Stratified Healthcare and Therapeutic Innovation GeCIP Domain

Description

The development of a new medicine costs approximately $2-3bn and is increasing. The genomic medicine era offers substantial potential to:

  • aid therapeutic innovation
  • aid clinical trials where treatment is modified according to a participants multi-omics profile (by combining omes into a set of ‘omes’, such as genome, proteome, transcriptome, epigenome and microbiome one can analyse the complex big data efficiently enough to find biomarkers easily which can be targeted by specific treatment)
  • use real-world pharmacogenetics data to select the optimal medicine first time and identify risks of side effects.

This GeCIP domain will harness the strength of UK infrastructure, such as the NIHR Clinical Research Network, the Stratified Medicine Network and the Structural Genomics Consortium. The formation of a stratified healthcare and therapeutic innovation GeCIP domain will provide the platform for a major scientific and healthcare initiative in this area. It will capitalise upon existing strengths and infrastructure and develop new partnerships to maximise patient benefit and industry partnership.

 
 

SUBDOMAINSUBDOMAIN LEAD/SRESEARCH DESCRIPTION
Target Discovery Bissan Al Lakzani
Chas Bountra
Mike Barnes
This GeCIP sub-domain will use available suites of software to evaluate the druggable genome for rare disease and cancer discoveries made by the 100,000 Genomes Project. The approach taken by this sub-domain will be to take advantage of major initiatives with extant industry interest such as the Open PHACTS suite of software and the Structural Genomics Consortium as any development will require their involvement.

Open PHACTS (Mike Barnes): A recent approach to address these issues is the integration of data from multiple different sources by means of semantic web technologies has led to the Open Pharmacological Concepts Triple Store (Open PHACTS) is an Innovative Medicines Initiative Knowledge Management project (IMI - 2nd call 2009). The Open PHACTS Discovery Platform offers a software suite include ChEBI, ChEMBL, SureChEMBL, ChemSpider, ConceptWiki, DisGeNET, DrugBank, Gene Ontology, neXtProt, UniProt and WikiPathways. By drawing together multiple sources of publicly-available biomolecular, pharmacological and physicochemical data, Open PHACTS offers a state of the art platform that responds to structured, well defined queries in a meaningful and reproducible way. This was created from an Innovative Medicines Initiative so has significant industrial buy in so could provide a within Genomics England package to prime genomic therapeutic discovery.

The CanSAR software suite (http://cansar.icr.ac.uk) created by Bissan Al Lakzani is a publicly available, multidisciplinary, cancer-focused knowledgebase which integrates genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and druggability data. It is used by 150,000 people worldwide to rapidly access information and help interpret experimental data in a translational and drug discovery context. canSAR's aim is to provide comprehensive multidisciplinary annotation for genes and biological systems to enable target validation and drug discovery in canSAR. http://cansar.icr.ac.uk/cansar/data-sources/).

The Structural Genomics Consortium – Prof Chas Bountra (Oxford). This initiative is funded by AbbVie, Bayer, Boehringer Ingelheim, Genome Canada through Ontario Genomics Institute Grant, GlaxoSmithKline, Janssen, Lilly Canada, Merck, Novartis Research Foundation, the Ontario Government, Pfizer, Takeda, and Wellcome Trust funding. This is a large-scale pre-competitive consortium that catalyses research in new areas drug discovery focusing explicitly on less wellstudied areas of the human genome. They have major programmes in DNA methylation, structural biology, target characterisation and recombinant antibodies. They have deposited more than 1500 high-resolution structures of medically relevant human proteins in public databases and generated 100’s of recombinant antibodies with therapeutic potential.
Innovative Clinical TrialsMatt Seymour
Patrick Chinnery
Prof Max Parmar
Harry Hemingway
The UK translational environment has an extremely strong platform due to NIHR, Higher Education and NHS investment in state of the art infrastructure for clinical research. The 100,000 Genomes Projects wishes to harness the potential opportunities from the National Institute for Health Research Infrastructure. The NIHR Clinical Research Network metrics show increasing trials UK-wide, greater industry studies and enhanced performance to time and target. More than 665,000 participants took part in clinical research studies supported by the Network in 2016-17. This is 10 per cent more than the previous year. Nearly 35,000 participants were recruited to studies sponsored by the life sciences industry. This has meant that over the last five years, more than 150,000 participants have had the opportunity to participate in high quality life sciences industry research and access cutting edge treatments. The new Health Data Research Institute offers potential to use the electronic health records of participants to follow-up participants in early phase trials over their life course or to do innovative trials in rare disease using real world data (this connects with the Electronic Health GeCIP).

Cancer Trials – Lead: Prof Matt Seymour (Leeds). The National Cancer Research Network and Institute represent a powerful framework for attracting new cancer trials alongside whole genome sequencing. The National Cancer Research Network has over 1000 clinical trials operating throughout the UK alongside which a re-engineered molecular and digital pathology in the NHS could attract significant new opportunities to the UK. This could sit extremely well with non-exclusive partnerships with Clinical Research Organisations, such as Quintiles IMS, who might take the offering of application of whole genome sequencing into bid defence to attract new clinical trials in cancer and rare disease into the UK.

Rare Disease Trials and the NIHR Translational Research Collaborative – Lead: Prof Patrick Chinnery (Cambridge). This will harness opportunities from the above NIHR investments to attract new trials in rare disease to the UK using the framework of the 100,000 Genomes Project. It will be possible from the new NHS Commissioned service to identify patients across the full repertoire of diseases using Many exciting new therapies are becoming available, and efficient designs to identify effective treatment regimens in a timely fashion are essential. In rare disease the excitement of gene editing of the somatic genome, renewed endeavour in gene therapies and potential in rare disorders fir cellbased therapy means we wish to specifically include Prof Bobby Gaspar and Prof Robin Ali in this subdomain.

Innovative Clinical Trial Design: Lead: Prof Max Parmar (UCL).leads the MRC Clinical Trials Unit at UCL has pioneered efficient adaptive designs such as multi-arm, multi-stage (MAMS) design. In the multi-arm element, several regimens are simultaneously assessed against a common control group, within a single randomised trial. In the multi-stage element, patient recruitment is discontinued to research arms that are not showing sufficient efficacy, based on a series of pre-planned, interim, lack-of-benefit analyses. One advantage the MAMS design has over other types of adaptive design is that it utilises an 'intermediate' outcome measure at the interim stages. This makes the design more efficient, because the expected number of patients and the length of time taken to complete the trial will be dramatically reduced. It also allows researchers to design a MAMS trial as a seamless phase II/III trial, further streamlining the treatment evaluation process.

The Health Data Research UK Institute and Real World Clinical Trials – Lead: Harry Hemingway (UCL). The new Health Data Research UK Institute is currently receiving regional applications to create a new MRC Centre (previously known as the Farr Institute) which provides the opportunity to undertake state of the art electronic health research. There is an extant Electronic Health Record GeCIP domain and an increasing opportunity for such an infrastructure to undertake real world trials where people are monitored via remote devices or in general practice with electronic health data recovery. Even though the randomised controlled trial remains the gold standard for medicines development but industry are beginning to question the applicability to the broader population and models such as the Glaxo Smith Kline Salford Lung Study recruited and entirely run in Primary Care may become an important model for affordable later phase trials.
Pharmacogenomics Dr Ana Alfirevic
Prof Sir Munir Pirmohamed
This aims to: 1) increase pharmacogenomics knowledge by identifying novel rare variants in pharmacogenes and drug targets that may contribute to drug response, and investigate/validate their function; 2) provide interpretation of results to guide and develop implementation of pharmacogenomics into clinical practice in support of the NHS Pharmacogenomics Working Group; and 3) assess the ethical issues of identifying pharmacogenetic variants in individuals who may need drug treatments that show variation in response. In partnership with several other GeCIP cross-cutting domains and in collaboration with international leaders in pharmacogenomics research, we will set scientific priorities and train healthcare professionals, patients and the public to reach the goal of better medicines and stratified/personalised healthcare globally. The domain will include a multidisciplinary team with clinical, academic, ethics, regulatory, and health economics expertise.

Dr Ana Alfirevic's research focuses on molecular pharmacology and pharmacogenetics and adverse drug reactions including drug-induced hypersensitivity, hepatotoxicity, antipsychotic drug-induced agranulocytosis and statin-induced myotoxicity.


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