1. Drug Development – a new way forward? Dr Ian Barwick Business Development Manager Systems Biology Ireland, UCD

2. Overview Background to drug development Current performance Issues The way forward? – Systems approaches – Personalized medicine Current work

3. Background Drug development is expensive, risky and with no guarantee of clinical or financial success We still don’t fully understand many of the diseases that affect us Probably half of all medicines prescribed do not work in patients

4. Drug Development Process Lead GenerationDiscoveryChemical Synthesis Scale-upFormulation DevelopmentSafety TestingPhase I TrialsPhase II TrialsPhase III TrialsNew Drug ApplicationProduct Approval 10 - 15 years

5. Current Performance

6. Decline in R&D Productivity Data for PWC – Pharma 2020: Virtual R&D

7. Drug Development Statistics Developing a new medicine takes an average of 10–15 years; the Congressional Budget Office reports that “relatively few drugs survive the clinical trial process” INDEFINITE Drug DiscoveryPreclinicalClinical TrialsFDA ReviewScale-Up to Mfg. Post-Marketing Surveillance ONE FDA- APPROVED DRUG 0.5 – 2 YEARS 6 – 7 YEARS3 – 6 YEARS NUMBER OF VOLUNTEERS PHASE 1PHASE 2 PHASE 3 5250~ 5,000 – 10,000 COMPOUNDS PRE-DISCOVERY 20–100 100–5001,000–5,000 IND SUBMITTED NDA SUBMITTED

8. Drug Development Costs Increased Billions (Constant Dollars, Year 2000) Sources: 1 J. DiMasi and H. Grabowski, "The Cost of Biopharmaceutical R&D: Is Biotech Different?," Managerial and Decision Economics, 2007; J. DiMasi et al., “The Price of Innovation: New Estimates of Drug Development Costs,” Journal of Health Economics, 2003.

9. Patent Cliff

10. Chronic Disease Projections (US) Number of People with Chronic Conditions (millions) Year 44.7% In the US, every 30 seconds, a lower limb is amputate as a consequence of diabetes

11. Medicine Approvals for Rare Diseases Rare diseases are those that affect 200,000 or fewer people in the U.S. There are between 6,000 and 7,000 rare diseases affecting 25 million Americans. The Orphan Drug Act (ODA) was passed in 1983 to encourage the research and development of medicines to treat rare diseases. Since then, the FDA has approved more than 200 medicines for rare diseases. Number of Drugs Approved f or Orphan Diseases

12. The Way Forward

13. Systems Approaches

14. Systems Biology Ireland Systems Biology Ireland (based at University College Dublin) is a highly interdisciplinary, research driven centre that combines expertise in computing, mathematics, engineering, chemistry, biochemistry and biology to address key questions in biology & biomedicine. It focuses on Growth factor receptor signalling Cell fate decisions in adult stem cells Cell motility and migration Hypoxia signalling Works out how we are wired together

15. Understanding the emergent properties of biochemical networks How do biochemical networks specify biological decisions? How does the network design determine functions? How can we manipulate these networks ? Integrated approach Mathematical, computational & statistical modelling Advanced imaging Omics technologies Cell & molecular biology Biochemistry Systems Biology Ireland

16. Research Areas Systems Biology Ireland Research Areas Application Areas Improved MSCs for therapy Cancer & inflammatory diseases New drug targets & rational drug combinations Predictive models of disease mechanisms Outcomes High throughput perturbation Proteomics Imaging Microfluidics Gene Arrays & Sequencing Computational modelling Technologies Systems Biology Ireland

17. Pathway Description: The MAPK/Erk signaling cascade is activated by a wide variety of receptors involved in growth and differentiation including receptor tyrosine kinases (RTKs), integrins, and ion channels. The specific components of the cascade vary greatly among different stimuli, but the architecture of the pathway usually includes a set of adaptors (Shc, GRB2, Crk, etc.) linking the receptor to a guanine nucleotide exchange factor (SOS, C3G, etc.) transducing the signal to small GTP binding proteins (Ras, Rap1), which in turn activate the core unit of the cascade composed of a MAPKKK (Raf), a MAPKK (MEK1/2), and MAPK (Erk). An activated Erk dimer can regulate targets in the cytosol and also translocate to the nucleus where it phosphorylates a variety of transcription factors regulating gene expression. MAPK/Erk in in Growth & Differentiation

18. Too much data? With the rise in experimental techniques and instrumentation masses of data are being generated Data Knowledge

19. Development Roadmap Simple Organisms Advances in Basic Concepts in Biology Humans Disease Models Systems Biology

20. Development Roadmap New Diagnostics Disease Models Diagnostics Biomarkers Clinical Screening Prevention Wellness New Targets New Treatments Personalized Medicine Reduced Animal Testing Patient Stratification Modelled Clinical Trials Pharmaceutical Industry Drivers Increased R&D Spend Increased generics competition Reduced Drug Approval Rates Patent Cliff Reduced Revenue Streams Reduced uptake by healthcare providers

21. Current Work

22. Work in Progress - background Previous work on ALC-01 new ‘protein’ wide spread affects on human health (dizzyness, nausea, memory-loss etc) [Carlsberg A., Guinness A., Daniels, J. - J of Irreproducible Results 2010] Recent work on elucidating the structure revealed hydroxylated form Renamed ‘protein’ ALC-OH-01 – many isomers! Wanted to look at the this effect in more detail

23. Hypothesis investigated The number of CHAOTIC delegates in the bar area related to concentrations of the ALC-OH-01 protein - d [AD] proportional d[ALC-OH-01] B – d[ALC-OH-01] C dT dT dT [CHAOTIC] = concentration of CHAOTIC delegates in the bar [ALC-OH-01] B = concentration of ALC-OH-01 Bought [ALC-OH-01] C = concentration of ALC-OH-01 Consumed

24. Model Predicts [CHAOTIC] Time Significant ‘noise’ due to Very Unsteady State Kinetics CHAOTIC Plateau Paper will be submitted shortly Hatt End Point

25. Systems Medicine Conferenece 10-13 September, Dublin