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What is the ME Association doing about Rituximab? Statement 8 July 2013

Firestormm

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I am rather laid up today - but you might all like to read the statement in full that was posted this morning. Dr Shepherd is taking questions on the MEA Facebook page at the moment if you have any.

What is the ME Association doing about Rituximab?


by Tony Britton on July 8, 2013
STATEMENT FROM THE ME ASSOCIATION

Unlike the situation with XMRV, where The MEA took a very cautious and sceptical approach from the very beginning, we have consistently maintained that the positive results from the initial case study reports, followed by the results from the phase 2 clinical trial [1] carried out in Norway [2], indicate that Rituximab could form a very significant development in finding a drug aimed at treating the underlying disease process in at least a sub-group of people with ME/CFS – possibly in those with a distinct disease pathway/immune system profile.


However, the fact that some of the anecdotal reports from people who have been prescribed Rituximab, but are not part of a formal clinical trial, have been disappointing (in relation to efficacy) or concerning (in relation to tolerance/side-effects) also has to be taken into account.

What has The MEA done so far?

We have been following all the key developments regarding Rituximab – research-orientated and aneotal – very closely and Dr Shepherd was with the two Norwegian researchers, Drs Øystein Fluge and Olav Mella, at the three day Open Medicine Institute research meeting in New York last year.

Dr Shepherd has also had discussions with a number of UK researchers and clinicians who might be interested in carrying out a clinical trial here in the UK (or peer reviewing the protocols) and has reported back to The MEA Board of Trustees at their regular meetings. His report to the April 2013 meeting can be found at the end of this statement.

We have also produced a comprehensive Question and Answer information sheet on Rituximab.
The MEA website version can be found here: www.meassociation.org.uk/?p=8459

Following the results of the phase 2 clinical trial, which indicate that Rituximab appears to be a safe and effective treatment for at least a sub-group of people with ME/CFS, we very much welcome the news that the Norwegian researchers do now have government funding to proceed with a phase 3 clinical trial [3]...

Read more....

It does go into a lot of detail about the regulatory hurdles and likely costings etc. Haven't read all of it myself but will try and come back to it later.
 

Firestormm

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Dr Shepherd just posted a link to Rituximab in Myostis from the Myostis Association, that I shall read later. Appears to contain some perhaps relevant observations that Ritux might be more effective in sub-groups:

'Some interesting comments in a Question and Answer on the use of Rituximab in myositis - inflammatory muscle disease with an autoimmune component:

"TMA Member: I read that there seems to be a particularly strong effect of rituximab for those with anti-Jo-1 antibodies. Could you please discuss this impact further.

Dr. Oddis: The only thing that we can say now is that the presence of anti-Jo-1 autoantibodies predicted a beneficial response to rituximab so if a patient has this marker then there is better chance of responding to the drug than if they did not have this marker in their blood. The impact of this after the data is peer-reviewed is that this is the most common antibody marker in myositis so it affects a lot of patients."

There are 32 comments relating to the MEA Rituximab statement now on the MEA Facebook page. I need to catch up with those too I think.

I believe the MEA have written to IiME and all the other ME Charities to hopefully get the ball rolling further on some sort of collaborative effort for clinical trials.

Quite liked the notion of trying to discover why patients respond to the drug and trying to better understand who might benefit before applying a scattergun approach.

Would make sense if patients receiving this drug were the ones most likely to benefit. Be interesting to also learn how those who test as likely benefit are different from the rest. Is it a defining characteristic of 'ME' or something else? Can you develop 'autoimmunity' if that is what we are talking about during the illness aka 'ME'?

Quite fascinating.
 

heapsreal

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If its the same artilce with dr shepherd, there was alot of arguing over xmrv etc in the question and answer section. An outsider looking into this, it wouldnt have been a good look. both sides seem to be at each other.??
the actual article was interesting.
 

Firestormm

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If its the same artilce with dr shepherd, there was alot of arguing over xmrv etc in the question and answer section. An outsider looking into this, it wouldnt have been a good look. both sides seem to be at each other.??
the actual article was interesting.

Not sure what you mean here, heapsreal. Can you clarify? I can't seem to find any arguing either on the MEA website or their Facebook page. Indeed the Statement and Q&A looks to have been very productive.
 

heapsreal

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Not sure what you mean here, heapsreal. Can you clarify? I can't seem to find any arguing either on the MEA website or their Facebook page. Indeed the Statement and Q&A looks to have been very productive.
Sorry cant clarify. Cant remember where I saw it. Apparently some cfsers took offence to dr Shepherd saying xmrv is unlikely as there is poor science backing up xmrv existence. The q and a I saw was basically about that and got way off track about rituximab. The q and a was under the initial article. It may have been on the other cfs site thats very pro retroviral cause of cfs but I cant remember.
 

heapsreal

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I just dont know. I think we mostly have chronic infections everywhere and rituximab lowers our immune function. Ebv etc might be in b cells but they also hide out in our nerves and brain etc. Unless they can say that one has no infections and its definately in b cells then I would wait for further research. I think we will find an auto immune subset to go along with the different herpes sub sets and bacterial subsets and mixtures of these. I would like to see combo therapies like avs and ritux as well as avs and ampligen. Also I think what might be important in all this is the pathogen studies??
 
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The Open Medicine Institute top priority study is a 2x2 RCT of Valcyte with Rituximab (i.e. in combo, singly, and neither), presumably looking at exactly the hypothesis that you've got to wipe out reservoirs as well as resetting the system.
This point was clarified at the Invest in ME conference, when the hypothesis was mentioned that in those who relapsed again after treatment ceased, they (by which I mean all the main researchers looking into rituximab and ME/CFS, I think; the presentation of this hypothesis led me to conclude that they had probably all discussed this subject) suspect that the initial cause of the B-cell abnormalities (virus) was still present and those reservoirs need to be cleared as well. I asked for confirmation that this was the rationale behind the OMI Valcyte/Rituximab study and that was confirmed.

See my write-up on Bansal's presentation at IiME, in particular the 'conclusions' and 'questions' sections:
http://phoenixrising.me/archives/17049
 

Firestormm

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From Charles Shepherd earlier on ME Association Facebook. Relevant to the MEA 'Ring-Fenced' funding pledge the other day; their earlier statement about Rituximab; and to yesterday's statement from IiME regarding Professor Edwards and UCL.

Just in case it isn't clear from the various MEA statements on Rituximab and my own comments on MEAF:

1 The MEA Ramsay Research Fund is very keen to help fund a high quality clinical trial to further assess the safety and efficacy of Rituximab in ME/CFS here in the UK and to see if the results from Norway can be replicated

2 We have made this position very clear in our statements on Rituximab dating back to 2011 when I first approached Professor Edwards (and others) for their advice and input on the way in which a UK clinical trial could/should be set up

3 We have set aside the sum of £50,000 from existing RRF research funds and received 'ring fenced' donations amounting to around £8,000 - making a total of around £60,000

4 I have again been discussing the possibility of a UK clinical trial with Professor Edwards (and others, including Professor Stephen Holgate) before going away on holiday and had a further very helpful telephone conversation with Professor Edwards this morning

5 I am very happy with the ideas he is putting forward for a small clinical trial which will hopefully turn into a formal proposal for funding at a later date

6 Provided the proposal meets the high standard of peer review that all research funded by the MEA RRF insists on we will be very happy to help fund a trial at UCL - which is where the ME Biobank is also situated

7 When I first discussed the possibility of a UK clinical trial with other research colleagues it emerged that the likely cost could be in the region of £400,000 - which is why we have suggested that the best way to get this moving would be a joint charity fundraising effort

8 I have already discussed this with most of the UK ME/CFS research funding charities and written to Invest in ME to suggest that it would be helpful to have a meeting of interested charities to see how a joint fundraising effort could be taken forward

9 I also confirmed to Professor Edwards this morning that the MEA RRF would be very happy to consider any funding proposals for preliminary work on immune function etc that may well be required before a clinical trial takes place

10 The MEA RRF is already funding Dr Amolak Bansal to carry out research in another area and is very happy to see that he is involved in this initiative

It's also worth noting, as in the MEA statement, that the licensing authorities will require strong and consistent evidence of both benefit and safety in relation to a very expensive drug such as Rituximab before it could be made available on the NHS as a possible treatment for ME/CFS here in the UK

Positive results from Norway plus a positive result from a small clinical trial in the UK will definitely help to take this process forward but will not be enough

This is just the start of what is likely to be quite a long process of establishing (or not establishing) a new and important use for Rituximab........
 

Sasha

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Good statement. As far as the last bit goes:

Positive results from Norway plus a positive result from a small clinical trial in the UK will definitely help to take this process forward but will not be enough

This is just the start of what is likely to be quite a long process of establishing (or not establishing) a new and important use for Rituximab........​
I think that's right but that we should remember that the UK trial is part of an international effort to get Rituximab trials up and running - just because that trial won't be sufficient on its own doesn't mean we shouldn't support it. We should!
 

Firestormm

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Here's a little more from Charles yesterday on Facebook about how the Ramsay Research Fund (the research fund arm of the MEA) goes about funding projects in the context of the above:

When the MEA Ramsay Research Fund helps to fund a research study at a significant level - as we are currently doing with the ME Biobank and the mitochondrial function study at the University of Liverpool - we do so on the basis that the proposal has been subjected to robust peer review (ie reviewed and critiqued by people with expertise in immunopharmacology and the use of Rituximab who are independent of the group carrying out the research).

So in relation to the proposed clinical trial at UCL, we would be very happy to receive an application from the research group once it has been prepared

We would then make a decision on funding

And if we were making a substantial financial contribution (ie £50,000 plus) we would, as with all our other research funding, make payments at (normally) three monthly intervals on the basis of receiving satisfactory progress reports from the research group.
 

Firestormm

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There is evident 'confusion' and a little niggling to be fair not least on Facebook in respect of the IiME fundrasing and the pledge from the MEA of £60,000; as the two charities have both separately been consulting with Prof. Edwards and UCL.

A little more from Charles Shepherd in response to a related question - again on Facebook yesterday - although the 10 points above do spell out again a willingness/need to collaborate if the large sum is ever to be raised in a reasonable time frame:

I'm sorry if my further 10 point statement regarding the proposed clinical trial of Rituximab at UCL still isn't clear to you

Yes, this is the trial that Professor Jo Edwards is advising on

Yes, this is the trial that Invest in ME are fundraising for

Yes, this is the trial that the MEA is very happy to help fund (we have around £60,000 raised so far) - provided it passes the peer review procedures referred to in my 10 point statement and the MEA website statement

As already noted, we have also taken advice from Professor Edwards dating back to 2011 and I spoke to him again in some detail yesterday

It should also be noted that a trial of this nature will require quite a lot of preliminary work, possibly including some further work on immune status, before a final protocol for the trial can be prepared

Professor Edwards has retired from UCL and my understanding is that the protocol will be developed by the Clinical Trials Unit at UCL

It then has to gain ethical approval - which may take a bit of time given the potential for this drug to cause serious adverse effects. So we are almost certainly looking at 2014 rather than 2013.

My understanding is that UCL is not involved in fundraising and £400,000 is an awful lot of money - so this is why I have suggested that a joint charity fundraising campaign is carried out by those ME/CFS charities who want to see a Rituximab trial carried out here in the UK sooner rather than later....

Both myself and our Chairman (Neil Riley) have been in correspondence with Invest in ME on the subject of inter charity collaboration - possibly in the same way that the very successful ME biobank at UCL is now being funded and organised. And I would be very happy to set up a meeting of interested charities (and there are others who might be willing to help).

I hope all is now clear but do come back if anything is not
 

Jonathan Edwards

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Dear All,
I am sorry if there is any sense of confusion here. To my mind it is straightforward. We are trying to find a way to set up a rituximab trial, because it may have several long term benefits for people with ME. IiME take the credit for having knocked the right heads together and got them thinking of getting something up and running - pretty impressive to my mind, because there are all sorts of reasons why those people might choose some easier things to think about! So now what we need is for everyone to do what they can. Dr Shepherd has indicated his enthusiasm for doing what he can. If we can get the MRC interested now or later that will help. And questions and critical comments about trial design are being helpful too - the more heads bash together here the better. I will probably post some further comments on the other thread about the study when I get time. I appreciate that people want to know everything at once, but those who are keen to actually get something done need a little thinking space. There is a lot of work to do, but that is not to say that protocol writing has not started. The general shape of a feasible trial looks fairly clear.

Last time I tried something like this I got it done. My role is different now but I would like to see this fly. What I do not want is anyone, be they patient or doctor or charitable donor, get involved in something in a way they later feel they should not have. That can be complicated but it has to be got right. I am not a great believer in the value of formal rules and procedures (a lot of innovative work gets done hand to mouth) but I do believe in making sure nobody is hard done by. Things will take time and everyone needs to be happy, but a lot has happened since June and I would like to see the momentum continue.

Best wishes to all

Jo Edwards
 

lilpink

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Jonathan Edwards. Thank you indeed for joining with the wonderful Invest in ME to try to bring this project to fruition. They are such wonderful guys who do such sterling work for no recompense whatsoever. As a member of the 'Let's Do it for ME' team of patients who are attempting to fund-raise to get this trial up and running, I have to say I'm spurred on by having someone of your calibre to advise Invest in ME and help create these trials in a way that can produce meaningful results..whatever those results may be. Other work using dubious criteria for our disease has left us in something of a no-mans land, and we desperately need the good brains that you and Invest in ME can bring to this venture.
 

lilpink

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Posting with permission from the author ...simply to clarify the real timeline of events surrounding the genesis of this planned trial, and in the interests of fairness. (Originally posted on the MEA Facebook page in response to comments made by Charles Shepherd).

Charles: This isn't about who takes credit, or who did what when or spoke to whom, it's about getting high quality research done to help as many of us as possible as soon as possible. However, the fact is that Invest in ME and their supporters - patients, parents and carers - have worked hard to achieve this level of interest and enthusiasm and investment of time, effort and resources, from 1st class researchers. The ME community deserves honesty and clarity, so now that Professor Edwards has made his position clear in a full statement and in his comment on Pheonix Rising, can we clarify a few points here once and for all, and I know you'll correct me if I'm wrong.

1. The instigation of the proposed rituximab trial at UCL had nothing to do with the MEA or any other UK charity or group or the newly-formed UK research collaborative. This opportunity arose from the 8th Invest in ME conference events at the end of May 2013. Dr. Jo Cambridge of UCL had significant input to the meeting prior to the conference. The meeting was attended by over 40 biomedical researchers from 9 countries. Professor Edwards attended the IiME conference the following day.

2. You were unaware of the proposed UCL trial when you published your statement in July announcing the ring-fencing of £50k from the RRF for a possible future ritux trial, and inviting further donations for a trial that you did not have in the planning stage and which you knew and stated may never happen. From the minutes of the Forward ME Group meeting held on 2nd July: "On Rituximab Dr Shepherd said that people were raising money for a trial in the UK, and the MEA would be putting out a statement the following week. The problem was that so far no-one in the UK wanted to do that research".

3. You were aware at that time that IiME had announced on 6th June that they were raising funds for a trial that they were arranging. You did not contact IiME prior to publishing your statement and made no mention of their announcement or any planned UK rituximab trial in your statement, nor in the statement published by Tony Britton re-announcing £50k in the ring-fenced MEA fund.

4. Tony Britton's statement was published a few hours after MEA Chairman Neil Riley had said on the old MEA Fb group that he knew nothing of a UK trial, and had been told that the research team would be announced shortly, in reply to his query about which researchers were involved. This was under a post announcing a matching donation period by Let's do it for ME for the ritux trial as part of our 2nd birthday celebrations. No mention was made of either the achievements or even existence of the ldifme campaign, let alone this opportunity to have donations matched, given that it's all for the ritux trial.

5. Your discussion with Prof. Holgate at the UK Research Collaborative was about the general possibility of a ritux trial, not about this particular trial, as you were unaware at the time that a trial was being planned at UCL and unaware of Professor Edwards' involvement.

6. Professor Edwards clearly states that his interest in ME/CFS was sparked by attending the IiME conference at the end of May 2013. You told me that you had spoken with him quite some while ago, after the Phase II Fluge and Mella research had been published and you have said right up until you knew that a trial was being planned at UCL that you had no researchers interested. When I told you of the announcement by IiME that Professor Edwards was acting as adviser to the charity on all aspects of the planned ritux trial (the research team had not been announced), you told me that would contact him to update him on what the MEA were now doing. When I gave you the link to the statements by Professor Edwards and Invest in ME, you told me you then phoned Professor Edwards.

So, to clarify your previous comment that both charities were raising funds for a ritux trial and both charities were being advised by Professor Edwards, as this was misleading. You were raising funds in case of some possible future trial, Invest in ME were raising funds for a trial they were organising. Professor Edwards had given permission for IiME to announce that he was acting in an official capacity, in his retirement, as adviser to the charity, you only rekindled your contact with Professor Edwards once this had been announced. I don't know why you have gone about matters this way. You say you want collaboration, yet you behave as though you are in competition. Let's do it for ME has been all about positivity and progress, we've criticised no-one, even for blatantly copying us instead of supporting us, as we take the view that imitation is the most sincere form of flattery, but enough now.

Let's wipe the slate clean, be honest and fair about the facts and chain of events, and help this excellent team of people who have already been working together with Invest in ME since the May conference, to get on and do their work, which is entirely for all our benefit and with the mutual benefit of collaborating with Professor Mella and Dr. Fluge. Of course, the UCL team can submit an application to the MRC, they are not inexperienced and they have a dedicated Clinical Trials Unit. This should be about the quality of the proposal, of which we patients supporting it are 100% confident. However, we know that high quality proposals for biomedical ME research have been turned down in the past, including an application by a Fellow of the MRC, so we won't hold our breath on that, and let's face it Charles, you say you have discussed with Professor Holgate but we know that such discussions often come to nothing and when they do, it takes too long as there is no sense of urgency. It took 3 years for the MRC Expert Group, in which you and Peter Spencer were involved, to come up with a list of symptoms to be studied, ostensibly to investigate possible causes of ME/CFS. Have things really changed now that the group has a new name with a not so new Executive Board? Let's see shall we, but not wait, we've done enough of that spanning decades now and too many of us are no longer here to tell the tale and reap the potential benefits of this breakthrough research.