Head to head
Published on 01 January 2010
The UK’s first trial comparing anti-TNF therapy against rituximab is being funded not by the big pharmaceutical companies but by Arthritis Research UK.
As more and more new biological therapies come onto the market – tocilizumab, certolizumab pegol and golimumab are the first of the next “wave” of exciting new therapies – patients with inflammatory arthritis will have more choice of treatment than ever.
Biological therapies, which include anti-TNF therapies, block triggers of inflammation and are used to treat inflammatory forms of arthritis. But the advent of these new drugs has prompted a question that both clinicians and patients need answering swiftly – which of them works best?
A lack of head-to-head trials has hampered the research community’s ability to answer that vital question. The unwillingness of pharmaceutical companies to submit their big money-making blockbuster against another company’s blockbuster has meant that most of these new medicines are only ever trialled against the drug used as first-line treatment for mild to moderate disease – methotrexate – which inevitably means a deeply favourable outcome on the part of the new drug.
In the case of tocilizumab, for example, it means that the pharmaceutical company producing it can quite truthfully claim that their new drug is six times better than existing therapy – meaning methotrexate.
Which biological therapy to use first?
“Comparing a new biologic drug against methotrexate doesn’t really show how effective it is and is used to meet regulatory approval to prove that a new drug works, but it doesn’t help rheumatologists who are faced with the question of which biological therapy to use first,” says senior lecturer and honorary consultant rheumatologist at Gartnavel General Hospital in Glasgow Dr Duncan Porter.
Researchers for the independent Cochrane Review found in a review of all available studies that although biologic drugs were all effective, there was little data on direct comparisons that could help doctors decide which to prescribe. “We believe that direct head-to-head comparisons of biological drugs in patients suffering from rheumatoid arthritis (RA) are needed,” said lead researcher Jasvinder Singh. “These trials should examine efficacy and safety at different stages and severity levels of the disease.”
At the moment clinicians are bound by guidelines laid down by the National Institute for Health and Clinical Excellence (NICE) in England and Wales and the Scottish Medicines Consortium (SMC) in Scotland, which state that one of the three anti-TNF (tumour-necrosis factor) therapies, infliximab, etanercept and adalimumab, have to be used if a patient fails on a conventional therapy such as methotrexate. The next choice is the anti-B-cell drug rituximab, which targets the body’s white blood cells.
However, it will only be a matter of time before rituximab’s manufacturer, Roche, decides to apply for a licence to use rituximab before anti-TNF therapy. And when that happens, the need to know which of the two types of drug is more effective will no longer be theoretical.
So with excellent timing, Arthritis Research UK has just awarded almost £1 million to fund the first head-to-head biologics drug trial in the UK, with more than 300 rheumatoid arthritis patients starting to be recruited across Scotland from January.
“We know these two treatments work, but we don’t have very good evidence about which works better, or about which offers the NHS better value for money, and that’s what we plan to find out,” says Dr Porter, principal investigator of the trial, called ORBIT (Optimal management of rheumatoid arthritis patients requiring a biological therapy).
Dr Porter will lead a team of researchers from the Scottish Collaborative Arthritis Network, and other colleagues from the Pathobiology of Early Arthritis Cohort (PEAC) Consortium, which includes researchers from around the UK.
Patients will be recruited from hospitals throughout Scotland and randomised onto one of the two types of drugs for12 months. If they fail to respond after 5 months they will switch to the other. The three-year trial will also be extended into England in late 2010/2011.
Impact on the NHS budget
ORBIT could have a significant impact on the NHS budget, as well as benefiting patients. The cost of anti-TNF therapy is approximately £9,000 – £10,000 a year per patient. Rituximab costs £4,700 to £7,000, so were rituximab to prove as effective as anti-TNF therapy, the NHS could save up to £20 million a year. If anti-TNF was shown to be more effective, this information would provide evidence to inform NICE/SMC appraisals which might otherwise conclude that rituximab offers a more cost-effective approach. The team is restricting the anti-TNF drugs to etanercept and adalimimab, which are both given by injection and are the current market leaders. (Infliximab, the third anti-TNF therapy is given by an infusion.) The NHS is paying for their supply on the trial, as both are NICE approved, while Roche will provide the rituximab.
Who will do better on what drug?
The research team will also to try to predict which patients will do better on which drug, something that cannot currently be done; testing patients’ blood at the start of their treatment by identifying specific biomarkers. “At the moment this is complete trial and error, and identifying this upfront would save the patient going on the wrong drug first,” added Dr Porter. Identifying and predicting patients’ response to drugs in advance is regarded as something of a Holy Grail by the research and medical community, as it brings ever closer the prospect of “personalised medicine,” reducing costs, and improving quality of life for patients.
While all patients on the trial will have blood taken for biomarkers, a subgroup will have a synovial biopsy, to compare different types of inflammation. The hypothesis the team is working on is that those with diffuse inflammation (where the inflammatory cells are scattered through the joint lining) will do better on anti-TNF therapy than those with focal inflammation (where the cells are affected together in clumps) who may do better on rituximab.
A related psychological study
The study is very much a collaborative venture, involving experts in the field such as Professor Iain McInnes from Glasgow University, who is the chief scientific investigator and Arthritis Research UK professor of rheumatology in Birmingham Chris Buckley. Dr Jon Packham from Keele University is running a related psychological study, based on the premise that response to anti-TNF is often influenced by a patient’s mood at the time they start their treatment, which should yield some fascinating results.
Medical director of Arthritis Research UK Professor Alan Silman said: “This research is a very exciting and important development which will be of enormous benefit not only to patients but also to the NHS and other funders of these very effective but expensive new therapies for rheumatoid arthritis."