Our programme has three inter-linked work strands (WS) and linked Industry and Patient Programmes. A visual representation is shown below.
WS1 will establish a UK-AILD cohort for detailed characterisation of treatment-naïve patients across the full spectrum of AILD, who will provide biosamples prior to starting conventional disease-modifying therapy. The same patients will be followed-up at 12 months to evaluate clinical outcomes, providing an additional, valuable dimension to the baseline dataset. Samples collected at baseline will be banked in a central biorepository and used for the discovery and validation panels of phenotyping platforms comprised of Immunophenotyping, Single Cell Transcriptomics, Metabonomics, Microbiomics, and Proteomics & Fibrosis Markers. These platforms have been selected based on current understanding of the pathogenic mechanisms involved in AILD, supported by pilot data and informed by the current drug-development pipelines of Industry partners. Comprehensive phenotyping in discovery will enable the derivation of a new taxonomy that will be confirmed in validation. Informative biomarkers will be prioritised for secondary, “real-world” validation in the UK-PBC, UK-PSC and UK-AIH cohorts maintained as part of the Industry Programme.
WS2 will develop and validate the new taxonomy. Co-ordinated by the MRC Biostatistics Unit, it will use statistical and machine-learning methodologies to explain the observed variation of biomarkers in terms of latent components to identify, in an unbiased fashion, phenotypic patterns across the AILD spectrum that are linked to pathogenic mechanisms. These components will be integrated and explored in classical disease forms, including high risk disease and overlap syndromes, to identify clinically meaningful predictive endotypes. The new disease taxonomy will be validated against clinical parameters such as treatment response and hard endpoints in the UK-PBC, UK-PSC and UK-AIH cohorts.
In WS3 we will develop a new trial model, a trials acceleration programme, which will use the new disease taxonomy, and will undertake the first fully personalised trials using this disease methodology, recruiting through the Industry Programme. We will work with our partners in the clinical, academic and industry sectors to maximise awareness of the new taxonomy and the linked trials model to maximise its utility. We believe that the new approach will ultimately deliver real advance in the understanding and management of AILD through the fully tailored model.
The fully-funded Industry Programme will enable long term maintenance of the existing UK-PBC, UK-AIH and UK-PSC cohorts with ongoing recruitment and follow-up data captured through NHS Digital. These cohorts will allow validation of new taxonomy markers; delivery of trials through targeted recall; population-level characterisation of symptoms, and data capture for health economic modelling. The concept behind this WS is that industry will invest directly into the element of the programme which will most directly link to their programmes.
The new Patient Programme will include priority setting activity, to ensure that the needs of patients with AILD are fully met in future research programmes, and the development of a model for patient initiated, developed and funded research in a patient priority area, representing a step change in patient involvement in research.