1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

2. Role of industrial research in the development of new drugs Malcolm Johnson GlaxoSmithKline R&D & NHLI,London

3. Key issues in formulating an hypothesis in drug discovery Biology Scientific understanding of disease state? What is the desirable mechanism? Chemistry What to make? Medicine Is mechanism acceptable in man? Can it be tested in man? Medical Need

4. Discovery/Development Strategies In house research In-licencing External collaborations Collaborative networks Promote external innovation

5. Disease selection Target identification and selection Lead identification Lead optimization Candidate pre-clinical evaluation Clinical proof of concept Drug discovery pipeline Exploratory discoveryDrug discovery

6. Disease selection Target identification and selection Lead identification Lead optimization Candidate pre-clinical evaluation Clinical proof of concept Drug discovery pipeline Exploratory discoveryDrug discovery Integrative pharmacology Tissue bioassay Isolated cells Immunohistochemistry Gene microarray Transgenic models Normal Disease Primary Transfection Normal Disease Receptors Enzymes Reporter genes

7. Disease selection Safety and develop- ability Phase IPhase IIPhase IIIPhase IV Gene to function Function to target Target to hit Hit to lead Lead optimi- sation Commit to disease Commit to product type Commit to target Tractable hit Candidate selection First time in man Proof of concept Drug discovery/development pipeline Drug discovery Drug development

8. Research/development strategy Biology Chemistry Clinical Information science Therapeutic objective Project team Drug candidate Exploratory development Full development Clinical trials Regulatory authorities Product licence application Market

9. How are drugs discovered? Chemistry/compound library Natural products Random screening Based on natural hormones Based on existing active drugs Based on molecular modelling Rational design

10. Pre-clinical studies Purpose Types of studies Study design Success rate Time - Determine bilogical activity - Assess specificity of action - In vitro studies - In vivo (animal studies) - Dose-response studies - 1 in 1000 compounds tested - Variable. Approximately 3.5 years for successful lead compounds

11. High Throughput Screening 1980:Salmeterol project- 10 compounds/week 2011;100,000 compounds/day: combinatorial chemistry smart screens cloned human receptors 96-well plate format low volumes robotics Future: 10 million /hour: lower costs smaller volumes (pl)

12. Molecular modelling Bioinformatics Proteomics Genetics Pharmacogenomics

13. Fluticasone furoate– an ‘enhanced-affinity’ glucocorticoid Biggadike et al J Med Chem 2008 FP FF

14. Vilanterol in receptor

15. Toxicology Acute Subacute Chronic Fertility and reproductive Mutagenicity - 2-week studies in 3 or 4 species maximum tolerated dose - 6-month studies in 2 species - 12-month studies in 2 species (rats & dogs) - Oncogenicity studies - 18 months in mice - 2 years in rats - Fertility, teratology and perinatal and postnatal studies in 2 species (rats and rabbits) - In vivo and in vitro tests

16. Phase I clinical trials Purpose Determine the primary safety profile and a safe dosage range Type of Pharmacokinetic and pharmacodynamic studies studies Study Normal, healthy volunteers (usually male) population Study designSingle dose escalation or short-term design multiple dose, placebo controlled, in specialised hospital units Success rate1 in 3 Time1 year

17. PurposeVerify effectiveness, closely monitor safety in long-term use, establish optimum dosage Type of studies Placebo, dose or comparator controlled efficacy and safety Study 1000 to 3000 patients, more heterogeneous population to reflect real patient population Study designMultiple end-point, double-blind, large multi-centre Success rate1 in 3 Time2 to 4 years Phase III clinical trials

18. New drug development process 12-15 years total 2.5 years 3+ years 2+ years 1 + year 3+ years Approval Regulatory review Marketing application filed with regulatory authority Phase III clinical studies – extensive clinical studies Phase II clinical studies – efficacy studies Phase I clinical studies – pharmacological profile Regulatory/ethical review committee approval Preclinical laboratory and animal toxicology studies

19. MARKETING IRD NDA Manufacture Clinical trials Process research Volunteer studies Toxicology Patenting Testing Screening Activity Safety Efficacy Regulatory 12-15 yr RESEARCH DEVELOPMENT 3 yr Patent

20. New drug development: A major high-risk undertaking Time12-15 years from discovery to market Cost Success1 in 4000 compounds synthesised or 1 in 5 tested in humans reaches the market Return1 in 3 drugs reaching the market recaptures development costs £900 million

21. Mortality Studies COPD: TORCH 6,100 patients studied for 3 years ( Cost 450,000,000 euros; Mortality p=0.052) UPLIFT 6,400 patients studied for 4 years (Cost ?; Mortality p=0.086)

22. Academic centre Academic centre Academic centre Academic centre External collaborations network Pharma Academic centre Clinical centre R & D

23. External collaborations objectives: –Increased product database efficacy/safety support –Extend product profile new claims? –Address competitor claims/issues –Increase number/value of citable publications

24. External Research Collaborations Non-project related: Muscarinic receptor mapping in the airways of COPD patients Role of innate immunity in lung repair in COPD Project related: Effects of Relovair on parasternal muscle and diaphragm in patients with COPD Functional enhancement of corticosteroid action by LABAs

25. GR nuclear translocation Non treatment Ito et al, NHLI FP (10 -10 M) FF (10 -10 M) 4 hr 30 hr

27. p38-alpha kinase inhibitor (Losmapimod- GW 856553) enhances steroid mediated suppression of IL-8 release in COPD Bhavsar et al, NHLI

28. MICA MRC Industrial Collaboration Award Industry’s contribution can be: Financial (FTEs) or “in kind” Consumables Equipment Resources Project Management % Industrial contribution = industrial costs/total cost

29. Objectives of ECLIPSE To define clinically relevant COPD subtypes in individuals with GOLD stage II–IV COPD To define the parameters that predict disease progression over 3 years in the clinically relevant COPD subtypes To acquire data on biomarkers that correlate with clinically relevant COPD subtypes To identify novel genetic factors and/or biomarkers that correlate with clinically relevant COPD subtypes

30. SP-D and COPD: Increased SPD Levels Predict Occurrence of At Least One Exacerbation Risk (Odds Ratio) of exacerbation for each 100ng/mL increase in SP-D* 95% CI All patients1.221.07 – 1.39 Upper quartile baseline level only 1.421.02 – 1.97 Upper quartile baseline level only, excluding outliers with SP-D >99 th percentile (382.7ng/mL) 1.581.02 – 2.44 Patients no reporting exacerbation in year prior to enrolment 1.231.02 -1.49 * Serum SP-D continuous variable in multivariate model adjusting for sex, percentage predicted FEV 1, reversibility and those taking corticosteroids Lomas DA, et al. Eur Respir J 2009;34:95-102

31. ECLIPSE/NETT Genome-wide asssociation study identifies BICD1 as a susceptibilty gene for emphysema. p=5.2x10-7 mild emphysema p=4.8x10-8 moderate/severe emphysema Kong et al, AJRCCM,2011

32. IMI Innovative Medicines Initiative: Europe-wide public-private initiative aiming to speed up the development of better and safer medicines for patients. Supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe.

33. CATALYST GSK: Open Bioscience Innovation Campus INCUBATOR – Small start-up companies ACCELERATOR - Established companies with possible leads