Funding rituximab studies in UK

At ME Research UK, we’ve been interested in the therapeutic role of rituximab since reports of its use in ME/CFS patients in Norway were published in 2009 and 2011 (see our comment on these studies below). Ideally, clinical trials would already have been conducted in the UK to confirm or refute the clinical usefulness of the drug for people with ME/CFS. However, none have taken place to date, and no established research group has actually come forward with a complete proposal for such a study.

Given the current speculation about the possibility of rituximab studies in the UK, we thought we’d explain where we are at the moment as regards supplying funding for a future study. We’ve funded some 35 different projects over the years, and our starting point is the receipt of a concrete application from academic researchers, which we send to external academic reviewers for formal advice on the robustness of the science. This way, we know exactly what we’re being asked to fund; we can have a good idea how the money will be spent; and we have the basis for a contract with the academic institution so that the money can be returned if the work is not done. This is our current modus operandi, and it has served us, and our supporters, well over the years.

We would like to see a clinical study of rituximab get off the ground in the UK, and we are very open to the possibility of providing funding or co-funding with partner organizations. In fact, a robust trial of rituximab would need funding partners; even a small–medium sized study will cost many hundreds of thousands of pounds given the extremely high cost of the drug and the clinical monitoring of patients that would be required during its course. Such collaboration is certainly a possibility – the success of the charity-co-funded ME/CFS Biobank project which recently obtained $1.5 million of funding from the National Institutes of Health in the USA has shown it to be feasible – and so we are in active discussions with other organizations about collaborative options if the need arises.

However, the first step is for there to be a concrete research proposal, drawn up by experienced researchers in the field and backed by a reputable scientific institution. Ideally, the proposal and the application based on it would be from investigators with previous or current experience of using rituximab in a clinical setting, though this need not be essential. Other issues, including funding – or co-funding with other charities or Class 1 funders like the Medical Research Council (MRC) – will arise at subsequent stages, after it is clear that the science is sound and that a clinical trial is both feasible and realizable.

We all hope that a good research proposal will be forthcoming, and will endeavour to keep our supporters informed about any developments as they occur.

Norwegian Rituximab Studies

(originally in Breakthrough, Spring 2012)

The publication of a scientific report in October 2011 showing an improvement of symptoms with rituximab (Fluge et al, PLoS ONE 2011) made a big splash in the ME world, and received widespread coverage in the press. Rituximab is a monoclonal antibody against the CD20 protein mainly found on the surface of a type of white blood cell, B-lymphocytes. The drug eliminates these B-cells, and has therefore been used to treat diseases (such as some cancers and autoimmune disorders) in which these cells are malignant, overactive or too numerous.

There is an interesting background to this investigation. Originally, the researchers at Haukeland University Hospital, Bergen noticed that one patient with ME/CFS experienced “unexpected and marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkin’s disease”. Because of this, they conducted a pilot case series in 2009 to explore the clinical effects of rituximab in 3 more people with ME/CFS, and found a “significant clinical response”. Building on these intriguing results, the researchers planned their newly published investigation – a double-blind, placebo-controlled phase II study – using 30 ME/CFS patients randomised to receive either rituximab or saline (two infusions two weeks apart) with follow-up for a whole 12 months.

The predefined “primary end-point” – self-reported fatigue score 3 months after treatment – was negative (i.e. there was no significant difference between rituximab and placebo). As the authors point out, however, differences in fatigue between the two groups were actually most evident after 6–10 months, suggesting that 3 months was too short a time to evaluate the effects of rituximab on symptoms, something that subsequent investigations will take into account. So, over the whole follow-up, a major or moderate “overall response” (defined as lasting improvements in self-reported fatigue) was seen in 67% of patients on rituximab compared with 13% of patients on placebo (p=0.003; see Table). Furthermore, rituximab was also associated with significant improvements in some quality of life measurements, and, what’s more, no serious adverse events were reported in patients receiving rituximab.

The Norwegian researchers suggest that the “delayed” responses to rituximab (starting after 2–7 months), in spite of rapid B-cell depletion, support the idea of ME/CFS as an autoimmune disease in which the gradual elimination of autoantibodies from the body leads to symptom improvement. However, they describe their results as preliminary and indicating only a “proof of principle”. In fact, they were probably as surprised as anyone else by the spin given by the media to these tentative findings. The next phase of the work is at the planning stage – a Norwegian national initiative to undertake a randomized, blinded, multicenter Phase III study to verify or reject these findings. Given the drastic action of rituximab (the destruction of B-cells which have an important role in immunity), and the cost of the drug (several thousand pounds for a single course), it is most likely that other research groups will proceed cautiously, awaiting the Phase III trial results with interest.