If Dimethylfumarate is used in drugs isn't it as toxic as they want to make us believe?

    3. Is this ban going to have an impact on the price of BG12? Because if you ban a product the production lines will be shut down and the supply will be much lower.

    I find it very interesting that the ban was spoken in the Phase 1 clinical trial of BG12. But that could be a coincidence, couldn't it?

    Don't get me wrong. I think it is one of the more interesting drugs because it has minimal sideeffects.

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    1. The Commission report you posted is interesting, and at first glance, I was worried about the dangers, but at second glance, I was more interested in the timing of the report and the release of the mass-marketed drug BG-12, now available in the US....


      In Article 2 of the report under the heading "Implementation," it states:

      "As of 1 May 2009 Member States shall ensure that
      products containing DMF and already placed or made
      available on the market are withdrawn from the market and
      recalled from consumers, and that consumers are adequately
      informed of the risk posed by such products."

      (Here, standing alone, one might think it a dangerous substance and seek to never go near it again!!!)


      But reading further, in Article 4 under the heading of "Period of application," it states:

      "This Decision shall be applicable until 15 March 2010."



      I don't think it was ever as toxic as they said it was; I think that was a way to encourage the average citizen from being able to obtain the substance and thus utilize it themselves when they found out what it could be used for, medically. Simply ban it. Then, when most of it is off the market, produce a pharmaceutical out of it, and make a lot of money. . . .


      . . . . . .Theory.

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  2. I have no idea I am sure that Biogen has knowledge and is not an issue for them.

    It seems the pdf is about removing the dimethyl fumarate from furniture and shoes as a mould killler, but it is causing allergies.

    The Biogen drug formulation will have gone through toxicity studies and its capapcity to cause dermatitis will be known.

    Always read the labels to see what the side effects are

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  3. That's interesting stuff. Has anyone thought of trying a much higher dose in humans? How were the doses arrived upon? It would be a shame if we are missing a neuroprotective trick because of inadequate dosing.

    More importantly, how do we assess whether a drug is neuroprotective during RRMS? We can see if it stops disability progression but in RRMS this is more about stopping relapses. We can see if helps SPMS but it might be too late by then so a failure here might unfairly lead to a conclusion it is not neuroprotective when, earlier on, it might be. How do we see whether it is stopping underlying 'hidden' neuro damage during the RRMS phase in a 2 or 3 year trial? Is our best bet for this MRI (MTR, atrophy etc) or is this where LP and neurofilament light comes in? Is anyone actually running a BG12 trial with a direct neuroprotective end point?

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  4. Higher doses. i.e 250mg is a big pill there are limits to how big a pill people want to take. People don't like taking horse drops.

    The more drug you have the more side-effects you are likely to have...Remember we want the drugs to be safe. Dosing limits are there for a purpose and should not be exceeded. In toxicity studies they work out how much animals can take. This helps inform phase I studies were the dose is slowly increased to see how it is tolerated

    The pharmacokinetics i.e. amount of drugs that gets absorbed and gets into blood and its desired concentration to mediate an effect helps determine drug dose also. This can be worked from animal studies and test tube tests. concentration. In the case of BG-12 there was a long history of human use so you have a working dose to affect the immune response. But for neuroprotection this is a bonus if it happens.

    I have thrown this question out there because it needs an answer and you also need to understand how it is excluded in heath and ask if that mechanism is present in MS. It may not be. also this is based on assumption that BG-12 is the active compound it may not be and the metabolites may have access to the brin. I do not know enough about the drug to answer these questions without doing homework. But these are things you think about and get answers to, but do not tell your competitors. Companies with nrf2 drugs maybe searching to see if their drugs get into the brain and so could get advantage over BG-12. Who knows

    We will see the MRI data at ECTRIMS this may give use clues on neuroprotection but the marketeers will spin this as it may give them a marketing advantage over other drugs.. The effects of other drugs have been reported if we see something more then that gives clues. For example it looked like laquinimod was doing more in that department but its effects on relapse were weak. Teva has put it on the shelf maybe they should have looked in PPMS/SPMS.

    As you say in trials we may get it wrong and drugs are not active at certain stages of MS or it takes too long to show they are active. An example of this could be both Lamotrigine and Cannabis trials, which may have failed because of trial design rather than issues with the drug. This is why we have to get different trials going. Some will fail and that is how it was with drugs for RRMS, the early trials failed because of wrong design and now you can get an idea that a drug is working in a few months because we know how to show this. It will be the same for progressive MS.

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  5. MouseDoctor, I guess you are aware of the work done in the Netherlands 2 years ago, where they compared some Nrf2 activators (BG12, tBhq, Protandim, Sulforaphan) in vitro, showing equal or better effects of the latter 3 to BG12 on Nrf2 activation. I know you are not fond of advising nutriceuticals to us MSers, but given the cruelty of the progressive stage, and the fact that no known therapy is available, would you say an empiric approach on any of these neutriceuticals would not be a crazy idea?

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