Monday, 11 February 2013

Initial thoughts on the IPMSC 1st Scientific Conference

"I am disappointed with the IPMSC poll results. The results are quite striking in that very few people who completed the poll were expecting a breakthrough! I this because we have been promising so much to progressive MSers for so long that we have lost all credibility?"

"However, there is lots of good news from the meeting. In my opinion, the results simply don't reflect the enthusiasm of the attendees at the meeting and this included the MSers who attended the meeting. You have to look at the innovations and progress that has been made in relation to MS over the last 20 years. It is simply a matter of time before breakthroughs in progressive MS occur. I am a great believer in innovation and man's ability to innovate; if we keep investing in research the breakthroughs will happen."



"Although there were a few MSers at the meeting they could have had more involvement in the meeting. I think a section run by professional/expert MSers would have been helpful in focusing the minds on the problems MSers face."

Session 1: Target identification and repurposing

"This section reviewed  the genetics and pathology of MS. In summary there are no genetic variants that have been identified that drive progressive disease. Not enough time was spent on discussing targets. Marco Salvetti stated that we have too little time to generate new knowledge and find new targets. He appealed to us to mine existing data sets and focus on repurposing existing drugs. His position is fine but blue sky research still needs to be funded. Basic science research is the 'soul of innovation' or the 'oil that flows through the innovation pipeline'."

Session 2: Experimental models

"Several of the speakers stated that there are no adequate animal models of progressive MS. Mouse Doctor should have been more vocal in supporting and pushing his model, which most of us think is an excellent model of progressive MS. It is really the only one on the block and we have used it to push forward several clinical trials. As always Bruce Trapp showed why he is the most erudite speaker in the field of MS; clear, provocative and to the point. Bruce made the important point that if we don't find the cause of MS how we can't really treat it. I agree! We need more resource allocated to finding the cause of MS. he hinted, what I have suspected for a long time, that the current autoimmune paradigm is incorrect. Hans Lassmann tried to cover too much in his talk; I had difficulty following the central thread of his argument. Hans did make the point that we should be focusing our treatments on targets in the innate immune system, which in his opinion is driving progressive disease. The obvious target being activated microglia; the cells in the CNS that clear up debris and produce a lot effector molecules; these are the molecules that do the damage, and are hence therapeutic targets."

Session 3: Proof-of-concept clinical trials

"I spoke in the session and reviewed the current dogma of MS and presented the three clinical trials we are involved in at present that are looking at neuroprotection in MS. The response to my talk was muted; probably because I sound like a stuck record. However, I did get the message through that lumbar punctures and CSF analysis is one of the ways forward. Jeremy Chataway gave an excellent talk on adaptive clinical trial designs. Massimo Filippi's talk on MRI allowed the MRIologists to hijack the session. This is not surprising as they have the most validated biomarkers for progressive disease. Jerry Wolinsky highlighted the issue of co-morbidities possibly driving progressive MS and stressed how superimposed diseases, for example hypertension, diabetes, etc. making MS worse. He also mentioned the effect of ageing on MS; this is something we have been working as well. Did you know the best predictor of the onset of progressive disease is age? There must be a clue to progressive disease in this fact! Raj Kapoor stated clearly were the investment is needed to make a difference."

Session 4: Clinical outcome measures

"This sessions highlighted the main problem in the field. Our current outcome measures for measuring progressive disease are not fit for purpose and need an overhaul. Despite this clear message from Jeremy Hobart it seems as we have to stick with the EDSS; this is what the regulators want. At least  there are initiatives to improve the EDSS and the MSFC (Multiple Sclerosis Functional Composite). This session also highlighted the need for using new technologies; for example tablet and smart phone Apps for measuring the impact of MS on function. Some of the emerging developments in this field are very impressive; including one that uses software that runs on an iPad strapped to your back."

Session 5: Symptomatic therapies

"This session highlighted the massive unmet need there is with symptomatic problems in progressive MS and how poor the current evidence base is. I personally think this section needs it own separate initiative. It will always get short changed by the DMT lobby. The main focus was on cognition; not surprising considering MS is probably a gray matter disease. The talk of the session that interested me most was the one on exercise therapy and it role in treating progressive MS.  It became clear in the question session that exercise studies are hard to do, for example how do you blind them and how do you control for the type and duration of exercise?"

Session 6: Non-profit, academia and pharma views

"This was the most inspirational session of all, in particular the talk by Steve Buchsbaum from the Melinda and Bill Gates Foundation. Wow, what and organisation. They are also studying the impact their organisation is having on Science; the early data suggests that they are changing the research agenda. Good for them, the world needs more people focusing on global health. I regret not reminding them as developing nations become healthy  that MS will be as much a problem as it is in countries like Iran and India. The session provided a lot of examples of how successful research networks function and what resources are required to make them work. The talk from Sarah Tabrizi on the Huntington's Disease (HD) Network is an example of how strong leadership with vision can make a difference; and money!  The HD Network has had ~$15M to run its cohort study. It is clear that we need something like this in MS. "

The following would be my list of action points from the meeting:

1. Start a new prospective progressive MS phenotype cohort study; for this to work it needs visionary and strong leadership with skilled administrative support. Data from this study will need to be stored centrally and shared via an open-source platform.

2. Mine existing data sources and repurpose existing drugs. To do this successfully we need an alternative to big pharma for drug development, in particular a regulatory framework for the licensing of off-patent drugs.

3. Develop new outcome measures; these need to be MSer friendly. A focus on new technologies would help (smart phones, etc.).

4. Promote existing animal models of progressive disease.

5. Actively promote and support new study designs; the more we do the sooner we will get drugs to progressive MSers.

6. Engage regulators at an early stage; we should have had people from the FDA and EMA at this meeting. 

7. Manage expectations of MSers; they need to understand the scientific process and time-lines involved. Science needs time to mature. 

8. Include CSF studies in all progressive MS trials. The Alzheimer's Networks came  to this conclusion years ago. 

9. Manage RRMS early and aggressively and collect data to help prove the hypothesis that actively treating RRMS prevents or delays the onset of progressive MS. Prevention is better than treatment.

10. Study and treat MS co-morbidities; this may prove to be the low hanging fruit in scoring an early hit in progressive MS.

11. Promote Big Pharma's role in treating progressive MS; there are several definitive phase 3 trial programmes running at the moment (fingolimod - PPMS, ocrelizumab - PPMS, natalizumab - SPMS, siponimod - SPMS). One of these trials may prove to be the tipping point. Big Pharma was too quite at this meeting. They have the resources and will to make the most difference for progressive MS, we should not forget this! 

15 comments:

  1. Dear Mr Gavin,

    I have a couple questions connected to the endpoint "Confirmed disability progression" as an endpoint in clinical studies, which I hope you can comment:

    When you read about that a MS-agent, at 2 years clinical study duration, reduce the risk of 12 week confirmed disbality progression by XX % vs placebo. What does that mean (?) - I don´t quit understand the meaning of it (?) Is it reffering to the fact, that the disabilty must be confirmed 12 weeks after the 2 years duration of the clinical study or what?

    Linked to this, I see in some reports that they use a more stringent criteria (!) with regard to disability progression; it must be sustained for 24 weeks.

    NOw, I would be happy if you could explain:

    1.
    Do you measure, that to be defined as a diability progression, the disability must be sustained for 3 months after a performed 2 years clinical study; i.e. 2 years + 12 weeks ?
    2.
    Depending on what your answer will be on the above question, isn´t a
    a more reliable, stringent criteria, to measure a sustained diability 6 months (24 weeks) after a clinical study with a duration of 2 years has ended ?

    If the disability is confimred 6 months after the 2 years study has ended, it is, in my view, more reliable than if it is confirmed 3 months (12 weeks) after the study has ended ?

    My above conclusions, of course, depending on from where on the time line you start to measure sustained disability progression; in my interpretation, ´starting point is after completion of 2 years clinical study. At that timeline, you see what disability the patient has - and to be confirmed as a disability, it must be sustained for 3 months after the clinical 2 years study has finished ?

    Hope you can clearify those issues for me and others.

    Sincerelly

    Anna

    ReplyDelete
    Replies
    1. Re "When you read about that a MS-agent, at 2 years clinical study duration, reduce the risk of 12 week confirmed disbality progression by XX % vs placebo. What does that mean (?) - I don´t quit understand the meaning of it (?) Is it reffering to the fact, that the disabilty must be confirmed 12 weeks after the 2 years duration of the clinical study or what?"

      It means that if someone starts at EDSS 3.5 and progresses in the trial to EDSS 6.0 or needing a walking stick they need to be assessed twice as having an EDSS 6.0 to be called sustained or confirmed increase in EDSS. If these assessments are 3, 6 or 12 months apart this called sustained or confirmed EDSS progression at 3, 6 or 12 months. Some people may improve before this assessment and therefore will not qualify for this outcome.

      "Do you measure, that to be defined as a disability progression, the disability must be sustained for 3 months after a performed 2 years clinical study; i.e. 2 years + 12 weeks?"

      Only of the EDSS increased in the last visit of the study, i.e. at 2 years do you need to assess them 12 weeks later. Most trials ignore these assessments and power the study for events that can be confirmed before 2 years.

      "Depending on what your answer will be on the above question, isn´t a
      a more reliable, stringent criteria, to measure a sustained disability 6 months (24 weeks) after a clinical study with a duration of 2 years has ended ?"

      That is correct. Some people are arguing for a 12 months endpoint.

      Re "If the disability is confimred 6 months after the 2 years study has ended, it is, in my view, more reliable than if it is confirmed 3 months (12 weeks) after the study has ended?"

      We use a survival analysis to assess disease progression. Once you have progressed in a study you can't progress again. That is why we tend not to examine study subjects past 2 years as those that progress at the last visit (2 years) make up a very small number and don't add much to the power of the study.

      Re "My above conclusions, of course, depending on from where on the time line you start to measure sustained disability progression; in my interpretation, ´starting point is after completion of 2 years clinical study. At that timeline, you see what disability the patient has - and to be confirmed as a disability, it must be sustained for 3 months after the clinical 2 years study has finished ?"

      Disability progression can occur at any time during a study; less than 10% or even 5% of confirmed progressions occur at the end of the study!

      Delete
    2. MOst grateful for your answer.

      Sincerelly
      Anna

      Delete
  2. It sounds as though a great deal was covered at the conference, almost as though the research community had a chance to 'get their ducks in a row' and see the size of the problem as a whole - and see where some of the solutions might come from. Thanks for your summary of all the talks, it sounds like real progress was made. If you think it a good idea for more MSers to attend, will the arrangements be publicised widely? Will there be an annual meeting?

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    Replies
    1. I have no idea! That will be up to Prof. Alan Thompson and the steering committee.

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  3. Sorry you are disappointed at the poll results. Maybe that is down to a different interpretation of 'breakthrough'? For MSers this probably means a treatment for progressive MS coming out of the week - a tall order! For researchers (maybe) it means to get a real handle on the problem including how to go about research in the broadest sense: funding, trial design, targets etc etc Just a thought...

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  4. What will happen to the actions on your list of action points? Thanks

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  5. Some of your action points G are very sharp - I also think that new technology should be used more widely (often not that expensive) & including regulators is also a very good move. Hopefully you gonna meet soon again - perhaps with additional experts from other neurodegenerative/immune diseases?
    It would be great if Bill Gates' foundation got involved in progressive MS!

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  6. I agree with the post above about the definition of the term breakthrough. Progressive MSers need treatment no, but I expect the earliest any treatment will become available will be 5-7 years time. While the neuro-protective trials (amiloride etc) are a step forward, I really can't see anyone funding the Phase 3 trials necessary for licensing. If any of the Phase 2 trials show efficacy, then neuros in discussions with their patients shoudl eb left to make a decision as to whether the patient coudl start the treatment. The conversation might go:

    Neuro: xxx drug has been shown to slow progression by 50% and has a long safety record. Here is a leaflet setting out the benefits / potential risks. Come back in a week and we can discuss whether you would be interested in me prescibing you this treatment. The final decisionw ill rest with you, but I'm happy to talk discuss the pros and cons in detail.

    Patient: thanks for giving me the choice. I'll read the materials and come back to you.

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  7. Prof G,

    There were some key messages in your note of the proceedings:

    "The main focus was on cognition; not surprising considering MS is probably a gray matter disease."

    "Bruce Trapp... hinted at I have suspected for a long time, that the current autoimmune paradigm is incorrect."

    If I'm right from my reading of these statements, you are sayign that MS isn't an autoimmune disease which targets myelin (white matter).

    If it's a grey matter disease, does this mean that the targets are nerves fibres / nerve cells? And if it's not the immune system turning on the body it is supposed to be protecting, what is causing the damage to the grey matter?

    What do the two statements above say about the current research / clinical trials which are underway - waste of time? What about myelin repair / replacement - waste of time?

    I wonder why I'm so cycnical about MS research, but then I realise why - as soon as it looks like we are getting near, it's all thrown up int he air again!!!!

    ReplyDelete
    Replies
    1. If it's a grey matter disease, does this mean that the targets are nerves fibres / nerve cells?

      No oligodendrocytes and loss of myelin are still implicated...what is causing the damage to the grey matter? The immunologists say immune cells others say virus.

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    2. And why would the immune cells damage the grey matter? What could drive them?

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    3. infected/distressed oligodendrocytes perhaps

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  8. Progress is too slow/ progression is too fast: catch 22.

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  9. Thank you for the excellent summary

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