MAximizing Sle ThERapeutic PotentiaL by Application of Novel and Stratified approaches (MASTERPLANS)

Systemic Lupus Erythematosus (SLE) is a chronic incurable disease caused by a person's immune system attacking organs and tissues such as the joints, skin, kidneys and brain. SLE affects one in 2000 individuals in the UK. Currently, treatment is selected based on a doctor's experience and on a 'trial and error' approach. Many agents take at least 6 months to show maximum improvement during which patients often require large steroid doses. It is recognised that long-term complications of lupus are associated with both ongoing 'grumbling' disease activity and chronic steroid use. Standard immunosuppressives such as mycophenolate mofetil (MMF) have had response rates of 50-60% in clinical trials and newer, more targeted' biological therapies such as rituximab, belimumab and epratuzumab also report response rates in trials of 40-60%. Clinical experience and a number of studies have however suggested that there are certain patients who respond very well to particular treatments. The goals of a stratified approach therefore would be to allow doctors to maximise major response rates whilst avoiding / minimising chronic steroid therapy and aligning therapy selection better with our understanding of the key disease process in an individual patient. Our consortium will identify and apply in the clinic, factors that predict excellent response to therapy to allow doctors to increase the early use of 'most effective' therapies. This 'stratified' approach will also improve the success of future trials of new treatments for lupus which to date has had a suboptimal record.
To do this we will combine expertise from clinical and laboratory-based investigators, and link these with researchers working in the pharmaceutical industry. Our focus will be to identify factors that predict which patients do extremely well on any particular lupus treatment. We will start by focusing on a small number of drugs. As we demonstrate that this approach works well, we will be able to expand this method to other lupus treatments which are currently in development. We plan to re-analyse data already available from a number of large studies ongoing in the UK and internationally as well as to re-analyse data from previous lupus clinical trials. From these studies we will look for key predictive factors; such factors may include the type of lupus, genetic markers that the patient inherited and results of blood tests . In order to examine this question in even more detail, we plan to set up two parallel studies; one in patients with skin rashes due to lupus and one in patients with kidney involvement. In both these studies we will take biopsies to examine the affected tissue and also take blood and urine samples on a regular basis. These samples will be used to look in detail at how cells, proteins and other molecules change over time after a patient has been treated with a particular therapy. Combining this detailed information with the information gained from the larger studies we aim to better predict excellent levels of response to treatment.
This information will be used to help develop devices and/or computer programmes for the clinic to help find the most appropriate and effective treatment choices for patients with lupus. We plan to test our results in a clinical trial to examine whether this approach actually has more benefit for patients. Running alongside this, we will study the economic costs of lupus to the health care system as well as the costs of lupus to the individual and society. We anticipate that treating the right patient with the right drug at the right time will help control lupus better in individual patients, improve their survival rates and reduce their needs for need for steroid treatment. We also anticipate that this approach will significantly improve the quality of life of patients with lupus whilst also providing financial saving for the healthcare and benefits system.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease affecting approx. 16,000 people in the UK. It is highly heterogeneous: each patient presents with a unique fingerprint of organs involved, severity, and response to therapy. The clinical heterogeneity is paralleled by a range of underlying genotypic and immune function abnormalities. A number of new therapies, with different mechanisms of action, have been developed. Overall response rates are only 40-60% but subsets of patients respond very well to each drug. Current therapy is based on a 'trial and error' approach often involving glucocorticoid co-therapy. Delayed and poor control of inflammation results in organ damage, cardiovascular disease and glucocortocoid toxicity. We aim to fundamentally improve care for SLE patients by identifying key endotypes associated with remission and low disease activity (LDA) on particular therapies.
Our goal requires a co-ordinated and co-operative approach. Our consortium combines expertise from academia with pharmaceutical and small and medium enterprise (SMEs) partners to identify predictors of response to exemplar therapies. Clinical and genotypic predictors of response will be sought by analysis of existing data from large studies. Two parallel prospective studies assessing tissue, blood and urine from patients with skin or renal lupus will study immunophenotypic predictors of response. These discoveries will be used to develop near-patient devices and algorithms to select therapy in clinic. We will test the benefit and cost-effectiveness of this stratification approach in trials.
Using the right drug at the right time will improve control of inflammation for people with SLE. Long-term benefits will be improved survival, improved quality of life and reduced glucocorticoid requirements, whilst providing financial savings for health and social care. MASTERPLANS will be the international model of best practice in delivering stratified medicine to SLE patients.

Immediate beneficiaries will be SLE patients who will be offered treatment that is targeted on the basis of disease mechanisms and biomarkers that predict high levels of clinical response to particular drug treatments. A limitation of current standard of care therapy is the dependence on chronic glocucortocoid use to control disease on a day-to-day basis. Deploying other therapies to maximise efficacy will contribute to reducing this burden for patients. This offers the likelihood of better disease control, fewer flares, improved quality of life and reduce long-term morbidity.
A predictive algorithm and biomarker-based approach to SLE therapy will significantly influence payers and healthcare policy makers. In the short term we will target the right treatment to the right patient for the treatments that we have studied. In the medium-long term this investigative model for evaluating and positioning drugs better will be an exemplar of best practice whereby other treatments can be evaluated within the treatment paradigm for SLE.
For the pharmaceutical industry our approach will be a key driver for a change in the way SLE trials are performed. Entry criteria for clinical trials are currently based on fulfilling classification criteria and a predetermined level of disease activity. This approach has resulted in a number of trials that have failed to achieve their primary end-point when randomising 'all-comers' without any regard to specific mechanisms. The approach we will take, using predictive biomarkers and algorithms, will shift the paradigm to a mechanism-based approach that will increase the statistical power of clinical trials and increase the likelihood of success in subsets of patients with SLE. Inclusion across the regulatory age groups including children and expertise within the consortium in supporting delivery of Paediatric Investigational Plans will be a key additional benefit for Industry.
The consortium will contribute to and build momentum around, stratified medicine in the UK. In particular it will build on the UK's recognised strengths in the area of immune-inflammatory diseases. A consortium focused on SLE will help to further build strength and capacity to complement that already underway in RA and other inflammatory diseases. It will also complement the work of the NIHR Translational Research Partnerships that seek to link UK academic researchers with industry to bring through novel therapeutics for condition such as lupus early in their development cycle. This synergy will be enhanced greatly by this award. The consortium also supports the aims and objectives of the MRC Clinical Pharmacology Training programmes which seeks to bring through a new generation of Clinical Pharmacologists. Stratified Medicine is a major theme of the TRP and the Clinical Pharmacology programmes and so by linking with such initiatives, our consortium will help increase the visibility of the UK research infrastructure focused on stratified medicine and inflammatory conditions of importance.
Globally, SLE is a disease with a major ethnic gradient being more common and severe in the developing world including people of Chinese, African and Hispanic ancestry. Whilst our consortium is based in the UK, we will have access to international cohorts through patients involved in industry-sponsored global clinical trial development programmes as well as the SLICC cohort. This will allow our studies and the models of analysis developed to have a global relevance. This will also mean we will have an impact in areas of the world where lupus is more common, prognosis is poor and where sequential use of therapies that may not work are unaffordable. A biomarker driven selective use of agents may however be cost-effective in such an environment and allow a wider population of patients to benefit from these new therapeutic developments.