Sir James Black Award for Contributions to Drug Discovery
Congratulations to Dr Francesco di Giovine who has been awarded the prestigious Sir James Black Award for Contributions to Drug Discovery by the British Pharmacological Society jointly with Professor Sir Gordon Duff and Professor George Nuki. The award was set up by the British Pharmacological Society in commemoration of the late Sir James Black to recognise the achievements of pharmacologists in drug discovery.
Franco recalls his involvement in the discovery of anti-TNF treatments:
"I undertook my PhD studies jointly between the University of Edinburgh, Dept Medicine (WGH) and the Molecular Immunology Unit (NGH) between November 1984 and May 1988. My supervisor was Professor Sir Gordon Duff and the Head of Rheumatology was Professor George Nuki.
In 1985 I developed an interest in Tumour Necrosis Factor, a cytokine that could be responsible for the increased levels of elastase and collagenase in the rheumatoid joint which I initially observed during my MD studies in 1981.
Following the observation by Professor Jeremy Saklatvala (Kennedy Institute, University of Oxford) that TNF alpha had cartilage resorbing activity, I set up a TNF assay based on cytotoxicity of L929 cells in July 1986. Specificity could be checked using specific monoclonal antibodies donated by Professor Jeremy Saklatvala.
Synovial fluids from well-phenotyped rheumatoid arthritis patients were tested from previously collected samples and the results were published as an abstract and a presentation at the British Society for Rheumatology in November 1986 (see image appended to this document). The audience were impressed and enthusiastic, including other investigators who later confirmed the same findings.
Our research was presented in the same session where Professor Jeremy Saklatvala reported TNF alpha to stimulate loss of proteoglycans in cartilage – and the two sets of research findings were complimentary.
My research was published in 1988 Tumour necrosis factor in synovial exudates. FS Di Giovine, G Nuki, GW Duff, Annals of the Rheumatic Diseases 47 (9), 768-772, 1988.
This publication led to a number of studies and in 1992 Professors Maini and Feldmann published laboratory research demonstrating a marked reduction in joint inflammation with a molecule that blocks the activity of TNF alpha.
In the same year, the Kennedy Institute carried out the world’s first clinical trial of an anti-TNF alpha drug, infliximab, in a small group of patients with rheumatoid arthritis. This was shortly followed by a larger clinical trial in Europe. Both clinical trials confirmed dramatic anti-inflammatory effects of anti-TNF alpha.
The remainder of the 1990s saw the development of further drugs designed to block the activity of TNF alpha. During the last decade they have been approved for the treatment of a range of inflammatory joint diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis.
Other anti-TNF alpha monoclonal antibodies, after infliximab (Remicade) such as adalimumab (Humira) and certolizumab pegol (Cimzia) are also entering trials or have been approved for use in human therapy. Another anti-TNF alpha drug etanercept (Embrel) targets the TNF alpha molecule in a slightly different way, but the downstream effects of this drug are the same as the monoclonal antibody-based anti-TNF alpha drugs.
The National Institute for Health and Clinical Excellence (NICE) have approved many of the anti-TNF biologic drugs mentioned above for use in the UK for a range of musculoskeletal diseases either in isolation or in combination with other disease modifying drugs such as methotrexate".
How does anti-TNF therapy feature in the NICE guidelines for the therapy of Rheumatoid arthritis? To be eligible to anti-TNF therapy the following conditions must be met:
- The patient must have tried at least 2 of the standard DMARDs (such as methotrexate, sulfasalazine, hydroxychloroquine and leflunomide) and one of these must be methotrexate.
- The level of disease (measured using an assessment called ‘disease activity score’ or ‘DAS’) should be above 5.1 on two occasions, one month apart. DAS is calculated by assessing inflammation in 28 joints and other humoural markers.
Meanwhile, the search for more effective and better tolerated biologic drugs for inflammatory joint diseases is still ongoing.
Sheila Francis, Head of Infection, Immunity and Cardiovascular Disease at University of Sheffield where Dr di Giovine has worked since 1990 said “the work by di Giovine, Duff and Nuki was instrumental in the introduction of a new drug to the market and opened the eyes of other scientists to the possibility of using biologic drugs for chronic inflammatory diseases. For these reasons and the fact that these drugs have helped millions of patients so far, this award is richly deserved”