Monday, 30 May 2011

How the oral DMTs stack-up againt each other in terms of efficacy

I keep getting asked what is the most efficacious oral DMT? The following table is a summary of the headline results of the phase 3 studies for the 5 oral DMTs:

                                      Reduction                       Reduction
                             Annual Relapse Rate      Disability Progression

1. BG12                        53%                                  38%
2. Cladribine                58%                                  33%
3. Fingolimod              54%                                  30%
4. Laquinimod             23%                                  36%
5. Teriflunomide          32%                                  30%

Please remember that all agents are associated with particular side-effects and other attributes; hence the decision on which one is more appropriate for a particular person will require some careful thought. Individualised Medicine!

CoI: I have conflicts of interests in relation to all of these compounds. Barts and The London is involved in the clinical development of all of these compounds and I personally have received compensation for acting as an advisor to Biogen-Idec (BG12), Merck-Serono (Cladribine), Novartis (Fingolimod), Teva (Laquinimod) and Sanofi-Aventis (Teriflunomide).

18 comments:

  1. "I personally have received compensation for acting as an advisor to Biogen-Idec (BG12), Merck-Serono (Cladribine), Novartis (Fingolimod), Teva (Laquinimod) and Sanofi-Aventis (Teriflunomide)."

    I thought you worked for the NHS? I personally don't like the way drugs companies use public servants to help them - they should have their own scientists. If I worked for the Department of Transport and received funding from BA and Virgin Atlantic there'd be uproar.

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  2. As with injectibles, the effects are modest at best. All only provide a reduction in disability progression in the 30%s. Seems to be little relationship between reduction in annual relapse rate and reduction in disability progression. Why can't the researchers focus on reduction in disability progression e.g. why is BG12 higher and how can we enhance this mechanism.

    I'm with the earlier poster. Too much money involved in MS research - funding from MS societies, funding from phama companies, big profits for MS drugs (which are only modestly effective at best).

    There must be a better way to fund MS research and get some real results. At the moment there's a comfort zone - researchers know they will get grants, drugs companies know they will make profits, hence no one will rock the boat. Payment by results would be one solution i.e. the promise in the research application must be delivered. If not, no more grants. We need to be incentivising researchers to make real breakthroughs with MS, not a made up mouse disease.

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    Replies
    1. Amen. I couldn't agree more.

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  3. There isn’t urgency in MS research. There doesn’t seem to be a need to explore the efficacy of drugs that have been licensed for other conditions that may actually benefit progressive MS patients more than they do say stroke victims. These drugs have already been approved and licensed so they can be fast tracked for use in MS with less in the way of red tape. None of the results for these 5 drugs mentioned are particularly brilliant yet this is the best they could do in the last 20 years of expensive research and heavy investment. It’s annoying when MS societies campaign in the name of finding cure because they’re so ill equipped to do something like that. There’s no way they have the gumption to execute a proper plan of action to effectively treat MS progression. You watch, MS progression will be just as untreatable in 10 years time as it is right now. I don’t know how any scientist can be proud of the efficacy results listed on this table because they’re mediocre at best.

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  4. Prof G,

    You've mentioned a few times that there are unrealisitc expectations as to what can be achieved. Unfortunately, these are often fuelled by the MS socities. The National MS Scoiety raised millions of $s for its Promise 2010 initiative. One of the aims of the initiattive was:

    "The Nervous System Repair and Protection Initiative, funded through the Society’s Promise: 2010 Campaign, is bringing the dream of protecting and repairing brain tissue and restoring function within our grasp."

    I contributed to this initiative back in 2005, but can't see any treatments for protecting and repairing brain tissue on the horizon. The only trail with any potential for neuro-protection is the CUPID trial - but this started before Promise 2010 - so annoying that it is being linked.

    I imagine to get funding for initiatives, some big claims are made e.g. repair of the nervous system. As soemone with MS, you can see how we get sucked in (and donate).

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  5. Pharma companies need expert clinicians to help design and run their trials and to monitor the safety of the subjects in the studies. These are called "steering" and "data and safety monitoring" committees, respectively. I sit on several of these committees in relation to these drugs and get paid compensation for my time. This in my opnion constitutes a conflict of interest and therefore needs to be disclosed.

    I think it is important or even critical for these committees to be made up of people who are independent of the companies involved. The regulatory authorities have produced guidelines to this effect.

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  6. "I contributed to this initiative back in 2005, but can't see any treatments for protecting and repairing brain tissue on the horizon."

    Is this a fact Prof G? Are things really that hopeless? You read about so much stuff going on that it seems a bit bad that there isn't anything on the cusp for protection or repair.

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  7. Tysabri offers a 68% reduction in relapse and 42% reduction in progression (according to their website).

    PML on the side, what is the point in funding USD 100s in less effective treatments?

    Do they really think that a rational patient will take a less efficient drug to avoid the hassle of going to a hospital once a month?

    Lots of money involved... We need an Arab Spring in MS economics!

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  8. "I think it is important or even critical for these committees to be made up of people who are independent of the companies involved. The regulatory authorities have produced guidelines to this effect."

    I can't see how one could be independent if the company pays you (not you specifically). At the end of the day a neuro will prescribe an MS drug and this should be done on the basis of what is best for the patient. Potentially the neuro could have been involved in the trails for the drug / paid for in an advisory role. The recent case involving Rebif (company paying neuros to push their product) show the dangers of mixing money and doctors. I want my doctors to be totally independent of drugs companies (which are focussed on profit).

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  9. Re repair and protection. There are therapies on the horizon. We have recently been funded on the back of our work in the PROMISE 2010 programme to test a neuroprotective drug phenytoin in optic neuritis. We have also submitted a second trial proposal to test the drug oxcarbazepine in SPMS; again this trial design is based on insights from our PROMISE 2010 work. The UK MS Clinical Trial Network have been working a new trial design for testing drugs in progressive MS. We anticipate this study starting in early 2013. It uses an interesting trial design called adaptive design. The chief investigator is Dr Jeremy Chataway, who is based at the National Hospital for Neurology and Neurosurgery.

    Finally, it appears that some of the newer DMTs may be neuroprotective; these include Fingolimod, Alemtuzumab, BG12 and Laquinimod. Biogen-Idec are also testing anti-Lingo, which is a molecule that should promote remyelination.

    I think the field is very active. Don't you?

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  10. Re independence. This is complicated issue and I take your point seriously. Just before his retirement, Professor Ian McDonald, my mentor, stated "the reality is that if we want to develop disease-modifying therapies for people with MS we have no option but to collaborate and work with the Pharmaceutical Industry. At a personal level you shoud not work with one company, but several." He implied that your only protection against bias and undue influence was to have many competing conflicts of interest. Any other suggestions?

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  11. Re Tysabri, or Natalizumab, being more effective. I agree, but it comes with more risks. Some PwMS may opt for a less effective drug that is safer.

    You must also realise that these results refer to the average effect in the trial and include patients that are responders and non-responders. At present we don't know how to predict who will be a responder or non-responder. We simply have to try the drug and switch patients that are non-responders. This the maintenance-escalation strategy I discussed in an earlier posting.

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  12. Re repair and protection

    Many thanks for setting out the position.

    I don't think any poster doubts your commitment to the cause. For those with the disease we would obviously like to see treatments now - so there is quite a bit of frustration for those with progressive MS. You've put your head up above the parapet by having this website and are, as a consequence, seeing some of the frustration.

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  13. The poster above is right Prof G. Most neurologists are terrified of the angst proliferating from the progressive MS community and will avoid it when possible. By having this website you will no doubt be confronted daily by steadily degenerating MS sufferers who live in denial that there is absolutely nothing medical science can do for them right now.

    Nonetheless, this is a great blog. I try and imagine just how frustrating the situation must have been 15 years ago when the average MS patient had no way of accessing information pertaining to their disease. Knowledge is power and the MS community need to learn as much as possible so that their consultants can't just undervalue them by providing unsatisfactory answers. Demand more from your neurologists. Make them work harder for you. Keep on their cases. Put them in a position where they're going to want to help you out and not just discard you till the next appointment in a year's time. Make them want to find effective treatments even more than what you do. Also, don’t be shy of showing off your understanding of MS and new treatments in development. An expert patient is worth their weight in gold.

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  14. "I think the field is very active. Don't you?"

    I guess. I suppose the expectations and demands are too high for you guys to really deliver. If this Anti-Lingo-1 stuff checks out then that would really be something. They say it may even encourage "axonal outgrowth", though I don't know if that a good or bad thing? The Anti-Lingo-1 phase 1 trials end tomorrow and let’s hope that phase 2 and 3, where the real work begins, go better than expected, though nobody should expect the drug to hit within the next decade because there’s way too many hoops of fire to jump through first. Still, it’s good to know remyelination is almost a tangible reality and not just fantasy.

    Keep doing what you're doing man. Hopefully there’ll be something to show for it in the end... though it'd be nicer if that something came sooner rather than later.

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  15. "your only protection against bias and undue influence was to have many competing conflicts of interest": Seems to me that this is a very good position to take.

    I'd like to echo what another commenter has said - this is a great blog. Thank you so much for doing this Prof G. I'm sure it takes a lot of time and energy.

    I hope the comments stay free of rants, flames, etc. All of us reading this blog share many of the same frustrations, but please do not use this as a forum to vent them.

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  16. Re "Seems to me that this is a very good position to take"

    This is not a position of design. If you want to help PwMS and offer participation in clinical trials as part of your clinical service you have to engage with Pharmaceutical companies developing MS therapies. In addition, you also develop relationships with key people in these organisations and are therefore in a position to influence strategy; for example to focus on symptomatic therapies.

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  17. Due to allergies I can't take any of the standard 4 injectable DMDs so I was part of the Cladribine cohort until Merck pulled it from the market here in Australia and for the last 18 months I have been waiting without treatment for BG12 to come along. Now in desperation I have started Aubagio 10 days ago even though it is the least effective of the orals. I have a couple of questions.
    1) Any idea when BG12 will make it to the market now? What is the state of play with the FDA at present?
    2) Can a person switch straight from Aubagio onto BG12?
    3) And finally, any idea how long the gastrointestinal side effects of nausea and diarrhoea last with Aubagio? Feeling a bit fed up with feeling so sick from it.

    Thanks.....

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