MRC/ABPI Inflammation and Immunity Initiative
The MRC’s Stratified Medicine Initiative has drawn on experience gained through investment in three pilot consortia under the MRC/ABPI Inflammation and Immunity Initiative:
- Chronic Obstructive Pulmonary Disease (COPD).
- Rheumatoid arthritis.
This initiative brought together industry and academic experts —covering basic, clinical and therapeutic development research—to develop disease-focused consortia addressing the challenges of disease stratification and biomarker identification.
COPDMAP: The COPD MRC/ABPI Partnership
Professor Chris Brightling, University of Leicester
COPDMAP is building a number of research questions around a group of COPD patients. The aim is to get a holistic view of disease progression — all studies are conducted on the same patient samples and groups with full clinical histories and phenotypes.
Data are shared across all partners in real time. Key areas for research include understanding the patients more deeply, investigating the exacerbation of symptoms after infection, identifying new disease mechanisms and better understanding the muscle wasting associated with COPD.
RA MAP: The Rheumatoid Arthritis Consortium
Professors Andrew Cope and John Issacs, King’s College London and Newcastle University
RA MAP aims to investigate two aspects of the disease, the first through the TACERA study —aiming to find a cure for early rheumatoid arthritis — and the second via a longitudinal observational study. This will be coupled with the development of an “immune toolkit” to identify the immunological changes that occur as early disease develops into more chronic rheumatoid arthritis.
MASTERMIND: MRC APBI STratification and Extreme Response Mechanism IN Diabetes
Professor Andrew Hattersley, University of Exeter
The mission of the MASTERMIND consortium is to establish a platform for a stratified approach to the treatment of type 2 diabetes. This will act as a springboard for future research and development by academia and industry.
Stratified Medicine Consortia Awards
In addition to the three pilot MRC/ABPI programmes, the MRC is supporting a further ten stratified medicine consortia focussing on:
- Rheumatoid arthritis (in partnership with Arthritis Research UK).
- Hepatitis C.
- A rare genetic condition called Gaucher’s disease.
- The liver disorder primary biliary cholangitis (formerly known as primary biliary cirrhosis).
- Hypertension (in partnership with British Heart Foundation)
- Systemic Lupus Erthyematosus
- Colorectal Cancer (in partnership with Cancer Research UK)
- Refractory Asthma
- Juvenile Idiopathic Arthritis (in partnership with Arthritis Research UK)
- Prostate Cancer (in partnership with Cancer Research UK)
- Alcoholic Hepatitis
- Idiopathic Nephrotic Syndrome & Chronic Kidney Disease
MATURA: Maximising Therapeutic Utility for Rheumatoid Arthritis using genetic and genomic tissue responses to stratify medicine
Professors Anne Barton and Costantino Pitzalis, University of Manchester and Queen Mary, University of London
Supported in partnership with Arthritis Research UK, the MATURA consortium aims to enable early, effective treatment and improve the cost-effectiveness of care for around 500,000 people in the UK who suffer from the painful inflammatory condition rheumatoid arthritis.
Specifically, it is searching for biological and genetic markers in blood and joints which could be used as clues to predict how patients will respond to disease-modifying drugs including methotrexate and anti-TNF biologic drugs. If successful it is estimated that a stratified treatment approach for this condition could save the NHS £13-18million a year.
STOP-HCV: Stratified Medicine to Optimise Treatment for Hepatitis C Virus Infection
Professor Ellie Barnes, University of Oxford
The STOP-HCV consortium has developed cutting-edge gene sequencing technologies and is integrating host and viral genetics. These will be used to determine why, in an era of new and highly effective (but expensive) drug therapies, some Hepatitis C infected individuals still fail to respond to treatment – especially those with advanced liver fibrosis and Hepatitis C Virus (HCV) genotype 3 infection.
In addition, the group aims to identify factors associated with clinical endpoints, including the development of liver cancer in patients with liver cirrhosis, so that stratification can be used as a tool to improve patient care for these individuals.
The consortium is working in close collaboration with its industrial partners to support UK clinical trials in the area of HCV infection, and is underpinned by HCV Research UK, a national clinical database and biorepository for >10,000 HCV-infected patients.
GAUCHERITE: Predictive Measures to stratify clinical outcomes in children and adults with Gaucher disease and responses to specific therapies
Professor Tim Cox, University of Cambridge
This aims to improve the care of people with Gaucher’s disease, a rare genetic disorder in which a build-up of fatty chemicals causes bleeding, painful skeletal complaints and swelling of some internal organs.
Even identical twins differ markedly in disease severity, indicating that non-genetic components play a role in the condition. Five treatments are currently available, but patients could respond differently to drugs because of the complexity of the disease. GAUCHERITE brings together specialist doctors and scientists led by Cambridge University, who are currently examining approximately 85 per cent of all UK patients and stratifying them by the nature of their disease to allow better targeted therapy interventions.
UK-PBC: Stratified Medicine in Primary Biliary Cirrhosis (PBC): Understanding Disease Mechanisms and Targeting Therapies
Professor David Jones, Newcastle University
PBC is thought to affect 20,000 people in the UK – currently, around 30% of patients with this condition do not respond to the only drug treatments available and their only option is a transplant. The new UK-PBC consortium will recruit half of those affected in the UK, 10,000, at sites around the country.
This study will provide a better understanding of why some patients respond to treatment and some don’t. Further aims are to work with pharmaceutical companies to develop new drugs; and design a national protocol to streamline treatment across the UK. This will help ensure that, in future, patients receive the right type and level of treatment depending on the severity of their disease and individual biological make-up, and determine whether that should be at their GP or in a specialist centre.
STRATA: Schizophrenia: Treatment Resistance and Therapeutic Advances
Dr James MacCabe, King’s College London
People with schizophrenia suffer from a range of symptoms as well as 'negative symptoms' such as a lack of motivation and withdrawal from social contact. The STRATA consortium aims to build on evidence from brain imaging and genetics studies suggesting that those who do not respond may have a completely different neurochemical abnormality in their brains, involving a chemical called glutamate.
Currently, antipsychotic medication is the mainstay of treatment and all existing drugs are thought to work by reducing transmission of a brain chemical called dopamine. However, around a third of patients fail to improve on these medications. STRATA aims to develop a method to predict, ultimately as early as first hospital admission, which patients will respond to standard dopamine drugs, and which people are instead more likely to respond to the new glutamate drugs currently under development.
PSORT: Psoriasis Stratification to Optimise Relevant Therapy
Professor Chris Griffiths, University of Manchester
The PSORT consortium aims to use existing knowledge about psoriasis, both clinical and scientific, and an unparalleled patient base, coupled to involvement of patient organisations and state-of-the-art investigative tools, to develop tests that can be used in the clinic to help direct personalised treatments.
Psoriasis is a common, chronic, potentially disfiguring disease that affects more than one million people in the UK. 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 per patent) and it remains the case that a significant number of patients fail to respond adequately.
AIM-HY: Ancestry and biological Informative Markers for stratification of HYpertension
Professor Phil Chowiencyzk, King’s College London
High blood pressure (hypertension) is extremely common within the general population in the UK and worldwide and is a major cause of heart disease, kidney disease and stroke. One in three of the UK population will require treatment for hypertension at some point in their lives. It is recognised to be the single biggest contributor to the global burden of disease, a burden that is particularly great in ethnic minorities in the UK and in lower and middle income countries. It is also the commonest reason for people to be prescribed long-term medication by their GP.
The AIM-HY consortium will examine whether treatment for high blood pressure can be improved by taking a person’s ethnic heritage into account together with other factors relating to local environment and life-style. This is based on the fact that people from certain ethnic backgrounds, such as people from Africa, are at higher risk of developing hypertension and respond better to some treatments than people of white European ethnicity.
MASTERPLANS: Maximising Sle ThERapeutic PotentiaL by Application of Novel and Stratified approaches
Professor Ian Bruce, University of Manchester
Systematic 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 1 in 2,000 individuals in the UK and there is huge variability in how well patients respond to the handful of drugs available to treat the condition. Each patient has their own ‘fingerprint’ of disease, with different organs involved and to varying degrees of severity. By defining a way to predict which patients will respond best to which drugs, many patients will achieve better responses earlier in their disease course and avoid the long periods of uncertainty and exposure to high doses of corticosteroids that characterises the current treatment pathways.
The MASTERPLANS consortium will work to identify factors that predict which patients respond well on any particular lupus treatment. Sample tissue, blood and urine from patients with skin or renal lupus will be used to identify biological predictors that will allow doctors to identify the treatment most likely to be effective.
S-CORT: Stratification in COloRectal cancer: from biology to Treatment prediction
Professor Tim Maughan, University of Oxford
Over 40,000 people were diagnosed and 16,000 died from colorectal cancer in the UK in 2011. If the disease is caught early, 93% can be cured by surgery to remove the tumour. However, in those whose disease is more advanced (metastatic), treatment options are limited to chemo or radiotherapy. But these treatments only work in about half of patients and cause toxic side effect, without benefit, in the remainder. This is because genetic changes in their cancer cells can cause treatments to fail in particular patients.
By learning more about these changes, the S-CORT consortium hopes to develop a clinical test(s) that could be given to all colorectal cancer patients upon diagnosis to allow them to have a tailor made treatment plan, which is guided by their individual biological makeup.
RASP-UK: United Kingdom Refractory Asthma Stratification Programme
Professor Liam Heaney, Queen’s University, Belfast
One in 50 people suffers from severe asthma, with treatment costs for this group alone exceeding those for the 10-15% of the UK population who suffer from a milder form of the disease. Despite the huge disparity in symptom severity, international treatment guidelines recommend a ‘one-size fits all’ approach, with all patients being given inhaled and oral steroids in escalating doses. Recent research has suggested that a stratified approach might be more successful and several drugs are in development that will target specific subsets of patients.
The RASP-UK consortium will take a two-pronged approach, assessing treatment adherence using remote monitoring technologies and also biological markers to stratify asthma patients into two broad groups, based on the different types of inflammation present in their lungs (T2-High and T2-Low severe asthma). New drugs are available and will be tested on the T2-High group, while the T2-Low patients will be studied further in a bid to understand more about their disease and potentially identify new therapeutic targets that will be effective for this group.
CLUSTER: Childhood arthritis and its associated uveitis; stratification through endotypes and mechanisms to deliver benefit
Professor Lucy Wedderburn, University College London
Childhood arthritis, classified under the umbrella term juvenile idiopathic arthritis, JIA, and its associated eye inflammation, JIA-uveitis, can be devastating for both child and family, and impose significant long-term economic burden on society. Despite improvements in the management of JIA, and increasing availability of new medicines, many children still undergo prolonged treatment with multiple drugs that may not work. This leaves them exposed to uncontrolled inflammation, side effects, and the damaging effects of disease, which include disability, vision loss, lower quality of life and reduced chances of employment.
The overall goal of CLUSTER is to define ‘endotypes’ of childhood arthritis and JIA-uveitis, which more accurately reflect likely treatment response and disease course, linked to biomarkers that are feasible to measure in children, to allow targeted treatment decisions.
Re-IMAGINE: The exploitation of a novel image-based risk stratification tool in early prostate cancer
Professor Mark Emberton, University College London
One in eight men will develop prostate cancer and the risk increases with age. Nowhere else in modern medicine are the errors of over-diagnosis, over-treatment, missed-diagnoses and poor risk stratification more extreme.
Re-IMAGINE will combine the underlying molecular changes in the cancer with state-of-the-art imaging. This will allow the prediction of prostate cancer status for the individual without recourse to biopsy. It will also allow the prediction of which prostate cancers are likely to progress over time and which are not. By doing so, men will be subject to fewer but better biopsies, improved risk stratification, appropriate treatment allocation, more benefit, less harm and more cost-effective care.
The consortium is built on recent research showing that magnetic resonance imaging (MRI) of the prostate was better at identifying men at risk compared to the standard prostate biopsy. The aim is to create a novel, image-based, measurable-disease endotype and to use it to risk stratify men with prostate cancer and, as a result, improve our ability to derive prognostic information and allocate men to the most appropriate and effective therapies.
Minimalising Mortality from Alcoholic Hepatitis
Professor Mark Thursz, Imperial College London
Alcoholic related liver disease (ALD) is responsible for more than 6000 deaths a year in the UK and costs the NHS £3.5bn. Alcoholic hepatitis is a florid presentation of ALD in which patients present with jaundice and liver failure. Unfortunately, around 30% of people admitted to hospital with this condition will die within 3 months. The treatment of alcoholic hepatitis is complicated by the fact that there is tremendous inflammation within the liver whilst the patient is very susceptible to infection. As a result treatment with drugs, such as steroids, which suppress the immune system may exacerbate the risk of infection. In a recent trial, it was demonstrated that prednisolone reduced mortality by a small amount one month after admission but the advantage was lost at three months. Therefore, at present there is no effective treatment for this condition.
The aim of this consortium is to develop clinical tests which improve the management of alcoholic hepatitis and which help the pharmaceutical industry to run trials in this area. Firstly, we will use a test which measures the amount of bacterial DNA in blood to stratify the risk of infection. Secondly, we aim to improve the way in which we predict the outcome of this disease.
NURTuRE: changing the landscape of renal medicine to foster a unified approach to stratified medicine
Professor Moin Saleem, University of Bristol
The objective of the consortium is to reshape the landscape of renal medicine in the UK, by utilising the large amounts of data and samples collected to date, in order to accelerate the mechanistic understanding of renal disease.
This proposal aims to exploit two main cohorts in idiopathic nephrotic syndrome (INS) and chronic kidney disease (CKD) - with a focus on INS-, to stratify each patient according to detailed genetic and molecular screening of patient blood and DNA samples. The reclassification will be the first since the 1970s, and is based on ground-breaking advances in our biological understanding of INS, based on study of the target cell of the disease in the kidney, the podocyte. This will lead to targeted therapy towards the podocyte, to replace current non-specific toxic treatments, using new biological agents. Furthermore, the proposal will generate large new datasets in CKD coupled with innovative analytic methodologies, to demonstrate how this approach has the potential to make hitherto challenging insights into disease mechanism in a multifactorial disease state.