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Research undertaken within Imperial College showed that corticosteroid resistance in inflammatory diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma, is explained by reduced histone deacetylase-2 and that reversal of this resistance is possible with theophylline (in low clinical doses) and PI3Kδ inhibitors, which restore HDAC2 function. This led to the founding of a spin-out company RespiVert to develop potent inhaled inhibitors of PI3Kδ. The company has been very successful in finding such new molecules, which have proven to be safe in Phase I studies. RespiVert was acquired by Johnson & Johnson in 2010 and Phase II studies are now in progress in COPD and severe asthma.
Research at the University of Manchester (UoM) has led a step-change in respiratory care for airway disease from oral to novel inhaled therapies targeted at asthma and chronic obstructive pulmonary disease (COPD) patients worldwide. UoM researchers carried out >250 studies, partnered industry to deliver >15 new inhaled drug formulations to market and were the first to test novel CFC-free inhalers. UoM led the development of global guidelines that influence better diagnosis and management of airways diseases. Through leadership within the Montreal Protocol since 1995, UoM researchers coordinated the safe global transition to CFC-free inhalers for ~200m patients with asthma and COPD, whilst protecting the ozone layer and climate.
Subcutaneous allergen immunotherapy is highly effective in hayfever sufferers who fail to respond to anti-allergic drugs, but carries the risk of severe allergic side-effects. Professor Durham's group at Imperial College have defined the mechanisms and shown that sublingual tablet immunotherapy is an effective, safer alternative that induces long-term disease remission. The tablet approach is now widespread in Europe and is being successfully extended to other allergies (housedust mite) and internationally (ragweed allergy in USA and Japanese Cedar pollen allergy). The work is quoted in guidelines internationally and regulatory bodies now recognise the disease-modifying potential of immunotherapy and its ability to induce long-term remission.
Research at Hull into hypersensitivity of the airways has provided novel insights into the epidemiology and causes of cough, and its burden on patients. This was achieved by the development of novel methodologies that allow the rigorous and objective testing of new and existing drugs. Patients benefit through the online provision of a diagnostic tool, and Proctor & Gamble have successfully exploited the cloned cell receptors in their drug development programme resulting in a new range of pharmaceuticals for cough. The work has underpinned the standardisation of cough challenge methodology through incorporation in national and international healthcare guidelines leading to a widespread improvement in patient treatment.
In 1994, Professor Barnes and colleagues at Imperial College showed that nitric oxide (NO) concentrations were increased in the breath of asthmatic patients compared to non-asthmatic controls and were reduced after treatment with inhaled steroids. They subsequently demonstrated that exhaled NO (FENO) could be reliably measured in the clinic, was correlated with eosinophilic airway inflammation in asthma, was increased with airway inflammation and decreased when asthma was controlled. Exhaled NO has subsequently been shown by many investigators to be a useful non-invasive biomarker of airway inflammation in asthma and to improve clinical management in selected patients. They demonstrated that nasal NO is very low in patients with primary ciliary dyskinesia and is now recommended worldwide as a diagnostic test for this disease as it is a much easier method than previously available tests.
Temozolomide is a major UK anti-cancer drug development success story. Following chemical synthesis at Aston University, early clinical evaluation of temozolomide carried out at Imperial College optimised how temozolomide was scheduled and delivered to patients to ensure maximum efficacy balanced acceptable side effects. Imperial's early trials demonstrated how the drug could be used effectively to treat patients with a type of brain cancer, glioma, and was pivotal to its subsequent market licensing. ESMO and NICE guidelines recommend temozolomide for use in patients with recurrent glioma and for patients with newly diagnosed Grade IV glioma. Glioma is a relatively rare cancer yet annual sales of temozolomide have been in excess of £900 million per year since 2009. Temozolomide given during and following radiotherapy is now standard of care for glioma and has improved survival compared to previous treatments or radiotherapy alone.
Between 1995 and 2004 researchers at Imperial College developed a T cell peptide allergy vaccine in an attempt to improve the quality of life of millions of allergy sufferers worldwide. A spin-out company (Circassia Ltd) was founded and subsequently sold to Circassia Holdings Ltd, a clinical-stage specialty biopharmaceutical company based in Oxford, UK. Circassia Holdings Ltd has raised £98 million of funding since 2008 and has developed a pipeline of products to treat common allergies. In October 2012 the lead product ToleroMune® Cat entered a phase III clinical study involving 85 clinical sites across the USA, Canada and Europe and enrolling 1186 patients in the largest single field study ever undertaken in immunotherapy. Circassia currently employs 25 highly skilled people in-house with an outsourced business model giving employment to an estimated further 200 people.
Southampton research has been central to the development and international licensing of one of only two novel asthma therapies in the last 30 years, transforming asthma control and survival for severe allergic asthmatics.
Key studies by the Southampton Group have underpinned the development of immunoglobulin (Ig)-E as a key therapeutic target for controlling allergic asthma, with the Southampton-led first-in- man safety and efficacy trials critical to the registration of the anti-IgE therapy, omalizumab.
This contribution also generated significant inward investment in UK R&D and opened up wider investigation of anti-IgE therapy in a broad range of atopic and inflammatory indications.
Asthma and Chronic Obstructive Pulmonary Disease (COPD) are common, global diseases which cause considerable morbidity and mortality. Worldwide, around 235 million people suffer from asthma, while COPD accounts for 3 million, or 5% of all, global deaths, according to the World Health Organization (WHO). The relationship between inflammation and airway dysfunction is central to an understanding of their pathogenesis and treatment. The respiratory medicine group in the Department of Infection, Immunity and Inflammation has shown that optimal management of these conditions requires measurement of airway inflammation to stratify treatment regimes, an approach incorporated into national guidelines in 2012. In the late 1990s the group characterised a new clinical syndrome: `eosinophilic bronchitis', which is one of the commonest causes of chronic cough. The group's work has helped to launch a new class of drugs for asthma and to change the conceptual framework by which anti-inflammatory drugs for asthma are being developed.
Questions about the benign or malignant nature of liver tumours are common and pressing since they determine how the patient is managed. Benign masses are frequently encountered; they usually do not require intervention but are easily mistaken for malignancies with conventional imaging methods. Work at Imperial College demonstrated that microbubble contrast agents have the special property of lingering in both normal liver tissue and in benign solid masses, whereas malignancies do not retain microbubble. The discovery of this property at Imperial has led to their use worldwide as a diagnostic tool. In 2012 NICE recommended their use as being cost-effective for this use.