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Stephen T Holgate, Faculty of Medicine, University of Southampton

Stephen T Holgate, Faculty of Medicine, University of Southampton. Personalized medicine for the European Citizen. sth@soton.ac.uk. But we now face very serious problems: Reductionist models are failing to account for much of the chronic inflammatory and degenerative disease facing society.

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Stephen T Holgate, Faculty of Medicine, University of Southampton

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  1. Stephen T Holgate,Faculty of Medicine,University of Southampton Personalized medicine for the European Citizen sth@soton.ac.uk

  2. But we now face very serious problems: • Reductionist models are failing to account for much of the • chronic inflammatory and degenerative disease facing society. • These non-communicable diseases are increasing as we survive longer and as developing nations adopt aspects of the Western lifestyle. • After years of improvement in public health, lifestyle influences (sedentary, smoking, diet, “recreational” drugs, stress ), especially on the young are creating a health “time-bomb” in NC diseases (e.g. cancer, obesity, diabetes, hypertension, COPD, asthma). • Unsustainable drug development industry based on “blockbuster, one size fits all” business model. William Osler: the Father of modern medicine “Medicine became a science by combining clinical observation with pathology and function and through the application of chemical, biological and physical sciences”.

  3. Drug discovery: a big challenge for addressing both developed and developing world diseases R&D for a New Medicine: 10+ years, $1 bn+ • Set against this is: • The explosion of new technology to interrogate complex cellular processes – the ‘omics (genomomics, transcriptomics, proteomics, epigenomics, microbiomics, metabolomics) and the exposome. • New non-hierarchical approaches to phenotyping complex disease (e.g. cluster analyses, machine learning). • Applications of informatics to interrogate large data-sets from biological collections, clinical trials and linked population-based case records and prescribing practice. Post-MarketingSurveillance RegulatoryReview Drug Discovery Scale-Up to Manufacture Preclinical Clinical Trials PhaseIII PhaseI Phase II ~ 5,000 – 10,000 250 5 Compounds 1Approved NewMedicine Pre-Discovery IND Submitted NDA Submitted Number Of Patients / Subjects 20 – 100 100 – 500 1,000 – 5,000 Indefinite 3 – 6 Years 6 – 7 Years 0.5 – 2 Years Source: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org;

  4. Information and knowledge Health practitioner Patient Information and knowledge Patient Health practitioner The Changing Focus of Healthcare: Massive cultural change to shift focus to pulling patients through whole pathways not just managing stages of diagnosis and treatment

  5. The emergence and rapid developmental evolution of ‘omics technology platforms The ’omics cascade Next “Genomics” What can happen What appears to be happening What makes it Happen What has happened & is happening

  6. The plummeting cost of complete genome sequencing How do these developments impact upon healthcare and drug development? Towards the $1000 genome

  7. Comparison of inhaled corticosteroid, leukotriene receptor antagonist and placebo in asthmatic patients (15 Years) not controlled on as required inhaled b2-agonists bronchodilators 50 40 Beclomethasone am-PEF (Mean Change From Baseline; L/min ± SE) 30 P<0.001 Montelukast 20 10 Placebo 0 -10 1 3 5 7 9 11 13 15 17 19 21 • Days in Active Treatment Malmstrom et al. Ann Intern Med. 1999; 130: 487-95.

  8. Distribution of individual asthmatic patient responses to the 2 active treatments Beclomethasone (n=246) Montelukast (n=375) 30 25 20 15 10 5 0 Worse Better Patients (%) <-30 -30 to <-20 -20 to <-10 -10 to <0 0 to <10 10 to <20 20 to <30 30 to <40 40 to <50 50 % Improvement in lung function

  9. Stratified Medicine: What are we talking about? “the tailoring of medical treatment to the individual characteristics of each patient …. involves the use of companion diagnostics to achieve the best outcomes in the management of a patient's disease or disease predisposition. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not”. Adapted from: “Priorities for Personalized Medicine” by the US President’s Council of Advisors on Science and Technology (PCAST), 2008 Personalised Medicine has arrived to an extent: Herceptin®, Gleevec®, SelzentryTM, Ziagen®, Vectibix® , IressaTM

  10. Stratified medicine for cancer therapyShaw EC & Johnson PWM. Drug Discovery Today 2012; 17: 261–26 (a) (b) A summary of the major disrupted cellular pathways in a series of pancreatic cancers, according to data on genetic abnormalities detected by sequencing, microarrays and transcriptomics: (a), with the specific gene alterations discovered in two of the cases mapped in detail (b), case Pa14C (c), case Pa10X). Similar evolution of lung cancer and chronic inflammatory disease (e.g. asthma – Th2, non-Th2 etc) (c) Abbreviations: JNK: Jun N-terminal kinases; TGF-β: transforming growth factor-beta

  11. Signatures of mutational processes in human cancerAlexandrov LB et al. Nature 2013: 500; 415–421 Genetic map of cancer reveals trails of mutation that lead to disease The first detailed map of genetic faults that cause cancers, offering profound insights into the disease. The map describes more than 20 "genetic signatures", or patterns of mutation, that alone or in combination drive 30 different types of cancer, including brain, lung, pancreas and breast tumours. Research that looked at more than 7,000 cancers to identify "signature" patterns in genetic mutations. These signature patterns suggest how the cancer-causing mutations arise. Almost five million mutations fell into 21 signature patterns. The causes of some of these signatures were identified.

  12. Signatures of mutational processes in human cancerAlexandrov LB et al. Nature 2013: 500; 415-21

  13. Multiple Companies Offer These Services

  14. ESF 2013: Personalised Medicine for the European Citizen: Towards more precise medicine for the diagnosis, treatment and prevention of disease Medicine will move from a reactive to a proactive discipline over the next decade; one that is predictive, personalised, preventive and participatory

  15. Forward Look on Personalised Medicine 80 recommendations … resulting in a Personalised Medicine “Target” ESF Forward Look launch Brussels 28 January 2013

  16. The promise of personalised medicine • More effective medicines • Safer medicines • Cheaper medicines • Better healthcare • Cheaper healthcare • Less (rather than more) healthcare disparity

  17. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation (most prevalent gating mutation) Ramsey BW, et al. N Engl J Med. 2011; 3658: 1663-72 • Vx-770; Ivacaftor Complex disease will be stratified into a series of pathway specific disorders creating opportunities for both companion diagnostics and targeted prevention and treatments. But also a new Taxonomy of disease will be created based upon knowledge of causative pathways and neyworksrather than signs and symptoms. Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Jih KY. et al. PNAS. 2013; 110: 4404-9 G551D is the third most common mutation, affecting ~4% of patients. For patients homozygous for D508, Vertex has another drug, VX-809, which acts by increasing the transport of CFTR protein to the cell surface. A phase 2 clinical trial of combined VX-809 and VX-770 treatment in D508 patients is in progress.

  18. Creation of a New Taxonomy first requires an “Information Commons” in which data on large populations of patients become broadly available for research use and a “Knowledge Network” that adds value to these data by highlighting their inter-connectedness and integrating them with evolving knowledge of fundamental biological processes Reclassification of human disease by identifiable causal pathways Toward Precision Medicine. US Nat Acad Sci 2011

  19. Biological Information Cross-Disciplinary culture Team Science Personalised or P4 Medicine: Predictive Preventive Personalised Participatory • The ‘holy trinity of biology’ where biology drives technology - drives computational/mathematical tools. • This requires a cross-disciplinary environment where scientists of many different disciplines learn to speak the languages of the other scientists and learn to work together in teams. • When this is practiced effectively enormous amounts of biological information can be generated rapidly. Wellness Quantified Disease Demystified

  20. Chronic infection with hepatitis B and C causes 75-80% of liver cancers diagnosed world-wide. Prevalence of hepatitis B and C Liver cancer per 10,000 Candidate Biomarkers Change in non-survivors vs survivors Prediction of outcome (survival) in acute on chronic liver failure patients

  21. Rapid diagnosis and staging of colorectal cancer via High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) Spectroscopy of intact tissue biopsiesMirnezami R et al.Ann Surg. 2013 Jul 15. [Epub ahead of print] Annotated HR-MAS NMR spectral profiles from centre of tumour(Ct) (A) and healthy appearing mucosa 5 cm from tumour margin (Hm) (B)

  22. Rapid diagnosis and staging of colorectal cancer via High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) Spectroscopy of intact tissue biopsiesMirnezami R et al.Ann Surg. 2013; Jul 15. [Epub ahead of print] Distinct HR-MAS NMR spectroscopy–based metabolic phenotypes according to T-stage.

  23. Integrating knowledge for Systems Medicine Auffray, Adcock, Chung, Djukanovic, Pison, Sterk. Chest 2010;137:1410-16 Patient reported Clinical The “Grand Challenge” is how to combine the different data types for interrogation Functional Cellular Molecular

  24. Metabolomics Functional imaging Lifestyle database DNA and RNA sequencing Imaging Microbiome Family history

  25. HARVARD MEDICAL SCHOOL BRIGHAM AND WOMEN’S HOSPITAL Scott T. Weiss, M.D., M.S. Professor of Medicine Harvard Medical School Associate Director, Channing Laboratory Brigham and Women’s Hospital Director, Partners HealthCare Center for Personalized Genetic Medicine Boston, MA Software to Implement Genetic Testing in the Clinic Setting MASSACHUSETTS GENERAL HOSPITAL

  26. Idiopathic Fibrotic NSIP SIDS 5 HPS Infant RDS IPF Fibrotic ILD Assoc RA LAM Berylliosis Idiopathic BOOP ARDS Progressive, Fibrotic ILD (inc. IPF, NSIP, ILD Assoc CTDs - RA / SLE / Sys Scl) 4 Silicosis Fibrotic ILD Assoc Sys Scl Cystic Fibrosis BPD AAT Deficiency Fibrotic ILD Assoc SLE Sarcoidosis Bronchiolitis COPD 3 PAH Bronchiectasis Unmet Need Index Chronic Cough RSV Nasal polyposis Asthma Influenza Peanut Allergy OSA Histoplasmosis 2 Chronic sinusitis AR HP - Farmer's Lung Atopic dermatitis PE AR - Pure + Mixed Pneumonia NAR - Pure Legionellosis Bronchitis - acute 1 0 100,000,000 100 1,000 10,000 100,000 1,000,000 10,000,000 US Population Prevalence/Incidence (Log Scale) Emergent science drives new disease opportunities Where science and unmet need converge Opportunities in “new” diseases featured in the business plan Core diseases Key emergent areas of science Lung repair COPD, fibrotic lung diseases (IPF, ILD, CF) Not just medical treatments but also applies to adverse and beneficial environmental exposures – the exposome Neuronal mechanisms Rhinitis, asthma, COPD, cough Immunomodulation Asthma, allergic rhinitis

  27. Implications of the exposome for exposure scienceRappaport S M. J Expos SciEnvEpid. 2011; 21: 5-9By embracing the exposome as its operational paradigm, exposure science can play a major role in discovering and mitigating these exposures. • Bottom-up exposomics: chemicals measured in air, water and food would identify potentially important exogenous exposures and their sources, but would miss endogenous exposures. • Top-down exposomics: chemicals measured in blood would identify all potentially important exposures, but would provide no information about their sources. Environmental exposures to chemicals arise from both external and internal sources. The exposome represents the combined exposures from all sources that reach the internal chemical environment

  28. Forward Look on Personalised Medicine • Final Report • Recommendations • Implementation ESF Forward Look - DG Research - Brussels, 11 September 2012

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