Predictive measures to stratify clinical outcomes in children and adults with Gaucher disease and responses to specific therapies

The overall aim is to improve the management of patients with Gaucher disease - a genetic disorder with very variable manifestations, but which causes disabling disease especially in the bones of the skeleton and affects the brain. Advances in biotechnology have introduced specific treatments: there are five licensed therapies manufactured by four companies which work in two distinct ways: formerly bone marrow transplantation (with high mortality) was used. Despite introduction of these high-cost therapies, many patients have persistent symptoms and suffer a long-term risk of bone injury, bone cancer and brain diseases such as Parkinson's. The exact reasons for this are unknown, but there is a clear need for improvement.

To achieve our aim, we will bring key practitioners for the treatment of Gaucher disease, who are based in highly specialized national centres, together in a comprehensive research consortium. We will also bring clinical scientists from academic institutions and commercial academic sectors together in the mission to improve the outcomes of treatment by better targeting and timing of therapy, and to build a starting point for the design of specific trials in an effort to improve health outcomes for Gaucher patients. We work closely in the consortium with major industrial partners, who will bring their unique expertise in line with our clinical and laboratory work and the entire project will be partnered with patient advocacy groups and international societies in this field.

Much of the specific scientific work of this consortium will be built on a comprehensive database reflecting the disease severity and manifestations of Gaucher disease in the entire national cohort of adults and children who suffer. Medical Researchers and specialized nurses will examine individual patients who have consented ethically to the study and from whom blood and other appropriate samples will be obtained and stored centrally for analysis. The data resource will be fully computerized, which will allow sophisticated analysis of the categories of disease and its behaviour to be aligned to additional information about the genetics of the condition and other variables obtained by laboratory measurement. The patients will be re-examined and clinical information obtained retrospectively about key events in their illness will be entered so that its course before and after various treatments can be described and, ultimately characterized. We are looking to define groups of patients who respond well or less well to specific therapies and whose disease progress can be characterized as 'stormy', 'sizzlers' or 'fizzlers'. We already have a range of treatments that have been authorized for prescription (because this is a rare disease they are 'high cost') and also a range of what are referred to as 'biomarkers' which may well be able to predict responses to treatment or serve as a target for when disease is controlled by therapy and complications are unlikely to occur. In the team of Investigators working alongside the UK clinical centres, there are biologists who will explore the role of these biomarkers in relation to disease behaviour so that the targeting of therapy, the best time to use it can be improved and that disease monitoring will be refined in further trials of innovative drugs. In this way, the groups 'cohorts' of patients stratified according to disease severity and behaviour will serve as an attractive platform for investment in clinical trials by the major biopharmaceutical companies. Technology companies will also be attracted to develop diagnostic kits using the biomarkers we discover to improve prognosis. Although rare, Gaucher disease promises unique insights into little-understood conditions that commonly affect the whole population. Large corporations (eg Sanofi) have been attracted to the field, and the key discoveries of the consortium will engage them strategically for future investment and health development.

To build a research consortium that will promote discovery and improve outcomes for patients with Gaucher disease, our overarching aim is to refine treatment using clinical stratification and severity categories based on therapeutic responses. Life-quality is impaired, survival is reduced and crippling skeletal disease, marrow failure, visceromegaly, cancers with disabling neurological effects, including late-onset Parkinsonism, supervene. Disease discrepant between siblings and identical twins, shows that clinical and treatment responses are not determined by genotype alone: in-depth phenotyping is critical for stratification and therapeutic advance. National specialized centres for Gaucher disease will recruit at least 85% of UK patients (~250) with a focus on neurological and osseous disease as research strands in major areas of disability in adults and children. Stratification will facilitate generation of a dynamic platform for advancing therapy and further understanding of disease causation. High-resolution stratification into clinical cohorts will use validated disease severity and life-quality scores to annotate therapeutic responses; we will explore the predictive value of the activated inflammasome and bioactive lipids, as well as established plasma enzymatic and chemokine biomarkers. Partner biostatisticians (MRC external staff) will conduct time-to-event and regression modelling analyses to develop treatment cohorts based on dosing studies (enzyme therapies) and stage of intervention; serial biological samples will be stored and data entered on the custom-designed central national Gaucher register accessed at all centres. Genzyme-Sanofi, Shire HGT and Actelion Pharmaceuticals will share expertise, registry data and key resources; success in building the consortium will render stratified patient cohorts in national Gaucher centres highly attractive for innovative clinical trials and commercial development of predictive and diagnostic biomarker toolkits.

At least one innovative agent, a small molecule of great potency as a substrate synthesis inhibitor, is in clinical trial in Gaucher disease (eliglustat tartrate - Genzyme-Sanofi): its development was stimulated by the licensing and subsequent approval of the first drug in this class for Gaucher disease, miglustat (Actelion) - a scientific initiative driven almost entirely by the Co-Applicant and Lead Applicant of this proposal. The timespan for progressing drugs to market through such a process is relatively short for Gaucher disease and its congeners, since it benefits from the legislation for orphan medicinal products. Clearly careful stratification to understand the determinants of neurological disease in this national cohort of Gaucher patients would stimulate further investment in small molecules currently in the pipeline for chronic neuronopathic Gaucher disease and related disabilities caused by sphingoliposes affecting the brain such as Tay-Sachs disease.

The maintenance of impact depends upon a combination of clinical need, scientific progress and commercial considerations. Therefore, despite our existing track record of impact, we see a major need to drive the proposed work of this consortium. The role of our research is not to compete head-to-head with the resources available to biopharmaceutical or industrial programmes, which are huge. Instead we aim to support their fragile viability, which can be readily lost by a commercial entity (as nearly occurred with Genzyme's catastrophic vesiviral contamination of the bioreactors serving the manufacture of its key 'blockbuster' enzyme products from 2009) by upgrading the company's investment in science beyond the de-incentivised post-authorization life-cycle phase: developing new diagnostic tools as adjuncts to prognosis and efficacy, and, as here, defining new targets for parallel approaches.

The Council's initiative is likely to have salutary effects on: (1) persistent major illness or disability in our patients (2) the critical gap in scientific and mechanistic understanding of the clinical behaviour of the disease (3) companies and regulatory authorities who need tools to meet the expectation of regulatory authorities for commensurate long-term efficacy and safety, and thereby generate a competitive need for their organizations to show commitment to deeper clinical research (4) biopharmaceutical research plans after licensing where the presence of five licensed (four approved) therapies in Western Europe is inimical to the conduct of naïve blinded and controlled clinical trials and (5) because the mission of the consortium project engenders an unconventional multi-disciplinary and collaborative approach which should stimulate therapeutic discovery and technical spin-off development, for example, in assay kits for newly discovered prognostic biomarkers.
The consortium includes many of the key practitioners in the treatment of Gaucher disease and this project is very much about directly improving the quality of the care they provide. The proposed project aims to improve therapeutic outcomes and targeting, develop better trials, and introduce new prognostic diagnostics and, where possible, innovative therapies.

Outside the consortium, the clinical scientists from both the commercial academic sectors in this field use the academic literature as a key route by which they their own patient care, making academic publication is a key mechanism by which the impact of this research will be delivered. This will be supplemented by the engagement with patient groups and international societies in the field.

Close engagement with the companies who have joined the consortium means that there is a direct link to the providers of medicines to Gaucher patients. Through the open exchange of knowledge across the consortium, these companies can use to the research to develop new therapies and predictive methods based on improved understanding of the disease population.