The Arthritis Therapy Acceleration Programme (A-TAP) supports the development of novel treatments for arthritis based on the underlying causes of inflammatory disease and provides a translational vehicle to “pull though” basic science discoveries into the clinic in early proof of principle experimental medicine studies along the M40 corridor. These devlopments are currently based on the internationally renounced expertise across the partnership in the Immune Mediated Inflammatory Diseases (IMIDs) of Rheumatoid Arthritis (RA), Inflammatory Bowel Disease (IBD), Sjögren’s Syndrome (SS) and Spondyloarthropathy (SpA).
In recent years, many exciting new targets have been identified for a range of IMIDs, such as anti TNF therapy for Rheumatoid Arthritis. Yet there remains a stubbornly resistant time lag between the first identification that a target is effective in experimental medicine studies and their use in clinical practice. Partly this is due to the regulatory process, and partly due to the artificial silos in which medical specialities are organized; but more importantly the pace of molecular technology and drug discovery has outstripped the ability of our 200 year old, organ based clinical taxonomies to keep pace with a molecular diagnosis and classification of disease, as happens now in the use of personalized medicine to treat different cancers. The current approach to IMIDs, such as RA, SS, IBD and SpA, is fragmented and concentrated within disease or tissue-specific expert groups. Moreover, there are real financial barriers to cross- discipline collaborative work, with tissue-specific funding from disease specific charities. This has resulted in a lack of co-ordination, with little attention given to the common pathological processes such inflammation, mucosal immunity and tissue regeneration that underpin most IMIDs. This is where the investment of £7m over seven years by the KTRR in support of the A-TAP will make a catalytic difference to the way in which we approach experimental studies in inflammatory diseases.
The IMID taxonomy of the 21st Century is still predominantly based on clinical features and on the organ system in which the disease first manifests; for example the skin, joints, eyes or intestines. And yet we know through the effectiveness of biologic treatments such as anti TNF that diseases such as RA, SS, IBD and SpA share many common features that mean that they should not be “owned” by one disease therapeutic area. Furthermore, there is a huge disconnect between the “clinical phenotypes” routinely used to classify these diseases, and “molecular patho-types” used to identify therapeutic targets. This has led to a major problem and a major challenge. The major problem is that we treat to symptoms rather than the underlying pathological mechanism. The major challenge is how to match the right target and right therapy to the right disease indication at the right time especially as the clinical endpoints in trials often do not match the molecular mechanisms that the drugs target.
If new treatments for RA, SS, IBD and SpA are to emerge, then a radical new approach which moves the field from an organ-based approach to a process-driven approach is urgently needed. Addressing this challenge will require a new way of thinking; that IMIDs should be approached as sharing common pathogenic pathways rather than distinct organ specific diseases, and that therapies should be targeted at these pathogenic processes rather than just the clinical features associated with the disease. This will facilitate the use of drugs based on the concept of process driven pathology. Addressing this challenge will also require a new way of working; focussed on the repurposing of drugs based on the molecular mechanisms they target in addition to the clinical symptoms they impact. Only in this way will the molecular marker match the molecular mechanism.
So how can the A-TAP help make a difference? The primary role of the A-TAP is to provide the missing link that will ensure world class basic science observations are “accelerated” into early phase experimental therapy for patients by providing the “infrastructure of people”. The A-TAP will bring an innovative new approach to translational inflammation research accelerating the assessment of novel therapies in the clinic by using pathology based outcome measures in basket trials in IMIDs to determine therapeutic utility and aid tissue based biomarker discovery. The results will help treat the cause of disease, not just their symptoms, and ensure expensive treatments are targeted to those most likely to benefit. The A-TAP uses a new type of trial design called a “Basket Trial” to facilitate a process-driven, pathway-focussed driven approach to the exploration and classification of the four IMIDs to be assessed in this programme. In such trials, one drug is tried out in a number of different diseases at the same time; rather than the traditional one drug for one disease at a at a time approach that is currently used. This speeds things up and helps make earlier decisions about whether to go ahead with a particular drug for a particular disease. A step change in our ability to deliver these innovative clinical trials in IMIDs to time and target would create a globally unique infrastructure attracting inward investment at the same time as contributing to the UK Government’s vision of a UK “lit runway” ensuring accelerated assessment and access to novel therapies within the UK.
The A-TAP comprises of an alliance between two Universities and seven NHS partners: University of Birmingham (UOB), University of Oxford (Oxford), Oxford University Hospitals NHS Foundation Trust (OUH), University Hospitals Birmingham NHS Foundation Trust (UHB), Sandwell and West Birmingham Hospitals NHS Trust (SWBH), The Dudley Group of Hospitals NHS Foundation Trust (DGoH), University Hospitals Coventry and Warwickshire (UHCW), Walsall Healthcare NHS Trust (WHT), and the Modality Primary Care Partnership (Modality). It builds on the infrastructure investment by the National Institute for Health Research in units in Birmingham, Coventry and Warwick and Oxford in early phase translational studies in the four IMIDs (RA, IBD, SS and SpA) along the M40 corridor.
One of the key objectives of the A-TAP is to provide a platform to perform Stratified Pathology: matching the right drug to the right indication early in drug discovery. We will work to develop and seek collaborations with industry partners for proof of concept and proof of mechanism with supporting biomarker studies. While there will be a focus on repurposing drugs or combination therapies we also wish to use high quality novel experimental drugs/probes to uncover new targets and pathways particularly those identified by scientists working in the Kennedy Institute .The A-TAP is not designed to replace or compete with traditional routes of funding, but rather it occupies a unique and critical niche within the translational space that will put the “A” back into Accelerated experimental studies.