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For more information, go to www.arthritisresearchuk.org

Focus on the Kennedy Institute – what happened after anti-TNF therapy?

Published on 01 July 2008
Source: Arthritis Today

In the first of a three-part report, Arthritis Today looks at the work of the clinical trials group at Arthritis Research UK’s West London institute.

Dr Matt Seymour performs an ultrasound examination on the hand of a rheumatoid arthritis patient
Dr Matt Seymour performs an ultrasound examination on the hand of a rheumatoid arthritis patient.

It doesn’t look very impressive, but the small, rather dingy rheumatology outpatient department in the bowels of Charing Cross Hospital in Fulham Palace Road in west London was the place where a drug therapy that would revolutionise the treatment of inflammatory arthritis was first tested on patients in the 1990s.

Anti-TNF therapy, pioneered and developed by scientists at Arthritis Research UK’s flagship Kennedy Institute of Rheumatology (KIR) next door to the busy NHS hospital, has transformed the lives of thousands of patients worldwide and led to much acclaim and a clutch of awards for two of the main investigators, Professor Sir Tiny Maini and Professor Marc Feldmann.

Now, several years after the licensing of infliximabetanercept and adalimumab, things have moved on. While Marc Feldmann has taken over from Professor Maini as director, the KIR has become part of Imperial College, although its core funding of £4.5m a year from Arthritis Research UK remains.

Professor Peter TaylorAnd as well as pursuing several strands of basic science in both inflammatory and degenerative forms of arthritis, translational research is being spearheaded by Peter Taylor, rheumatologist, Professor of Experimental Rheumatology and head of the KIR Clinical Trials Unit. For the past 4 or 5 years he has been building up the team of clinical researchers and research nurses (Arthritis Research UK-funded) plus a willing cohort of arthritis patients drawn from the local catchment area and more widely through a network of collaborators, with the aim of tackling unmet patient need.

Although anti-TNF treatment has been remarkably effective in 70 per cent of patients, there is a need to find something for the 30 per cent in whom it doesn’t work, to find early diagnostic and prognostic markers, and to establish better ways of assessing a satisfactory response to therapy.

With funding from various sources, including Arthritis Research UK, the KIR trustees, and the pharmaceutical industry and the support of the newly formed Imperial College NHS health trust, a new imaging unit has been set up several floors above rheumatology outpatients, contrastingly bright and airy, and full of the latest imaging equipment, used for both research and clinical purposes.

Early-stage clinical trials

Peter Taylor is very conscious of the concept that lightning rarely strikes twice in the world of research, and that the likelihood of another treatment as successful as anti-TNF therapy emerging from basic science at the KIR for a rheumatoid arthritis (RA) indication is remote, however many new molecular targets are identified by his scientist colleagues, both for rheumatoid arthritis and other musculoskeletal disorders.

Hence, anticipating that basic science research by Professors Jerry Saklatvala and Hideake Nagase could lead to the testing of new therapies in osteoarthritis may yet be some years in the future, Professor Taylor is preparing the ground and developing a new approach to conducting early-stage clinical trials.

He is recruiting patients on whom to test new drug targets, and developing effective outcome measures using new imaging techniques to assess disease progression and damage and response to treatment ever more effectively, such as high frequency ultrasound and specialist image analysis in association with magnetic resonance imaging. And in parallel to the basic science work at the KIR which he expects to at some point yield new molecular targets to test on his clinical trial cohort of patients, Professor Taylor is also working closely in collaboration with the pharmaceutical industry on early “proof of concept” trials which permit validation of a series of novel outcome measures.

“It may be many years before my scientist colleagues at the KIR’s research work reaches the clinical trial stage, and because there is potentially a long gap between basic science discoveries and the availability of related therapies in routine clinical use, I am trying to speed the process up,” he explains.

“50 per cent of new drugs don’t make it to the market place”

With this goal in mind, Professor Taylor’s clinical trials unit is engaged in early testing of novel therapies on patients to find out if they are suitable for development for further large-scale clinical trials designed for drug registration purposes.

Professor Peter Taylor and rheumatology nurse specialist Cathering McClinton“Many potentially promising new therapies will never be tested unless new approaches are adopted to the design of early phase clinical trials,” he says. “You can test some drugs on animals, but there are no perfect animal models for osteoarthritis, rheumatoid arthritis and ankylosing spondylitis and ultimately you have to do experiments in man. You also have to think about the likely future benefits, potential toxicities and the well-being of patients. It’s a completely new way of conducting clinical trials. There are dozens of potential targets for therapy for musculoskeletal disorders and a correspondingly high number of new compounds that need to be tested. We will focus on a few of greatest interest and relevance to our basic science programme. At present, about 50 per cent of new drugs fail at the phase III development phase and don’t make it to the marketplace. I hope that by employing more sensitive measures of response to a test therapy at the earliest stages of new drug development, that we will be able to rationally select those drugs most likely to be successful and benefit future generations of patients.”

Patient safety, comfort and well-being is always the first concern at the KIR clinical trials unit. However, recruitment to the KIR clinical trials cohort has been a challenge, partly as a result of the media coverage and public perception of clinical trials following experimental work at Northwick Park Hospital 2 years ago when two volunteers were left in a critical condition when they suffered unexpected reactions. It’s also increasingly difficult to recruit rheumatoid arthritis patients, even those who attend Professor Taylor’s early arthritis clinic at Charing Cross Hospital, because there are now relatively fewer patients with severe disease than was the case ten years ago, or who aren’t already on effective therapies. It is slightly easier to recruit osteoarthritis patients as there are still no effective disease-modifying drug treatments and so patients are more willing to put themselves forward for something new and experimental.

Potentially enormous patient benefit

Peter Taylor is optimistic that the clinical trials work will lead to potentially enormous patient benefit. “We might not find another anti-TNF therapy but we might find a much better, more effective, safer way of doing clinical trials, and that will be very worth while,” he says.

One of the trials they are currently conducting is on new oral therapies against new molecular targets for rheumatoid arthritis patients with an inadequate response to conventional oral drugs, and new therapies for ankylosing spondylitis that are anticipated to deliver the benefits of anti-TNF therapy at reduced costs.

Former KIR director Tiny Maini’s mantra was “from bench to bedside”; in other words, stressing the importance of developing treatment from the laboratory to the patients speedily.

Peter Taylor agrees, but turns the saying around. “We have a clear vision, a cohesive programme, yes, to take research from the lab to the clinic, but also to go from the bedside back to the bench – addressing unmet needs and using targeted therapies to investigate what patient response can tell us about the biology of disease. That’s exactly what we are doing.”

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