MICA: Psoriasis Stratification to Optimise Relevant Therapy (PSORT)

Psoriasis is a common, chronic, potentially disfiguring disease that affects more than 1 million people in the UK. It can cause considerable psychological and social disability. In the past 10 years there has been a dramatic improvement in clinical outcomes for patients with severe psoriasis due to the introduction of a new class of injectable drugs called biologics. These work by targeting specific parts of the immune system which are important in causing psoriasis. However, these drugs are very expensive (estimated annual cost is £10,000) and it remains the case that a significant number of patients fail to respond adequately. If we could predict which patients will do well with a particular biologic drug then we could devise new treatment plans that would be personalised for each patient rather than the current system of "trial and error" prescribing. This would be of added benefit to society as a whole since it could result in significant cost savings to the NHS and aid the pharmaceutical industry in development of new drugs.
The programme of research in the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium aims to use existing knowledge about psoriasis, both clinical and scientific, our unparalleled patient base coupled to involvement of patient organisations and state-of -the-art investigative tools to develop tests that we can use in the clinic to help direct personalised treatments. Specific questions we will ask are: i) do levels of a drug in the blood and a patient's immune response to that drug effect outcome; ii) are there specific changes in the skin and blood that predict which drug is likely to be more useful in a particular patient; iii) is there variation in a patient's genetic make-up, linked to psoriasis and how drugs work, that may predict response to treatment; and iv) does bringing all the information collected in i-iii above, though computer based data analysis, have more power to predict response to treatment?
Successfully achieving such a goal requires a number of important criteria to be met. Perhaps most importantly we need consent from large numbers of patients to enter studies and provide samples of blood and skin. From the start of the study, we have engaged with the Psoriasis Association (patient organisation) to ensure the study met with their approval. As a consequence of patient engagement, in the UK we have arguably the world's leading safety registry for patients receiving biologic drugs for psoriasis. During the lifetime of our proposal, it will have accumulated comprehensive information on 7,000 patients including responses (good and bad) to biologics. The PSORT consortium includes representatives from 4 of the largest psoriasis clinics in the UK. These will provide the source for patient recruitment.
The experiments will take advantage of several factors. First, in contrast to many other chronic diseases, change in psoriasis severity is simple and accurate to determine after starting therapy. Second, target organ tissue (i.e. skin) can be sampled in a minimally invasive way by skin biopsy (patient feedback tells us that this is acceptable to them). Third, internationally competitive expertise exists across the consortium between investigators and collaborators in all of the scientific disciplines required to successfully deliver the programme. Fourth, appropriate research infrastructure exist at each of the three main centres namely Manchester, Newcastle and London. This includes the registry itself (Manchester) and NHS funded facilities (Newcastle and London). Finally, we have developed an extensive network of pharmaceutical company partners who bring specific expertise and resources to the programme. Not only will this help in achieving the short term goals but it will also provide the necessary platform for translating the outcomes into clinically useful tests.

Biologic therapies for severe psoriasis are currently prescribed in a stochastic manner that is neither efficient nor cost-effective. The vision of the PSORT consortium is to better understand determinants of response to biologic therapies and deliver, in close collaboration with commercial partners, a PSORT stratifier (algorithm) to guide psoriasis management. This will optimise clinical pathways for psoriasis, inform the management of other less accessible immune-mediated inflammatory diseases and deliver health care savings. To deliver this vision PSORT has brought together a powerful grouping of world-leading psoriasis researchers, bioinformaticians, statisticians, health economists and industry partners. Patient representation informs the consortium which utilises NIHR and MRC funded platforms and an established, high-quality clinical bioresource the British Association of Dermatologists' Biologic Interventions Registry (BADBIR) involving 143 UK dermatology centres (5500 patients by 2014). Two parallel, interlinked Work Strands will provide clinical, adherence, pharmacological, genetic, transcriptomic, and immune data in blood and skin on psoriasis patients treated with biologics. Deeply-phenotyped Discovery and Refinement cohorts sponsored by academia and industry are complemented by large scale validation in BADBIR and in a prospective clinical pilot study of minimal effective dosing of biologics. The data will be integrated and interrogated through TranSMART infrastructure enabling a combination of bioinformatics, machine learning and biostatistics for the discovery of drug response endotypes/biomarkers. Working with our partner diagnostics companies these will be scalable for clinical use. Operational management will be proactive and milestone driven with oversight provided by an Independent Advisory Board. It is anticipated that the PSORT consortium will be a major catalyst to deliver novel personalised medicine approaches in the management of psoriasis.

The main beneficiaries of the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium will be people with psoriasis, who will have improved access to effective treatment. The majority of people who develop psoriasis are young - 75% develop the condition before 35 years of age. Thus, this predominantly lifelong condition can have a significant detriment on an individual's chances of achieving their full potential. For instance, loss of sleep and time away from school for healthcare visits and hospital admission, difficulty in forming relationships and exclusion from social and sporting activities because of the stigma of psoriasis and exclusion from public-facing employment. The wider patient impact is also important in that family members are frequently involved with the care of psoriasis patients. These all contribute to a significant burden from a disease that affects at least one million people in the UK. Optimised treatment results in improvements in quality of life, and also has the potential to impact on important associated co-morbidities such as depression, psychosocial and physical disability and cardiovascular disease.

The outputs from PSORT will allow more accurate matching of the treatment to the disease, facilitating more rapid and individualised transitioning onto the most effective and safest drug. Those who fail to respond to the initial treatment will be recognised more quickly allowing them to progress to more suitable treatment, with less exposure to ineffective treatment. Currently, patients whose disease is completely suppressed by biologic treatment continue this treatment indefinitely. PSORT will allow tailoring of drug dose to the minimum that is effective and in some, whose disease is in remission, treatment may be interrupted or stopped, reducing the risk of side-effects. It is likely that issues related to pharmacokinetics and drug immunogenicity and their association with the mechanisms of treatment failure will relate equally to patients with other immune mediated inflammatory diseases such as rheumatoid arthritis and Crohn's disease, allowing these impacts to benefit an even greater number of patients.

The pharmaceutical and biotechnology industries involved with the development of small molecules, biologics and biosimilars for psoriasis treatment will benefit from stratification, both in the identification of new therapeutic targets and in clinical trial design. These benefits will include: de-risking of drugs (for instance in dose optimisation); and using the PSORT classification of psoriasis to design adaptive trials to test new drugs in small, well-characterised cohorts of patients, including through the NIHR Translational Research Partnerships. Diagnostic companies will be able to use potential psoriasis stratifiers to develop and commercialise companion diagnostics.

Professional bodies (e.g. British Association of Dermatologists) and National Institutions (e.g. NICE and Scottish Intercollegiate Guidelines Network) responsible for the development of clinical practice guidelines will benefit from stratification of psoriasis in that patient pathways and guidance for starting and /or switching biologics will gain a substantial evidence base. In terms of education of clinical professionals, classification of psoriasis will inform future teaching and learning.

The NHS and other healthcare providers and their funders will benefit from an effective and efficient use of expensive drugs by an approach that targets those patients who are at highest likelihood of responding, informing evidence-based policy making. Dose minimisation strategies and drug discontinuation in patients who have achieved remission has the potential to make significant cost savings whilst maintaining patient benefit. Early, targeted disease altering management will benefit not only the health of individual patients but would significantly increase their contribution to society.