What is the ME Association doing about Rituximab? | 8 July 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].

Replicating the results from Norway

However, there is also an urgent need to see if other clinical trial groups outside Norway can replicate these findings in relation to both efficacy and safety.

This is because the two regulatory authorities – the MHRA/Medicines and Healthcare products Regulatory Agency: www.mhra.gov.uk/Aboutus/index.htm here in the UK and the EMA/European Medicines Agency: www.ema.europa.eu/ema/ in Europe – that license and regulate drugs for use in specific conditions have be satisfied that a drug is both safe and effective for a specific condition before it can go into general use. In the case of Rituximab, the use in ME/CFS would also have to be endorsed by NICE, or the Scottish Medicines Consortium in Scotland.

To issue a product license the regulatory authorities require consistent and robust evidence from a number of independent clinical trials – carried out by different research groups – to confirm both safety and efficacy.

Taking a new drug to market, or establishing a new use for an existing drug, is a long complex process that inevitably takes several years to accomplish.

What is so disappointing at this stage is that these replication trials are still not taking place – either here in the UK or elsewhere in the world.

This means that we are still several years away from looking at a product license for Rituximab – if it does turns out to be a safe and effective form of treatment for some people with ME/CFS.

Why are these replication trials not taking place?

The reasons for this are complex and relate to a number of factors:

1 Rituximab is a very expensive drug. So with the cost of carrying out a high quality clinical trial involving a good number of patients, we could be looking at costs of up to £400,000 or more – unless there is help with the cost of supplying the drug from a pharmaceutical company.

2 Rituximab has the potential to cause very serious side-effects, even fatalities. So the NHS research ethical committees that approve and oversee clinical trials here in the UK are going to take a very cautious view. They are likely to want to ensure that the research group includes people with good practical experience of using Rituximab.

3 Finding a multidisciplinary group of NHS doctors here in the UK with the necessary expertise in immunology, pharmacology and clinical trials, as well as ME/CFS, along with ready access to good quality ME/CFS patients, who want to carry out a proper clinical trial has not been easy.

MEA Ramsay Research Fund funding for a UK clinical trial

As far as funding is concerned, the MEA has consistently maintained that The MEA Ramsay Research Fund would welcome applications from any high quality research group who wants to carry out a clinical trial. But no such application has been received by The MEA to date.

We are also very happy, given the likely cost, to join with other charities or funding bodies, to help co-fund a trial – as has already happened in the case of the UK ME Biobank where three funding charities and a private donor have successfully collaborated on both funding and steering the project. Joint funding of some sort is probably the only way to achieve this aim here in the UK – if we are going to move without further delay. The MEA RRF is also willing to help fund a multicentre international trial – provided it has a UK arm – as has been discussed by Dr Shepherd as a follow up to the OMI meeting.

We have just processed a major donation to The MEA Ramsay Research Fund which has been ring-fenced for a Rituximab trial at the request of the donor.

But we want to go further than this and speed up the process of getting a UK trial started. So MEA trustees have agreed to set aside up to £50,000 from The MEA Ramsay Research Fund to help co-fund a trial that meets our criteria of robust peer review of any research application and this could involve looking at ways in which the patients are selected through disease pathway/immune system profiling – in other words identifying a tighter sub-group who may be more likely to respond. We also need to take note of anything that has emerged about the use of Rituximab in ME/CFS since publication of the phase 2 trial.

Donations to the The MEA Ramsay Research Fund (RRF)

If anyone wants to make a donation to The MEA Ramsay Research Fund to help co-fund a UK Rituximab trial this can be done by making your intention clear with any cheque or credit/debit card payment. The donation will then be ‘ring fenced' for two years – in other words it can only be used to help fund a Rituximab trial. If we are unable to take this forward within the next two years, the money will then be used for other biomedical research funded by The MEA RRF.

Dr Shepherd has also raised the issue of Rituximab with other ME/CFS research funding charities at the Forward ME Group meeting held at the House of Lords on Tuesday 2 July. Professor Stephen Holgate from the UK Research Collaborative was in attendance and took part in the discussion on Rituximab.

To donate to The MEA Ramsay Research Fund this can be done by sending a cheque made out to The MEA Ramsay Research Fund to:

The ME Association
7 Apollo Office Court
Radclive Road
Gawcott
Buckingham MK18 4DF

Or by credit/debit card by calling MEA Head Office on 01280 818964 or 818968 and speaking to Gill or Helen.

When paying by cheque or calling the office to make a card payment please specify that the donation is for the Rituximab trial.

All donations to The MEA RRF Rituximab fund will be recorded by name (or anonymous if preferred) and the total listed at regular intervals on the MEA website.

All money donated to The MEA RRF is ring-fenced for research purposes. There are no salaries to pay and all the administrative expenses relating to our research projects are currently paid out of MEA general funds.

Further information

Dr Shepherd will be answering questions on this statement on the MEA Facebook page this week: www.facebook.com/pages/ME-Association/171411469583186

1. A phase 2 clinical trial aims to provide information on efficacy, short term tolerability and side-effects as well as information on the dose that gives the best balance between efficacy and tolerability.

2. Abstract of phase 2 clinical trial results:

PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19.

Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study.

Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O.
Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. oystein.fluge@gmail.com

Abstract

BACKGROUND:

Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.

METHODS AND FINDINGS

In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m(2) or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms.

Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44).

Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.

CONCLUSION

The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00848692.

3. A phase 3 clinical trial is a longer term study that involves larger numbers of patients. The aim is to confirm effectiveness and monitor any adverse effects from longer term use.

Report to April 2013 Board of Trustees meeting

RESEARCH AND RAMSAY RESEARCH FUND (RRF)

RITUXIMAB

CS updated trustees on MEA and other initiatives that have been taking place since publication of results from the clinical trial that took place in Norway.

The MEA has worked with UK representatives of the Norwegian research group in order to obtain media publicity for the trial results. Examples include coverage via the BBC, New Scientist and Daily Mail.

CS has briefed the APPG on ME at Westminster, and the Forward ME Group, on the results. The Chair of the APPG has written to the Medical Research Council to add encouragement to the need to set up a UK trial. This was discussed with Sir John Savill when he attended an APPG meeting in 2012.

CS has discussed the results, and a possible preliminary protocol for a UK clinical trial, with leading experts at University College London in the use of this drug and with the chair of the MRC Expert Group on ME/CFS research. Rituximab was also discussed in some detail at the research meeting that CS attended in New York in June 2012 – see meeting reports in the first part of this summary.

The MEA has made it clear that the Ramsay Research Fund is very happy to look at funding proposals for a UK clinical trial. Preliminary discussions have therefore taken place with UK researchers who may be willing to organize some form of further clinical trial – even if this was small in number given the enormous costs involved.

Unfortunately, this initiative has not progressed into a formal application for funding being received. Trustees have discussed a number of other options to try and stimulate interest here in the UK – including the possibility of raising guaranteed financial support, which would need to be well in excess of £200,000 – with a UK group of research-funding ME/CFS charities. We have also discussed the possibility of funding an overseas group that have indicated interest in carrying out a clinical trial and stated that we would be willing to consider a proposal if those involved want to submit one.

A note of caution: This was one small clinical trial. We need to see the results from further clinical trials before coming to any firm conclusions about the way in which Rituximab might work in ME/CFS and whether or not it is an effective form of treatment for what may be a sub-group of people with ME/CFS who have an autoimmune component. We do not want to see a repeat of the false hopes created by the XMRV research.