Role of industrial research in the development of new drugs

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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? Medical Need Medicine Is mechanism acceptable in man? Can it be tested in man? Chemistry What to make?

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

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

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

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

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

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

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

11. High Throughput Screening1980:Salmeterol project- 10 compounds/week2011;100,000 compounds/day: combinatorial chemistry smart screens cloned human receptors 96-well plate format low volumes roboticsFuture: 10 million /hour: lower costs smaller volumes (pl)

12. Molecular modelling • Bioinformatics • Proteomics • Genetics • Pharmacogenomics

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

14. Vilanterol in receptor

15. Acute Subacute Chronic Fertility and reproductive Mutagenicity Toxicology - 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 design Single dose escalation or short-term • design multiple dose, placebo controlled, in specialised hospital units • Success rate 1 in 3 • Time 1 year

17. Phase III clinical trials • Purpose Verify 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 design Multiple end-point, double-blind, large multi-centre • Success rate 1 in 3 • Time 2 to 4 years

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

19. 12-15 yr FINISH MARKETING 1 IRD Patent Regulatory NDA DEVELOPMENT 2 Manufacture Efficacy 3 yr 10 Clinical trials Process research RESEARCH Safety 100 Volunteer studies Toxicology Patenting Activity 10000 Testing Screening START

20. New drug development:A major high-risk undertaking Time 12-15 years from discovery to market Cost £900 million Success 1 in 4000 compounds synthesised or 1 in 5 tested in humans reaches the market Return 1 in 3 drugs reaching the market recaptures development costs

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

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

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 * Serum SP-D continuous variable in multivariate model adjusting for sex, percentage predicted FEV1 , 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