Friday, 20 February 2015

CrowdSpeak: some initial comments from the crowdfunding survey

More discussion and ideas about crowdfunding. #CrowdSpeak #MSBlog #MSResearch

"As a follow-up to my posts this week on crowdfunding. The following are a taste of some of the comments that have come through the survey. Please note that to stimulate conversation I proposed two projects of potential interest a hematopoietic stem cell therapy (HSCT) trial and the Charcot project (see below). It is clear that whatever we do we definitely need to address the unmet need in relation to progressive MS."

"Thank you for engaging with this initiative. I beginning to come around to the idea that we should continue to explore ways of taking this initiative forward. Please note the survey is still open."

Edited comments from the online survey

I think it would be good to use this to get quick, early, proof of concept answers to the questions we all want to know the answers to, to determine whether it is worth proceeding with a full blown study (i.e. so we don't need to waste 5 years waiting for a "no").

Here's a few ideas:
  1. Do "NEDA" Lemtrada patients have ongoing atrophy/neuroinflammation at 2, 5 & 10 years. (i.e. recruit patients who are already at those milestones - not proposing enrolling them at Year 0).
  2. Do "NEDA" BMT patients have ongoing atrophy/neuroinflammation at 2, 5 & 10 years.
  3. Does BMT and/or Lemtrada get rid of OCBs at 5 & 10 years. If not, why not (given that Tysabri does).
  4. Combination drug trials in patients with severe, active MS (over a year)
  5. Effect of "highly effective" DMDs on atrophy over 1 year in progressive patients
  6. Prove or disprove therapeutic lag with a highly effective DMT (this would be a paradigm shift and would force pharma to adjust their trials
  7. Set up a register with neuros across the country to log patients with MS (obviously with their consent), listing age, disease onset date, disease type, and then tracking EDSS, relapse rate and lesion count year on year, alongside recording which treatment they are on. Being able to interrogate such a database at will would be hugely insightful in terms of top level data, and justifying future trials.
  8. BMT in progressive MS. Does it have *any* impact for PPMS, according to EDSS progression, neuroinflammation and atrophy.
  9. Is NEDA enough? Look at patients with MS who have no lesions, relapse or EDSS progression for 2 years, and check whether they have atrophy (neurofilaments) and ongoing neuroinflammation detectable in blood/CSF. If so, again that's a paradigm shift as it would warrant ongoing maintenance therapy after induction therapies.
  10. LDN - Any effect on progression, atrophy, relapse or lesions? Any impact (as claimed) on microglial activation?
  11. Vitamin D register. At top level, do patients taking vit d do better than those who do not? Can we demonstrate a strong enough indicative effect from registry data to warrant further investigation?
  12. Patients who undergo HSCT also have 6-12 months prophlaxis consisting of anti-viral, anti-fungal and antibiotics (which is a pretty rare combo - certainly over such a sustained period). If there is increasingly compelling evidence that the environmental trigger is a virus/bacteria/organism of some kind, can we demonstrate an effect by using an all-encompassing Howitzer approach of one year of very strong combo of antiviral/fungal/biotic drugs (and then worry about narrowing it down to individual drugs/targets later if an effect is proven)? The drugs are cheap and safe, and you can have them at high doses for a year without mega risks. So why not try it? I'd do it!
  13. How much immunoablation is enough? Comparator trial of different levels of immune ablation (e.g. high intensity chemo with bulsafan vs BEAM vs CYC & ATG vs CYC & Rituxumab vs Alemtuzumab). Use flow cytometry to investigate T cell epitopes before and after.
  14. What is the target of OCBs? Wide spectrum testing of proteins for cross reactivity.
There's a few anyway. Some obviously easier than others.

As a general principle, I think the idea of some kind of national register - maintained by neuros rather than patients, to give it some credibility/impartiality - should be a priority. This would be so valuable as it would, without even doing extra trials, enable us to answer questions like "what percentage of patients on alemtuzumab are NEDA at 5 years)", and to monitor long term follow-up without the ball-ache of having to set up trials which many people drop out of due to moving, or moving on. Far fewer drop out of seeing their own neuro. And if it was set upon the NHS, it wouldn't even matter if they changed neuros. You could still follow them as Patient ID would be the unique identifier.

I think it's got legs. Happy to be involved in helping to set it up, if that would be helpful.

Unfortunately having a relapse just now so can't help but I have years of experience using internet for fundraising for non profits. This is as professional fundraiser. There seems to be a bit of a disconnect on this blog about how easy this is. It isn't but I think a small project as a test could work, again a lot of things you need to think about before dipping a toe in. First I'd suggest working on strategy for this, identify some discrete projects, get a strong narrative together (using examples of individuals etc), find the right platform (s), get the operational plan together plus backup, identify the possible, pitfalls etc etc. I wish I could help but not possible at moment.

I think that academic institutions need to be able to think "outside the box" when it comes to neurodegeneration. This would include projects that normally would not get funded by traditional routes due to their speculative nature, an example would be the Charcot Project. Give young researchers some funding and see where different perspectives lead.

I think neuros should come up with 5-10 proposals per year based on the criteria of research without other funding streams. These should be presented & explained to the crowd. Crowd should vote with funds they wish to donate. Each project has a "reserve". If the minimum reserve is met the project goes forward, if not, try the next year. All crowd founders should receive regular weekly or monthly simple reports on what is happening with their funded projects (not restricting progress updates to only crowd funders, but at least the funders). Yearly renewals should be handled the same way.

Good luck!

I think alemtuzumab and HSCT are both already known to be very good at damping down inflammation and thus relapses. One may be a little bit better than the other. Is this what the trial is trying to establish? Whether one is much better than the other in the long term at preventing progression or disability ie in 20 years time, is a long time to wait for the outcome of a trial.

The Charcot project is innovative and may lead to new treatments for MS.

Would be possible to include PPMSers in both trial? May be off - trial?

I get the feeling the Charcot Project would be easier to crowdfund.

I hope you can include Australians! There is a huge interest in HSCT here after Kristy Cruise's story aired on national TV last year.

Zeus trial appears to be more involved and $$ compared to antiviral trial. Plus, Charcot trial has bigger potential to change current treatment practice.

I can't see why HSCT needs to be double/single blinded. Why not let candidates choose an option?

I like both. I think EBV/HERVs is straight forward and easier to implement with crowd funding.

As a Lemtrada reciepient I am very interested in the head to head with stem cells. I think this project has more moving parts & would be more complex to be run with crowd funding.

Couldn't add above, but did not see f/u studies to the Nature Med article 

I live in Australia - hence my no''s

Questions, rather than suggestions. I am an MS researcher myself and had been wondering how to go about getting crowd-funding, as the conventional sources of funding are so competitive and the nature of the research we wish to do requires a lot of funding, just to gather preliminary data for grant applications. How do you get around the criticism that crowd-funded projects mustn't be very good or worthwhile, if they cannot obtain funding through grant applications? Also, what sum of money is a good target amount?

Get a celebrity involved, even just to appear briefly in a video promoting the project. Someone with a friend or family member who has MS for example. I suspect there are some celebrities that would do this at no charge. This could help draw public attention to the project. It's just an idea.

SPMS - using drugs already licensed for other conditions that show promise for neuro-protection, axon growth, re-myelination. (similar to MS-smart)

Phase I is to identify the drugs possible
Phase II is allow large scale testing of willing volunteers, not necessarily blinded, over at least 2 years

Clemastine in remyelination. I think this is being done at UCSF. A confirmatory study?

Melatonin? Also a small scale for simplicity for crowdfunding.

Glyburide? I read a journal article: TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis.
Source: Nature Medicine. Dec2012, Vol. 18 Issue 12, p1805-1811. 7

The effect of artesunate on JCV titers in natalizumab patients. It would be helpful to find a simple, safe and effective way to lower JCV titers and potentially PML risk. Techniques to de-risk an extremely effective medicine would be quite valuable to say the least.

"The following are the two proposed projects."


The proposed ZEUS trial below has had a lot of interest from you the readers. To get this project off the ground, and funded, we would need to explore the community's attitude to the trial and whether it is addressing an unmet need. Exchanges and surveys done via this blog are not necessarily representative of the wider community. We as a group have no expertise in HSCT and we would therefore need to include groups and centres that do have expertise. Paolo Muraro's group at Imperial College would be a natural fit us. In fact Paolo has expressed an interest in leading this trial.

What we would need to answer are the following list of questions:
  1. Do MSers understand the immediate risks associated with HSCT?
  2. Do MSers understand the undefined risks associated with HSCT?
  3. Would MSers be prepared to be randomised to receive alemtuzumab or HSCT?
  4. Would British Neurologists be prepared to refer patients for a HSCT trial?
  5. Do haematology units in the UK have enough capacity to handle a large national MS-HSCT trial?
  6. What are the economics of HSCT? How do they compare to alemtuzumab treatment?
  7. Would a non-myeloablative or a myeloablative protocol be best?
  8. What is the optimal trial protocol?
  9. Would we only target DMT failures or MSers naive to DMTs?
  10. Would eligible MSers have to have highly active MS or just active MS?
  11. Would the NIHR or MRC be prepared to discuss funding a trial of this nature?
  12. Etc.?
Charcot Project

We as a group would want to focus on targeting both EBV and HERVs (human endogenous retroviruses) with antivirals in MS. Before doing a formal clinical trial we would need to do a small exploratory study using a combination of anti-EBV and anti-retroviral drugs. The primary outcome of the study would be to makes sure our anti-EBV drug is safe in combination with HAART (highly-active anti-retrovirals) and whether the combination were suppressing both EBV and HERV activity within the body. We would propose doing a small open-label study of approximately 20 MSers looking at EBV shedding, and EBV viral loads, and HERV activity in the peripheral blood before and after treatment with the combination of anti-virals. If positive data from this enabling study would be used as part of a grant application to fund a phase 2 trial assessing the efficacy of combination antivirals on MS disease activity. Ideally we would want the phase 2 study to be a parallel design placebo-controlled double-blind study, rather than the cross-over study we have just completed for raltegravir (INSPIRE TRIAL).

This is a community project so please feel free to comment. Thank you."

CoI: multiple

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