The following background information may be helpful
1 Summary of points relating to Rituximab from Dr Amolak Bansal's prsentation at the Sussex Research and Management meeting in May:
RITUXIMAB
During the Question and Answer session Dr Bansal provided a comprehensive update on the current situation regarding the proposal to carry out a clinical trial of rituximab here in the UK to see if this could replicate the benefits that have been reported from the Norwegian trial.
However, feedback relating to people in the UK who have been treated with rituximab in America, as well as US citizens who have been treated with rituximab, has been nowhere near as positive as the results that have been reported from Norway. Consequently, questions are now being asked as to how a UK trial could/should proceed and whether this is the right time to commence a UK trial.
Dr Bansal noted that it is possible that the failure of these people to respond to rituximab could be explained by different trigger factors being involved in the Norwegian population, and/or that there is something different about the patient selection process in Norway.
These concerns and uncertainties about the UK trial are due to be discussed with US colleagues shortly.
Dr Shepherd pointed out that the MEA Ramsay Research Fund still has around £60,000 of ring-fenced money to help fund a UK clinical trial of rituximab – if a suitable protocol can be developed by the group concerned (which includes Dr Bansal) and there is a definite intention to move forward with a clinical trial, and a formal application is received.
However, if a UK trial of rituximab is not going to take place, or it is going to be delayed until the results from the phase 3 clinical trial in Norway are published, the MEA Ramsay Research Fund will have to reconsider our position. This is because we have other requests for funding, including a commitment to keep the ME Biobank going for the next two years (at a cost of around £40,000 per year), which will need to be taken into consideration.
Full report here:
http://www.meassociation.org.uk/201...ghlights-of-burgess-hill-meeting-14-may-2016/
2 My notes from the presentation by Dr Jo Cambridge at the 2016 Invest in ME Conference:
DR GERALDINE (JO) CAMBRIDGE – PRINCIPAL RESEARCH FELLOW INFLAMMATION, DIVISION OF MEDICINE, FACULTY OF MEDICAL SCIENCES, UNIVERSITY COLLEGE LONDON (UCL) AND FANE MENSAH
B-cell biology and Rituximab treatment in patients with ME/CFS
Dr Jo Cambridge gave an excellent and easy-to-understand presentation on B-cell function in general, how B-cell dysfunction and the production of autoantibodies might relate to the immunopathology of ME/CFS, and the practical aspects of using rituximab to treat non-malignant conditions.
She explained that she belonged to a group of researchers at UCL – including Professor Jonathan Edwards – who have a particular interest in how a drug called rituximab, which was originally used to treat a malignant condition called lymphoma, depletes the population of a specific type of immune cells called B-cells. Rituximab was then found to effectively treat some cases of rheumatoid arthritis (RA) and other autoimmune conditions such as SLE/lupus where inflammation is an important part of the underlying disease process.
Among the key points made in relation to the use of rituximab in RA and to the way in which it might also act in ME/CFS:
* This research has produced information about how rituximab can produce a significant remission of symptoms (in around 70% of RA patients) and the resumption of symptoms (in around 60% of RA patients) once the B-cell population has been restored.
* Patients with high levels of autoantibodies (= antibodies that attack the body’s own tissues) have a far more pronounced and predictable response than those with no evidence of autoantibodies.
* B-cells are killed off very quickly by rituximab; the drug binds to cells that express what is called a CD-20 receptor. This usually occurs within a week of the infusions which are given intravenously over 6 hours. The B-cells therefore start to disappear from the blood within days and from other tissues at varying rates. But the dynamics of the clinical response – which takes from 1 to 5 months after depletion of the B-cells – suggests that for remission to occur it is the constantly generated B-cell product (possibly an autoantibody) and not the B- cells themselves that need to be reduced.
* A considerable proportion of the B-cells are not depleted and remain in protective sites in lymphoid and inflamed tissues.
* Levels of autoantibodies can therefore remain raised, even in the presence of an improvement in clinical symptoms.
* These observations suggest that only a proportion of parent B-cells and autoantibodies are actually ‘pathogenic’ (that is involved in disease causing mechanisms). And, as a proportion of patients then relapse, the autoimmune response underlying the disease causing process must be self-sustaining.
* Patients are not therefore normally ‘cured’ by rituximab and symptoms can worsen when the B-cells start regenerating within 6 to 9 months after the infusion. However, some patients have a more extended period of remission after the B-cells return.
* Side-effects are rare and, although there are reductions in serum antibody levels (which provide protection against infections) , the effects on protective immunity are mild and serious infections are not a problem.
In relation to the use of rituximab in ME/CFS, we are very much at the beginning of a learning process which follows on from the clinical trials that have been carried out and published by Drs Fluge and Mella in Norway.
The UCL research team is concentrating on investigating B-cell biology in order to try and identify differences between people with ME/CFS and healthy controls to see if this can help identify people with ME/CFS who are more likely to respond to this drug.
The group has hypothesised that rituximab may be reducing fatigue levels in ME/CFS as a result of decreasing the production of immune system chemicals called cytokines (i.e interferon alpha) through the removal of autoantibody containing (pro-inflammatory) immune complexes. Rituximab would therefore be working by stopping the production of (as yet) only tentatively identified pathogenic antibodies.
Fane Manesh, a PhD student at UCL, then spoke about the work that has been carried out into phenotyping sub-populations of naïve and memory-B cells in people with ME/CFS.
The group has published data on these B-cells and this shows that a specific cell maturation marker called CD-24 is upregulated or retained by the newly generated B-cells. As a result, they have been using cells from patients and healthy controls to follow B-cell development patterns, and interactions with T-cells, in response to certain stimuli. The group has also established an
in vitro system (i.e. it is performed in a test tube) where they can compare the metabolic function of B-cells in ME/CFS patients and in healthy controls as well as what is termed mitochondrial mass.
Dr Cambridge did not put any ‘meat on the bone’ regarding which clinicians might/would be involved in a UK trial; where the trial might/would take place; the development of the protocol; and when a clinical trial might/would take place here in the UK until the Q and A session, where she explained the difficulties involved in setting up a UK trial for a drug like rituximab.
According to Dr Cambridge, it is going to be very hard to get a clinical trial going here in the UK due to a combination of developing a protocol, obtaining ethical approval, finding committed clinicians to carry out the work, the work being expensive in both cost and time, and the lack of pharmaceutical backing for a drug that is quite expensive to use. This has also occurred in other clinical trials involving rituximab.
Dr Cambridge also repeated the advice that has come from Drs Fluge and Mella in Norway that in our present state of knowledge rituximab should not be used on patients with ME/CFS outside proper clinical trials.
[
CS note: I was going to ask Dr Cambridge over lunch what she thought about the less positive patient evidence from people with ME/CFS who have been treated with rituximab in America outside the Norwegian clinical trial (an important point that was raised during the clinical and research meeting in Sussex with Dr Amolak Bansal and myself three weeks ago) but wasn’t able to do so.
Further information:
Mensah F
et al. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Clinical Experimental Immunology. 2016,184 :237-47.
Full conference report here:
http://www.meassociation.org.uk/201...y-for-sharing-ideas-on-research-20-june-2016/
3 Follow up comments from Prof Edwards on PR discussion:
Thanks CS, especially liked the information from UCL.
One thing though: Why should it be hard to make a protocol for a rtx-study, in light of Haukeland already having one?
Maybe I should comment here. Dr Cambridge has never been directly involved in the setting up of a trial, only in background research. Speakers at the IiME meeting were often asked questions that had nothing to do with their talks at all. There was a question to Dr Cambridge about setting up trials and she did her best to give her thoughts on the difficulties but only because she felt she ought to produce some sort of answer. She was not speaking for those involved in trial planning.
In relation to Marky90's question we need to distinguish a treatment protocol from a trial design. Haukeland have devised a treatment protocol. It would be sensible to use the same protocol in other studies until we know more, but that has nothing to do with designing a trial that will answer a question. The size of trial that there is a budget for in the UK would not provide statistically powerful evidence just for efficacy over and above the Norwegian phase 3 study. It was always assumed that a UK trial would address a different scientific question - perhaps about markers of response or dose ranging - which could usefully be assessed in a relatively small trial.
Dr Cambridge is right to point out that it is essential to have a dedicated principle investigator with a team that understands both ME/CFS and rituximab. Trials run by subcontractors are not a good idea. At present it is not clear that there is a suitable PI in the UK to take a trial forward.
Although Fane Mensah has been working hard at detailing B cell subsets in ME/CFS we do not yet have a replicated marker that could be used look for correlation with response. That means that it is not clear what scientific question a UK trial would answer. I appreciate the enthusiasm for a UK trial but we cannot treat people with a drug with potential harmful effects without justifying that with a clear scientific objective. Drs Fluge and Mella would not wish that. Discussions continue but my own view is that setting up a trial in the UK should wait until either we have new findings that provide a clear direction or until we have a positive outcome from Norway phase 3, which would justify a small dose ranging study. Above all we need some handle on a B cell abnormality that we can follow so that we know what is going on.
As people will realise, I have been through this mill once before (more than once in fact) and it is far from simple. It is not a question of if things go wrong but when, and how best to pick up pieces when they do, to ensure the best outcome. That does not mean getting cold feet, it just means being patient about when is the right time to move forward. Pharmaceutical support can be helpful but only if the science has been well sorted out in advance. Company trials can distort design in ways that are not in the patients' interests. The Norwegians have done everything by the book and all credit to them for getting this far. I do not think we should be muddying the waters with underpowered or badly controlled studies done in haste.
An important part of exploring use of rituximab in other countries is to get a feel for clinical response outside a trial setting, which is a legitimate objective at this stage. Quite a large number of people with ME/CFS have now been treated in the USA, Germany and Norway at least and it would be useful to have published reports from these centres. Unfortunately at present we only have hearsay.
4 The most recent (May 2016) MEA statement on the £60,000 we have reserved in the Ramsay Research Fund to help fund a UK trial - if a protocol can be prepared. and there is a UK PI and a clinical trial unit that wants to proceed with a trial, and formal research grant application is submitted to the RRF:
http://www.meassociation.org.uk/2016/05/rituximab-update-by-the-me-association-23-may-2016/
Dr Charles Shepherd
Hon Medical Adviser, MEA